No abstract

The identification of xenobiotics in biological fluids generally involves a panel of automated immunoassays for the most common drugs, and of chromatographic techniques ideally coupled to specific detectors (mass spectrometers or UV-diode array detectors). Nevertheless, failures are not uncommon, particularly when polar compounds, with no or little UV absorbency are involved. However, mass spectrometry (MS) is more specific and reliable than DAD and should always be preferred when possible. As GC is limited to volatile and thermally stable compounds, the coupling of MS with HPLC has long been considered as a possible means of increasing the range of compounds amenable to MS [1]. ANALUSIS, 2000, 28, N°10© EDP Sciences, Wiley-VCH 2000 Dossier Structure elucidation by LC-MSBecause electron ionisation (El) produces universally reproducible mass spectra, this ionisation mode is generally regarded as the gold standard for the specificity of MS detection. In the past, only moving belt and particle beam interfaces were compatible with EI sources [2], but both suffered from an unavoidable volatilisation step by heating and thus were not suitable for polar or thermally labile compounds.More recently, atmospheric pressure ionisation sources of the electrospray (ES) or APCI type have superseded all the other types of interfaces/ionisation sources for LC-MS. Unfortunately, ES and APCI are not compatible with EI and, on the contrary, involve a soft ionisation process. This limitation can be bypassed by using collision-induced dissociation (CID), which provides thorough fragmentation of the compounds. CID consists of accelerating the ions generated and making them collide with molecules of a neutral gas, either in a specialised "collision cell" or in the intermediate pressure part of the mass spectrometer, between the atmospheric pressure source and the high vacuum of the mass analyser (so called "in-source CID"). The first solution, necessitating tandem mass-spectrometers, cannot be readily applied to a "general unknown" screening procedure because it supposes that a limited number of parent ions are selected in the first MS stage (which is not applicable to a priori unknowns), before being submitted to fragmentation in the collision cell. It can be easily used, with or without chromatographic separation, to confirm the identity of suspected compounds as long as fragmentation energy is standardised (in terms of nature and pressure of collision gas, and ion kinetic energy) and a library of mass spectra of compounds of interest is built [3,4]. As an alternative we [5] and others [6] have suggested using in-source CID. The fragments produced by in-source CID, generally used as confirmation ions for quantitative methods using single-quadrupole instruments, are most generally the same as those produced by conventional CID in the collision cell of a MS/MS instrument. Moreover, contrary to the latter where a precursor ion is selected before fragmentation, in-source CID needs to be preceded by a thorough separation of compounds for g...

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia.

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. . Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C max and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.