The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.

BACKGROUND AND OBJECTIVE Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process. METHODS In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples. RESULTS The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms. CONCLUSIONS This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms

Rapid response to the earthquake emergency of May 2012 in the Po Plain, northern Italy

Rapid-response seismic networks are an important element in the response to seismic crises. They temporarily improve the detection performance of permanent monitoring systems during seismic sequences. The improvement in earthquake detection and location capabilities can be important for decision makers to assess the current situation, and can provide invaluable data for scientific studies related to hazard, tectonics and earthquake physics. Aftershocks and the clustering of the locations of seismic events help to characterize the dimensions of the causative fault. Knowing the number, size and timing of the aftershocks or the clustering seismic events can help in the foreseeing of the characteristics of future seismic sequences in the same tectonic environment. Instrumental rapid response requires a high degree of preparedness. A mission in response to a magnitude (ML) 6 event with a rupture length of a few tens of kilometers might involve the deployment within hours to days of 30-50 seismic stations in the middle of a disaster area of some hundreds of square kilometers, and the installation of an operational center to help in the logistics and communications. When an earthquake strikes in a populated area, which is almost always the case in Italy, driving the relevant seismic response is more difficult. Temporary station sites are chosen such as to optimize the network geometry for earthquake locations and source study purposes. Stations have to be installed in quiet, but easily reachable, sites, and for real-time data transmission, the sites might need to have optical intervisibility. The operational center can remain in a town if there is one within the damaged area, and it should coordinate the actions of the field teams and provide information to colleagues, the Civil Protection Authorities and the general public. The emergency system should operate as long as the seismic rate remains high; the duration of any mission might also depend on the seismic history of the area involved. This study describes the seismic response following the May 20, 2012, ML 5.9 earthquake in northern Italy, which included rapid deployment of seismological stations in the field for real-time seismic monitoring purposes, the coordination of further instrumental set-ups according to the spatial evolution of the seismic sequence, and data archiving