Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid.

Ibrutinib is an orally administered first-in-class irreversible Bruton's tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 × 2.1 mm; 1.7 µm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 µL·min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng·mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng·mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% α-risk (ß = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at ±25% for the LLOQ and ±15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples.

Analysis of plasticizers in PVC medical devices: Performance comparison of eight analytical methods.

A wide variety of medical devices (MDs) used in hospitals are made of flexible plasticized polyvinylchloride (PVC). Different plasticizers are present in variable amounts in the PVC matrix of the devices and can leach out into the infused solutions and may enter into contact with the patients. The ARMED1 project aims to assess the migration of these plasticizers from medical devices and therefore the level of exposure in patients. For the first task of the project, eight methods were developed to directly detect and quantify the plasticizers in the PVC matrix of the MDs. We compared the overall performances of the analytical methods using standardized and validated criteria in order to provide the scientific community with the guidance and the technical specifications of each method for the intended application. We have shown that routine rapid screening could be performed directly on the MDs using the FTIR technique, with cost-effective analyses. LC techniques may also be used, but with limits and only with individual quantification of the main plasticizers expected in the PVC matrix. GC techniques, especially GC-MS, are both more specific and more sensitive than other techniques. NMR is a robust and specific technique to precisely discriminate all plasticizers in a MD but is limited by its cost and its low ability to detect and quantify plasticizer contamination, e.g. by DEHP. All these results have been confirmed by a real test, called the " blind test " carried out on 10 MD samples.

An in vitro evaluation of infusion methods using a syringe pump to improve noradrenaline administration.

BACKGROUND: International guidelines recommend noradrenaline (NA) as the vasopressor of choice to treat septic shock. The aim of this study was to determine the best way to infuse patients with NA. METHODS: The in vitro study was designed to measure NA concentration at the end of each studied assembly line. Three infusion systems used the double pump method and three single pumps, which differed as regards NA concentrations (0,2 - 0,5 - 1 mg/h), dead space volume of the devices and the use of saline. Infusion systems were compared according to the time necessary to reach an NA mass flow rate steady-state plateau after the onset of infusion or after a flow change. RESULTS: Times were significantly different between the six methods for infusing NA. The system using the double syringe method with a standard extension set was the longest to reach the steady state after the onset of infusion [40.00 min (19.57 - 49.22)]. The steady-state plateau was obtained most rapidly with the double-syringe pump systems using very low dead-space volume extension sets and single-syringe pump systems containing diluted noradrenaline at the beginning of NA infusion. CONCLUSION: A combination of a low dead-space volume extension set and a double pump method with a constant saline flow rate at 5 ml/h might be the solution to provide the most reliable NA infusion delivery.

Impact of noradrenaline infusion set on mean arterial pressure: a retrospective clinical study.

OBJECTIVES: Noradrenaline (NA) can be infused through various systems including single or double syringe pumps. The aim of this study was to define the best and most efficient infusion system in an emergency context. STUDY DESIGN: This was a retrospective clinical study based on the analysis of patients' hemodynamic data. PATIENTS AND METHOD: Three infusion lines used presently in our postoperative ICU were compared through a retrospective clinical study: an NA syringe pump at 2mL/h and a saline carrier solution syringe pump at 8mL/h (infusion system 1- IS1) or 5mL/h (IS2), both connected to a very low dead-space volume set (V=0.046mL); IS3 with the same NA syringe at 2mL/h directly connected to the central venous catheter. Mean arterial pressure (MAP) was obtained from retrospective data analysis of ICU patients with postoperative septic shock criteria. Infusion systems were compared according to the time required to reach an MAP greater than 65mmHg after the onset of infusion. RESULTS: Data from 37 patients was analysed. The MAP objective was attained in 14:00 minutes (9:20 - 26:10, n=15) with IS1, in 19:10 minutes (12:20 - 27:20, n=13) with IS2 and in 34:10 minutes (23:10 - 62:30, n=9) with IS3 (P=0.00032). CONCLUSION: The use of a double syringe pump system associated with a very low dead-space volume infusion set appears to be the most appropriate system for NA infusion.

[Major haemodynamic incident during continuous norepinephrine infusion: Beware of the infusion line. An avoidable postoperative hypertensive peak?]. / Incident hémodynamique majeur pendant une perfusion continue de noradrénaline : attention à la ligne de perfusion. Un pic hypertensif postopératoire évitable ?

The restoration of patients' mean arterial pressure after ineffective fluid resuscitation is obtained by vasopressive treatment such as norepinephrine. However, no guidelines exist concerning a norepinephrine infusion method: whether it be the norepinephrine concentration in the syringe, single or double pump administration via a carrier such as an isotonic saline solution, or use of minimized dead-volume extension sets. We present the case of a female patient requiring norepinephrine treatment, who quickly suffers a major haemodynamic incident (a sudden rise in systolic blood pressure above 220 mmHg associated with tachycardia up to 189 b/min). The main causes of this incident are discussed and infusion parameters considered with a view to developing an optimal infusion method for a drug with a specific therapeutic index.