Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 23

Publication Record

Connections

Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.
Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E
(2015) J Control Release 220: 751-7
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Biological Availability, Biotransformation, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Chemistry, Pharmaceutical, Cross-Linking Reagents, Cytochrome P-450 CYP3A, Delayed-Action Preparations, Dose-Response Relationship, Drug, Drug Carriers, Drug Stability, Female, Gastric Juice, Glucuronosyltransferase, Intestinal Secretions, Kinetics, Mice, Nanomedicine, Nanoparticles, Particle Size, Polyesters, Quercetin, Solubility, Tamoxifen
Show Abstract · Added February 15, 2016
We report the synthesis and encapsulation of polyester nanosponge particles (NPs) co-loaded with tamoxifen (TAM) and quercetin (QT) to investigate the loading, release and in vitro metabolism of a dual drug formulation. The NPs are made in two variations, 4% and 8% crosslinking densities, to evaluate the effects on metabolism and release kinetics. The NP-4% formulation with a particle size of 89.3 ± 14.8 nm was found to have loading percentages of 6.91 ± 0.13% TAM and 7.72 ± 0.15% QT after targeting 10% (w/w) each. The NP-8% formulation with a particle size of 91.5 ± 9.8 nm was found to have loading percentages of 7.26 ± 0.10% TAM and 7.80 ± 0.12% QT. The stability of the formulation was established in simulated gastrointestinal fluids, and the metabolism of TAM was shown to be reduced 2-fold and 3-fold for NP-4%s and NP-8%s, respectively, while QT metabolism was reduced 3 and 4-fold. The implications for improved bioavailability of the NP formulations were supported by cytotoxicity results that showed a similar efficacy to free dual drug formulations and even enhanced anti-cancer effects in the recovery condition. This work demonstrates the suitability of the nanosponges not only as a dual release drug delivery system but also enabling a regulated metabolism through the capacity of a nanonetwork. The variation in crosslinking enables a dual release with tailored release kinetics and suggests improved bioavailability aided by a reduced metabolism.
Copyright © 2015 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
27 MeSH Terms
Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver.
Liu W, Ramírez J, Gamazon ER, Mirkov S, Chen P, Wu K, Sun C, Cox NJ, Cook E, Das S, Ratain MJ
(2014) Hum Mol Genet 23: 5558-69
MeSH Terms: DNA Copy Number Variations, Gene Expression Regulation, Genetic Variation, Glucuronosyltransferase, Humans, Liver, Peroxisome-Targeting Signal 1 Receptor, Polymorphism, Single Nucleotide, Receptors, Cytoplasmic and Nuclear, Transcription Factors, Transcription, Genetic
Show Abstract · Added February 22, 2016
The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74-217% and 52%, 39-105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 6-58%; 47%, 9-58%; and 52%, 24-75%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.
Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, Morse GD, Court MH
(2014) J Antimicrob Chemother 69: 2175-82
MeSH Terms: Adult, African Continental Ancestry Group, Alkynes, Anti-HIV Agents, Benzoxazines, Cyclopropanes, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP2B6 Inducers, European Continental Ancestry Group, Female, Gene Dosage, Glucuronosyltransferase, HIV Infections, HIV-1, Humans, Male, Polymorphism, Single Nucleotide, Prospective Studies, Reverse Transcriptase Inhibitors, Secondary Metabolism
Show Abstract · Added March 13, 2015
OBJECTIVES - Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.
METHODS - Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations.
RESULTS - Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations.
CONCLUSIONS - Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
Johnson DH, Venuto C, Ritchie MD, Morse GD, Daar ES, McLaren PJ, Haas DW
(2014) Pharmacogenet Genomics 24: 195-203
MeSH Terms: Acquired Immunodeficiency Syndrome, Adult, Antiretroviral Therapy, Highly Active, Atazanavir Sulfate, Bilirubin, Female, Genome-Wide Association Study, Glucuronosyltransferase, HIV Protease Inhibitors, Humans, Hyperbilirubinemia, Male, Middle Aged, Multivariate Analysis, Oligopeptides, Polymorphism, Single Nucleotide, Prospective Studies, Pyridines, Ritonavir
Show Abstract · Added March 13, 2015
BACKGROUND - Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
METHODS - Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.
