ABSTRACT
A key challenge in the development of central nervous system drugs is the availability of drug target specific blood-based biomarkers. As a new approach, we applied cluster-based pharmacokinetic/pharmacodynamic (PK/PD) analysis in brain extracellular fluid (brainECF ) and plasma simultaneously after 0, 0.17, and 0.86 mg/kg of the dopamine D2/3 agonist quinpirole (QP) in rats. We measured 76 biogenic amines in plasma and brainECF after single and 8-day administration, to be analyzed by cluster-based PK/PD analysis. Multiple concentration-effect relations were observed with potencies ranging from 0.001-383 nM. Many biomarker responses seem to distribute over the blood-brain barrier (BBB). Effects were observed for dopamine and glutamate signaling in brainECF , and branched-chain amino acid metabolism and immune signaling in plasma. Altogether, we showed for the first time how cluster-based PK/PD could describe a systems-response across plasma and brain, thereby identifying potential blood-based biomarkers. This concept is envisioned to provide an important connection between drug discovery and early drug development.
Subject(s)
Biomarkers/blood , Dopamine Agonists/pharmacokinetics , Metabolomics/methods , Quinpirole/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Brain/metabolism , Dopamine Agonists/administration & dosage , Male , Pharmaceutical Preparations , Plasma/metabolism , Quinpirole/administration & dosage , RatsABSTRACT
Determining the order of events in a criminal investigation can be crucial in many ways. Although the use of fingermarks is one of the most important forensic tools as a modality of individualisation, placing them in time is a long lasting difficulty. In the study presented in this paper we describe the effects of light and the temperature on depositions of standard solutions containing squalene and cholesterol on paper. The results obtained give a clear view on what type of processes take place during a temperature and a light influenced degradation of the two materials in this study. Using well known methods for the determination of reaction constants it was determined that the degradation mechanism of cholesterol is following a radical route, where the decay of squalene is more affected by temperature.
