The Experts below are selected from a list of 8790 Experts worldwide ranked by ideXlab platform

Martina S. Wesley - One of the best experts on this subject based on the ideXlab platform.

  • Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS
    'Frontiers Media SA', 2021
    Co-Authors: Martina S. Wesley, Kelvin T. Chiong, Kelly E. Seaton, Christine A. Arocena, Sheetal Sawant, Jonathan Hare
    Abstract:

    The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based Assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection

Kenneth K Chan - One of the best experts on this subject based on the ideXlab platform.

  • characterization of decomposition products and preclinical and low dose clinical Pharmacokinetics of decitabine 5 aza 2 deoxycytidine by a new liquid chromatography tandem mass spectrometry quantification method
    Rapid Communications in Mass Spectrometry, 2006
    Co-Authors: Guido Marcucci, Michael R Grever, Jim J Xiao, John C Byrd, Kenneth K Chan
    Abstract:

    Aberrant DNA methylation patterns resulting in gene transcriptional repression are observed in numerous cancers. Decitabine, a DNA methyltransferase inhibitor, is being clinically evaluated in patients with hematologic malignancies and solid tumors. Decitabine is rather unstable and decomposes to 1-beta-D-2′-deoxyribofuranosyl-3-guanylurea under basic conditions and several additional unknown products under neutral conditions. This has greatly limited application of Pharmacokinetic Assays to clinical development of decitabine. In this paper, a high-performance liquid chromatography/ultraviolet multi-stage mass spectrometry (HPLC-UV-MSn) study of the decomposition of decitabine in water and human plasma revealed that these previously unknown products are isomers of the intermediates formyl-1-beta-D-2′-deoxyribofuranosyl-3-guanylurea and 1-beta-D-2′-deoxyribofuranosyl-3-guanylurea. A HPLC tandem mass spectrometry (MS/MS) method for the determination of decitabine concentrations in human and rat plasma has been developed. This method was based on a specific fragmentation pathway of the molecular ion of decitabine at m/z 229 to generate a unique fragment ion at m/z 113 under collision-induced dissociation. Separation of decitabine and the stable internal standard dihydro-5-aza-cytidine from the endogenous interfering substance in plasma extract was carried out on a C18 Aquasil column under an isocratic elution with a mobile phase consisting of 5% water/acetonitrile and 10 mM ammonium formate. The detection of decitabine was via selected reaction monitoring (SRM, 229 > 113), and its ionization was enhanced by post-column addition of acetonitrile. Effects of sample preparation and handling parameters on the stability of decitabine were also evaluated in human plasma at various temperatures. The accuracy and precision of this Assay showed a coefficient of variation of <15% over the range of 0.5–25 ng for rat plasma and 0.1–25 ng for human plasma injected on-column. Pharmacokinetics of decitabine in rats following intravenous doses of 1.0 and 5.0 mg/kg were characterized. In the rat, plasma concentration-time profiles were found to follow a biexponential decline and the Pharmacokinetics was dose-independent. Application of this decitabine Pharmacokinetic Assay to human studies is therefore justified and ongoing. Copyright © 2006 John Wiley & Sons, Ltd.

Gene D Morse - One of the best experts on this subject based on the ideXlab platform.

James Carmichael - One of the best experts on this subject based on the ideXlab platform.

  • relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility
    Carcinogenesis, 1992
    Co-Authors: Roland C Wolf, C Dale A Smith, A C Gough, Julie E Moss, Katherine A Vallis, Graham Howard, Frank J Carey, Ken I Mills, William Mcnee, James Carmichael
    Abstract:

    There have been a series of reports on the association of a genetic polymorphism at the cytochrome P450 CYP2D6 gene locus with cancer susceptibility. Many of these reports have remained contradictory either because of small numbers of patients studied or because of the limitations and controversy surrounding the Pharmacokinetic Assay used to identify affected individuals (poor metabolizers; PMs). We have recently developed a DNA-based Assay that will allow the unequivocal identification of poor metabolizers and have applied this to the study of 1635 patients with different forms of cancer. Out of 361 lung cancer patients studied no statistically significant change in the proportion of PMs relative to controls was found. However, a significant increase in the proportion of poor metabolizers or heterozygotes was seen in leukaemia, bladder cancer and melanoma patients. This could be explained by a role for CYP2D6 in carcinogen detoxification or by linkage to another cancer-causing gene.

Jonathan Hare - One of the best experts on this subject based on the ideXlab platform.

  • Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS
    'Frontiers Media SA', 2021
    Co-Authors: Martina S. Wesley, Kelvin T. Chiong, Kelly E. Seaton, Christine A. Arocena, Sheetal Sawant, Jonathan Hare
    Abstract:

    The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based Assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection