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You searched for +publisher:"University of Southern California" +contributor:("Burckart, Gilbert J."). Showing records 1 – 2 of 2 total matches.

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University of Southern California

1. Bi, Lucun. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.

Degree: PhD, Pharmaceutical Sciences, 2008, University of Southern California

High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI). To investigate the pharmacologic mechanisms involve with the virologic failures, a comprehensive study was undertaken to evaluate the intracellular concentration of the active moiety (ddNTP) of these respective nucleoside analogs.; Triple nucleoside combinations were tested at physiological concentrations revealed reductions of 5 to 33% of the respective ddNTP. In vitro studies evaluating TFV and ABC in a concentration dependent manner showed a reduction of 40% and 30% in intracellular CBV-TP and TFV-DP. Similar findings were demonstrated with TFV and ddI, where 40% and 25% reduction in ddATP and TFV-DP, respectively, was detected. The level of dATP and dGTP, endogenous nucleotides, were increased by 2.4- and 2.7-fold, respectively, when cells were treated with 20 ┬ÁM TFV, which can dilute the effect of ddNTP.; The expression of MRP2 and MRP4 were increased in cells serially passaged in either ABC or TFV, which correlated with cellular viability in the presence of high concentrations of nucleosides. Moreover, these cells had significantly lower level of ddNTP accumulation as compared to the wild type counterparts.; A clinical study was undertaken to evaluate whether the in vitro findings were also observed in humans. The combination of ABC and TDF resulted in a 2-fold increase in intracellular TFV-DP in patients receiving the combination of ABC and TFV as compared to TDF alone. Increases in TFV-DP may be attributed to higher plasma level of TFV, which was detected in the second phase of this study. A 4-fold increase in CBV-TP was detected three of nine patients, while the other six (6/9) had a 41% reduction. The degree of CBV-TP reduction is consistent with what is seen in vitro.; These findings suggest that cellular adaptive are critical in reducing intracellular levels of nucleoside analogs and their corresponding ddNTP, which may increase risk of virologic failures. The underlying pharmacological mechanisms may include but are not limited to, the competitive inhibition of anabolic enzymes, increase expression of efflux transporters and increase dATP and dGTP, where the resultant effect is reduced antiviral activity. Advisors/Committee Members: Burckart, Gilbert J. (Committee Chair), Louie, Stan (Committee Member), Shen, Wei-Chiang (Committee Member), D'Argenio, David (Committee Member), Wang, Clay C. C. (Committee Member).

Subjects/Keywords: nucleoside analog; NRTI; intracellular drug-drug interaction; efflux transporters; MRP2; MRP4; cellular adaptive response; ddNTP; TFV; ABC; ddI; endogenous nucleotide pools; PNP

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Bi, L. (2008). Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609

Chicago Manual of Style (16th Edition):

Bi, Lucun. “Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.” 2008. Doctoral Dissertation, University of Southern California. Accessed March 08, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609.

MLA Handbook (7th Edition):

Bi, Lucun. “Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine.” 2008. Web. 08 Mar 2021.

Vancouver:

Bi L. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. [Internet] [Doctoral dissertation]. University of Southern California; 2008. [cited 2021 Mar 08]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609.

Council of Science Editors:

Bi L. Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine. [Doctoral Dissertation]. University of Southern California; 2008. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/47592/rec/3609


University of Southern California

2. Wang, Jian. ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients.

Degree: PhD, Molecular Pharmacology & Toxicology, 2009, University of Southern California

Tacrolimus and mycophenolic acid (MPA) are commonly used in clinic to prevent rejection in transplant recipients. The influence of ABCB1 polymorphisms on tacrolimus dosing has been questioned in previous studies with contradictory findings. Inosine 5'-monophosphate dehydrogenase (IMPDH), catalyzes the rate-limiting step of de novo pathway for purine synthesis, and is the major target of the immunosuppressive drug MPA. Variants in genes IMPDH may account for the interindividual variability in baseline enzyme activity, immunosuppressive efficacy and side effects in transplant recipients receiving MPA. In this study, three ABCB1 haplotypes CGC, TTT and CGT accounted for 44.1%, 40.7% and 7.6% of the total haplotypes, respectively in a total of 91 lung transplant patients. The tacrolimus [L/D] value in the CGC-CGC haplotype was significantly lower than in patients with CGC-TTT and TTT-TTT genotypes throughout the first post transplant year. As for IMPDH2, nine genetic variants were identified with frequencies of the rarer alleles ranging from 0.5 - 10.2%. A novel nonsynonymous variant L263F was identified, and the kinetic assay demonstrated that the IMPDH activity of L263F variant was decreased to 10% of the wild type. Seventeen genetic variants were identified in the IMPDH1 gene in our study, with frequencies of the rarer alleles ranging from 0.2 - 42.7%. Six tagging SNPs were selected to present two haplotype blocks in IMPDH1. No differences in the allele frequencies between ethnic groups were observed except SNP rs2288553. No significant associations were observed between each IMPDH1 SNP and incidence of leukopenia in MPA treated transplant patients. Two SNPs, rs2278293 and rs2278294, were significantly associated with the incidence of biopsy-proven acute rejection in the first year post transplantation. Both of these SNPs had positive and negative predictive values for acute rejection greater than 50%.; This study demonstrates that 1) analysis using the haplotypes derived from three common ABCB1 polymorphisms is predictive for tacrolimus dosing in lung transplant patients when eliminating the confounder CYP3A5 genotype; 2) IMPDH1 polymorphisms are associated with the incidence of biopsy-proven acute rejection in the first year post transplantation. Future studies of the multi-factorial nature of acute rejection should take into account IMPDH1 polymorphisms in MPA treated patients. Advisors/Committee Members: Burckart, Gilbert J. (Committee Chair), Beringer, Paul (Committee Member), Shen, Wei-chiang (Committee Member), Richmond, Frances J. (Committee Member), Watanabe, Richard M. (Committee Member).

Subjects/Keywords: pharmacogenetics; ABCB1; IMPDH; transplantation; polymorphism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Wang, J. (2009). ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535363/rec/458

Chicago Manual of Style (16th Edition):

Wang, Jian. “ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients.” 2009. Doctoral Dissertation, University of Southern California. Accessed March 08, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535363/rec/458.

MLA Handbook (7th Edition):

Wang, Jian. “ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients.” 2009. Web. 08 Mar 2021.

Vancouver:

Wang J. ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients. [Internet] [Doctoral dissertation]. University of Southern California; 2009. [cited 2021 Mar 08]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535363/rec/458.

Council of Science Editors:

Wang J. ABCB1 and IMPDH functional and genetic contributions to tacrolimus and mycophenolic acid therapy in transplant patients. [Doctoral Dissertation]. University of Southern California; 2009. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535363/rec/458

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