We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.
Treponema denticola is strongly implicated in the etiology of periodontal diseases. However, genetic transformation of this organism has not been reported. We now demonstrate a gene transfer system in T. denticola by electroporation using a broad host plasmid pKT210 as a shuttle vector. Plasmid extraction, Southern blot hybridization as well as the polymerase chain reaction indicated the presence of the plasmid in T. denticola transformants. The restriction patterns of plasmid pKT210 rescued from the T. denticola transformants in Escherichea coli suggested that some of the rescued plasmids were identical to the original pKT210, but some of them had been modified. This transformation system could be a potentially useful tool for genetic manipulation of oral spirochetes.
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