RESULTS - Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.
CONCLUSION - Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.
0 Communities
1 Members
0 Resources
19 MeSH Terms
High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.
Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A
(2013) Nature 499: 346-9
MeSH Terms: Amino Acid Sequence, Animals, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Contact Inhibition, Disease Resistance, Fibroblasts, Glucuronosyltransferase, Guinea Pigs, Humans, Hyaluronan Synthases, Hyaluronic Acid, Mice, Mole Rats, Molecular Sequence Data
Show Abstract · Added September 6, 2013
The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.
1 Communities
0 Members
0 Resources
16 MeSH Terms
Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study.
Cox AJ, Ng MC, Xu J, Langefeld CD, Koch KL, Dawson PA, Carr JJ, Freedman BI, Hsu FC, Bowden DW
(2013) Atherosclerosis 229: 155-60
MeSH Terms: Aged, Bilirubin, Cardiovascular Diseases, Diabetes Complications, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genetic Variation, Genome-Wide Association Study, Glucuronosyltransferase, Humans, Male, Middle Aged, Multigene Family, Polymorphism, Single Nucleotide, Risk Factors, Vascular Calcification
Show Abstract · Added February 15, 2014
OBJECTIVE - A negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality.
METHODS - This investigation included 1220 self-described European American (EA) individuals from the DHS, a family-based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome-wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality.
RESULTS - A genome-wide association study detected 18 SNPs within the UGT1A gene family associated with TBili at p < 5 × 10(-8). The top hit was rs887829 (p = 8.67 × 10(-20)). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p = 0.05-0.88). There was, however, evidence of association with all-cause mortality (p = 0.0004-0.06), the top hit being rs2741034.
CONCLUSION - These findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Sonic hedgehog signaling directly targets Hyaluronic Acid Synthase 2, an essential regulator of phalangeal joint patterning.
Liu J, Li Q, Kuehn MR, Litingtung Y, Vokes SA, Chiang C
(2013) Dev Biol 375: 160-71
MeSH Terms: Aggrecans, Animals, Base Sequence, Body Patterning, Chondrogenesis, Extracellular Matrix Proteins, Extremities, Gene Expression Regulation, Developmental, Glucuronosyltransferase, Hedgehog Proteins, Hyaluronan Synthases, Hyaluronic Acid, Joints, Kruppel-Like Transcription Factors, Limb Buds, Mesoderm, Mice, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Promoter Regions, Genetic, Proteoglycans, Signal Transduction, Zinc Finger Protein Gli3
Show Abstract · Added October 25, 2013
Sonic hedgehog (Shh) signal, mediated by the Gli family of transcription factors, plays an essential role in the growth and patterning of the limb. Through analysis of the early limb bud transcriptome, we identified a posteriorly-enriched gene, Hyaluronic Acid Synthase 2 (Has2), which encodes a key enzyme for the synthesis of hyaluronan (HA), as a direct target of Gli transcriptional regulation during early mouse limb development. Has2 expression in the limb bud is lost in Shh null and expanded anteriorly in Gli3 mutants. We identified an ∼3kb Has2 promoter fragment that contains two strong Gli-binding consensus sequences, and mutation of either site abrogated the ability of Gli1 to activate Has2 promoter in a cell-based assay. Additionally, this promoter fragment is sufficient to direct expression of a reporter gene in the posterior limb mesenchyme. Chromatin immunoprecipitation of DNA-Gli3 protein complexes from limb buds indicated that Gli3 strongly binds to the Has2 promoter region, suggesting that Has2 is a direct transcriptional target of the Shh signaling pathway. We also showed that Has2 conditional mutant (Has2cko) hindlimbs display digit-specific patterning defects with longitudinally shifted phalangeal joints and impaired chondrogenesis. Has2cko limbs show less capacity for mesenchymal condensation with mislocalized distributions of chondroitin sulfate proteoglycans (CSPGs), aggrecan and link protein. Has2cko limb phenotype displays striking resemblance to mutants with defective chondroitin sulfation suggesting tight developmental control of HA on CSPG function. Together, our study identifies Has2 as a novel downstream target of Shh signaling required for joint patterning and chondrogenesis.
