The pharmacokinetics of florfenicol (FF) was studied in plasma after a single dose (40 mg/kg) of intramuscular (i.m.) or oral gavage (p.o.) administration to crucian carp (Carassius auratus cuvieri) in freshwater at 25 °C. Ten fish per sampling point were examined after treatment. The data were fitted to two-compartment open models follow both routes of administration. The estimates of total body clearance (CL(b) ), volume of distribution (V(d) /F), and absorption half-life (T(1/2(ka)) ) were 0.067 L/h/kg and 0.145 L/h/kg, 2.21 L/kg and 1.04 L/kg, 2.75 and 1.54/h following i.m. and p.o. administration, respectively. After i.m. injection, the elimination half-life (T(1/2(β)) ) was calculated to be 38.2h, the maximum plasma concentration (C(max) ) to be 16.82 μg/mL, the time to peak plasma FF concentration (T(max) ) to be 1.50 h, and the area under the plasma concentration-time curve (AUC) to be 597.4 μg/mL·h. Following p.o. administration, the corresponding estimates were 2.17 h, 29.32 μg/mL, 1.61 h, and 276.1 μg/mL·h.
Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.
The Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), the most common HIV/AIDS-associated tumor worldwide. Involvement of the oral cavity portends a poor prognosis for patients with KS, but the mechanisms for KSHV regulation of the oral tumor microenvironment are largely unknown. Infiltrating fibroblasts are found within KS lesions, and KSHV can establish latent infection within human primary fibroblasts in vitro and in vivo, but contributions for KSHV-infected fibroblasts to the KS microenvironment have not been previously characterized. In the present study, we used Illumina microarray to determine global gene expression changes in KSHV-infected primary human oral fibroblasts (PDLF and HGF). Among significantly altered candidates, we found that a series of interferon-induced genes were strongly up-regulated in these KSHV-infected oral cells. Interestingly, some of these genes in particular ISG15 and ISG20 are required for maintenance of virus latency through regulation of specific KSHV microRNAs. Our data indicate that oral fibroblasts may represent one important host cellular defense component against viral infection, as well as acting as a reservoir for herpesvirus lifelong infection in the oral cavity.
Purpose Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU). Methods Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC–MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally. Results taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 µg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40–55% of the i.v. taTHU dose, 6–12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5–2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU. Conclusions The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.
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