Postmortem redistribution of fentanyl in the rabbit blood.

Postmortem redistribution of fentanyl in the rabbit was investigated after application of the 50-μg/h Durogesic pain patch. Patches were applied for 48 hours. Two cycles of patch administration were used before characterization of the postmortem redistribution.

The ontogeny of drug metabolizing enzymes and transporters in the rat.

Knowledge of the ontogeny of the various systems involved in distribution and elimination of drugs is important for adequate interpretation of the findings during safety studies in juvenile animals. The present study was designed to collect information on plasma concentrations of total protein and albumin, enzyme activity and mRNA expression of cytochrome P450 isoenzymes (CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A1/2, and CYP4A1), carboxylesterase and thyroxin glucuronidation (T4-GT) activity in liver microsomes, and mRNA expression of transporters (Mdr1a/b, Mrp1-3 and 6, Bsep and Bcrp, Oct1-2, Oat1-3 and Oatp1a4) in liver, kidney and brain tissue during development in Sprague-Dawley rats. Enzyme activities were determined by measuring the metabolism of marker substrates; expression of mRNAs was assessed using RTq-PCR.

Real life juvenile toxicity case studies: the good, the bad and the ugly.

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use.

Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K.

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage.

Responsibilities of test facility management and sponsor in a GLP environment.

Compliance with the Organisation for Economic Co-operation and Development (OECD) principles of good laboratory practice (GLP) is discussed in particular as regards the responsibility of the management of a test facility (TF) when performing a monosite study as compared to the responsibility in a multisite study. Other issues of interest in this context are dealt with, such as the qualification and training for professionals and technicians, the meaning of validity of standard operating procedures (SOP), the relation between management and quality assurance (QA), the role played by study plans, test and reference items, archives, master schedule, communication lines, validation of methods and calibration, and related activities. Furthermore, the consequences for the TF management and sponsors during multisite studies are discussed, with particular regard to the existence of other responsibilities set forward by health authorities in countries with not negligible differences in the applicable regulations.

Modeling anti-KLH ELISA data using two-stage and mixed effects models in support of immunotoxicological studies.

During preclinical drug development, the immune system is specifically evaluated after prolonged treatment with drug candidates, because the immune system may be an important target system. The response of antibodies against a T-cell-dependent antigen is recommenced by the FDA and EMEA for the evaluation of immunosuppression/enhancement. For that reason, we developed a semiquantitative enzyme-linked immunosorbent assay to measure antibodies against keyhole limpet hemocyanin.

MODELING ANTI-KLH ELISA DATA USING TWO-STAGE AND MIXED EFFECTS MODELS IN SUPPORT OF IMMUNOTOXICOLOGICAL STUDIES.

During preclinical drug development, the immune system is specifically evaluated after prolonged treatment with drug candidates, because the immune system may be an important target system. The response of antibodies against a T-cell-dependent antigen is recommenced by the FDA and EMEA for the evaluation of immunosuppression/enhancement. For that reason, we developed a semiquantitative enzyme-linked immunosorbent assay to measure antibodies against keyhole limpet hemocyanin.