Search results for "inducer"
showing 10 items of 178 documents
T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease
2012
Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell-defici…
Ethoxyresorufin-O-deethylase induction potency of polychlorinated diphenyl ethers in H4IIE rat hepatoma cells
1996
Polychlorinated diphenyl ethers (PCDEs) are structurally similar to polychlorinated biphenyls (PCBs), and some PCDE congeners have been reported to cause toxic responses similar to those caused by some of the non-ortho-substituted PCBs, which are mediated by the aryl hydrocarbon receptor (AhR). Twenty-nine PCDEs were tested for their potency as AhR agonists relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) by measuring their ability to induce the cytochrome P-450 1A1-associated enzyme activity, ethoxyresorufin-O-deethylase (EROD), in the H4IIE rat hepatoma cell bioassay. All PCDE congeners tested were found to be inactive as EROD inducers except for PCDE 156, which was a weak E…
Strategies to In Vitro Assessment of Major Human CYP Enzyme Activities by Using Liquid Chromatography Tandem Mass Spectrometry
2008
At the early stage of drug discovery, thousands of new chemical entities (NCEs) may be screened before a single candidate can be identified for development. Determining the role of CYP enzymes in the metabolism of a compound and evaluating the effect of NCEs on human CYP activities are key issues in pharmaceutical development as they may explain inter-subject variability, drug-drug interactions, non-linear pharmacokinetics and toxic effects. Reliable methods for determining enzyme activities are needed to characterize an individual CYP enzyme and to obtain a tool for the evaluation of its role in drug metabolism in humans. Different liquid chromatography tandem mass spectrometry methodologi…
Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme inductio…
2000
The use of primary hepatocytes is now well established for both studies of drug metabolism and enzyme induction. Cryopreservation of primary hepatocytes decreases the need for fresh liver tissue. This is especially important for research with human hepatocytes because availability of human liver tissue is limited. In this review, we summarize our research on optimization and validation of cryopreservation techniques. The critical elements for successful cryopreservation of hepatocytes are (1) the freezing protocol, (2) the concentration of the cryoprotectant [10% dimethyl-sulfoxide (DMSO)], (3) slow addition and removal of DMSO, (4) carbogen equilibration during isolation of hepatocytes and…
Pharmacokinetic interaction between efavirenz and ketoconazole in rats
2009
It is well known that efavirenz and ketoconazole act as an inducer and inhibitor of CYP3A4, respectively. As a result of these actions, co-administration of these drugs may result in changes in the pharmacoki- netic parameters of one or both of them. 2. Duodenum-cannulated rats have been used to compare the effect of intraduodenal (KC i.d. ) and intrave- nous administration of ketoconazole (KC i.v. ) on the pharmacokinetics of efavirenz after intraduodenal administration, as well as the potential effect of efavirenz as a CYP450 inducer on ketoconazole phar - macokinetic profile. 3. While KC i.v. did not show any significant effect on efavirenz pharmacokinetic profile, KC i.d. increased sig-…
Combining dasatinib with dexamethasone long-term leads to maintenance of antiviral and antileukemia specific cytotoxic T cell responses in vitro
2012
Maintaining graft versus leukemia (GvL) and antivirus responses of cytotoxic T cells (CTLs) while suppressing graft-versus-host disease (GvHD) remains a challenge after allogeneic bone marrow transplantation. Clinical observations indicate that combining glucocorticoids with multi-tyrosine-kinase inhibitors could be a successful therapeutic approach. We and others have shown that the BCR-ABL/SRC kinase inhibitor dasatinib may enhance or suppress T cells in vitro. In this report, we evaluated combination effects of dasatinib and dexamethasone on CD3 + and virus-specific CD8 + T cells directly ex vivo and on antigen-specific leukemia-reactive and alloreactive CD8 + T cell clones. Functional o…
H-2(d) mice born to and reared by HBeAg-transgenic mothers do not develop T cell tolerance toward the hepatitis B virus core gene products.
2000
The function of the secretory core gene product (HBeAg) of the human hepatitis B virus (HBV) is unknown. It has been proposed that this protein may be passed from the mother to her offspring at the perinatal stage where it might induce immune tolerance. In a previous study we have shown that the murine placenta presents an efficient barrier for the HBe protein and that H-2(b) mice born to HBeAg-positive transgenic mothers do not develop tolerance of specific cytotoxic T cells. In the present work we demonstrate that transgenic mice expressing high serum levels of HBeAg secrete only small amounts of this protein into their milk and excrete minute amounts of the viral gene product in their ur…
Coordinated induction of drug transporters and phase I and II metabolism in human liver slices
2008
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24 h with prototypical inducers: phenobarbital (PB) (50 mu M) for CAR, beta-naphthoflavone (BNF) (25 mu M) for AhR, and rifampicin (RIF) (10 mu M) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2136, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, …
Influence of concomitant medications on the total clearance and the risk for supra-therapeutic plasma concentrations of Citalopram. A population-base…
2014
Introduction: The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations. Methods: A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested between 2006 and 2013 was conducted. Results: Concomitant drugs inhibiting at least 2 different CYP subtypes involved in the metabolism of citalopram decreased statistically significantly the total clearance (Clt). Compared to younger patients over 64-year-old patients had on average a 4.5 times higher risk rate of supra-therapeutic plasma concentration…
Assessing drug-drug interactions through therapeutic drug monitoring when administering oral second-generation antipsychotics.
2016
Second-generation antipsychotics (SGAs) are frequently co-prescribed with drug metabolic inducers and inhibitors. SGA pharmacokinetic drug-drug interactions (DDIs) with inducers and inhibitors have not received enough attention in the literature but can be studied in by using therapeutic drug monitoring (TDM).The limited information available on oral SGA pharmacokinetic DDIs is reviewed. A systematic literature search on the available oral SGA TDM studies is completed. By integrating TDM studies with the information on in vitro metabolism studies, case report/series and prospective studies, a table is provided to manage average SGA patients taking inducers or inhibitors by using TDM and/or …