Copyright © 2013 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
24 MeSH Terms
Cost-effectiveness analysis of UGT1A1 genetic testing to inform antiretroviral prescribing in HIV disease.
Schackman BR, Haas DW, Becker JE, Berkowitz BK, Sax PE, Daar ES, Ribaudo HJ, Freedberg KA
(2013) Antivir Ther 18: 399-408
MeSH Terms: Adult, Antiretroviral Therapy, Highly Active, Cost-Benefit Analysis, Female, Genetic Testing, Genotype, Glucuronosyltransferase, HIV Infections, Humans, Male, Middle Aged, Quality-Adjusted Life Years
Show Abstract · Added March 13, 2015
BACKGROUND - Homozygosity for UGT1A1*28/*28 has been reported to be associated with atazanavir-associated hyperbilirubinaemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform the choice of an initial protease-inhibitor-containing regimen in antiretroviral therapy (ART)-naive individuals.
METHODS - We used the Cost-Effectiveness of Preventing AIDS Complications computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 USD) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed the UGT1A1-associated atazanavir discontinuation rate reported in the Swiss HIV Cohort Study (a *28/*28 frequency of 14.9%), equal efficacy and cost of atazanavir and darunavir and a genetic assay cost of $107. These parameters, as well as the effect of hyperbilirubinaemia on quality of life and loss to follow up, were varied in sensitivity analyses. Costs and QALYs were discounted at 3% annually.
RESULTS - Initiating atazanavir-based ART at CD4(+) T-cell counts <500 cells/μl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinaemia by UGT1A1 testing reduced loss to follow-up by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario.
CONCLUSIONS - Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS Clinical Trials Group Study A5202.
Ribaudo HJ, Daar ES, Tierney C, Morse GD, Mollan K, Sax PE, Fischl MA, Collier AC, Haas DW, DS Clinical Trials Group
(2013) J Infect Dis 207: 420-5
MeSH Terms: Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Atazanavir Sulfate, Bilirubin, Genetic Variation, Genotype, Glucuronosyltransferase, HIV Infections, HIV-1, Humans, Jaundice, Oligopeptides, Pyridines, Ritonavir
Show Abstract · Added March 13, 2015
The UGT1A1*28 variant has been associated with hyperbilirubinemia and atazanavir discontinuation. Protocol A5202 randomly assigned human immunodeficiency virus type 1 (HIV-1)-infected patients to receive atazanavir/ritonavir (atazanavir/r) or efavirenz, with tenofovir/emtricitabine or abacavir/lamivudine. A total of 646 atazanavir/r recipients were evaluable for UGT1A1. Homozygosity for *28/*28 was present in 8% of whites, 24% of blacks, and 18% of Hispanics and was associated with increased bilirubin concentrations. There was an association between *28/*28 and increased atazanavir/r discontinuation among Hispanic participants (P = .005) but not among white or black participants (P = .79 and P = .46, respectively). The positive predictive value of 28*/28* for atazanavir/r discontinuation among Hispanic participants was only 32% (95% confidence interval, 16%-52%).
0 Communities
1 Members
0 Resources
14 MeSH Terms
Phase I and pharmacokinetic study of IHL-305 (PEGylated liposomal irinotecan) in patients with advanced solid tumors.
Infante JR, Keedy VL, Jones SF, Zamboni WC, Chan E, Bendell JC, Lee W, Wu H, Ikeda S, Kodaira H, Rothenberg ML, Burris HA
(2012) Cancer Chemother Pharmacol 70: 699-705
MeSH Terms: Adult, Aged, Antineoplastic Agents, Phytogenic, Camptothecin, Dose-Response Relationship, Drug, Female, Glucuronosyltransferase, Humans, Irinotecan, Liposomes, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms, Polyethylene Glycols, Treatment Outcome
Show Abstract · Added March 11, 2014
PURPOSE - IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D).
PATIENTS AND METHODS - In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.
RESULTS - Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months.
CONCLUSIONS - IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.
0 Communities
1 Members
0 Resources
16 MeSH Terms