Relationship between dexmedetomidine dose and plasma dexmedetomidine concentration in critically ill infants: a prospective observational cohort study.

BACKGROUND: Dexmedetomidine is a highly selective central α2-agonist used as a sedative in pediatric intensive care unit (PICU). However, little is known about the relationship between dexmedetomidine dose and its plasma concentration during long-term infusion. We have previously demonstrated that the sedative plasma dexmedetomidine concentration is moderately correlated with the administered dose in adults (r = 0.653, P = 0.001). We hypothesized that there would be a similar relationship between the sedative dexmedetomidine concentration and administered dose in infants. METHODS: All patients admitted to the PICU at Nagoya City University Hospital, Japan, between November 2012 and March 2013 were eligible for inclusion in the study. Plasma dexmedetomidine concentration was measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: We measured the plasma dexmedetomidine concentration in 203 samples from 45 patients. Of these, 96 samples collected from 27 patients < 2 years old were included in this study. All patients received dexmedetomidine at 0.12-1.40 µg/kg/h. The median administration duration was 87.6 hours (range: 6-540 hours). Plasma dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml. Plasma dexmedetomidine concentration was not correlated with the administered dose (r = 0.273, P = 0.007). The approximate linear equation was y = 0.690x + 0.423. CONCLUSIONS: In infants, plasma dexmedetomidine concentration did not exhibit any correlation with administered dose, which is not a reliable means of obtaining optimal plasma concentration.

Metabolomics approach of infant formula for the evaluation of contamination and degradation using hydrophilic interaction liquid chromatography coupled with mass spectrometry.

In this study including the field of metabolomics approach for food, the evaluation of untargeted compounds using HILIC-ESI/TOF/MS and multivariate statistical analysis method is proposed for the assessment of classification, contamination and degradation of infant formula. HILIC mode is used to monitor more detected numbers in infant formulas in the ESI-positive scan mode than the reversed phase. The repeatability of the non-targeted contents from 4 kinds of infant formulas based on PCA was less than the relative standard deviation of 15% in all groups. The PCA pattern showed that significant differences in the classification of types and origins, the contamination of melamine and the degradations for one week were evaluated using HILIC-ESI/TOF/MS. In the S-plot from the degradation test, we could identify two markers by comparison to standards as nicotinic acid and nicotinamide. With this strategy, the differences from the untargeted compounds could be utilized for quality and safety assessment of infant formula.

Quantitative determination of total L-carnitine in infant formula, follow-up formula, and raw materials by liquid chromatography with tandem mass spectrometry.

We developed a rapid and useful routine screening assay for total L-carnitine content in various infant formulas and materials by liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS) and alkaline hydrolysis. For separation of L-carnitine, a multi-mode octadecylsilane (ODS) column was used that contained ODS ligands, anion ligands, and cation ligands to avoid using ion-pairing agents. The stable isotope L-carnitine-d3 (m/z 165 → 103/85) was used in electrospray MS/MS in the multiple reaction monitoring mode with the ion transitions of m/z 162 → 103/85 for detection and quantitation of L-carnitine. Alkaline hydrolysis of short/medium chain (C2 - C15) acyl-L-carnitines in infant formula was analyzed by LC with quadrupole time-of-flight mass spectrometry (QTOF-MS). The majority of short/medium chain acyl-L-carnitines were hydrolyzed to free L-carnitine. The overall standard deviations for L-carnitine in infant formula, follow-up formula and raw materials ranged from 2.1 to 4.0. The overall mean recoveries ranged from 90.2 to 94.2%.

Determination of dicyandiamide in infant formula by stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry.

Dicyandiamide is a compound for reducing the negative effects of greenhouse gas emissions and nitrate leaching into waterways. In this study, the trace contamination of dicyandiamide in infant formula was analysed by stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS). Dicyandiamide and a stable isotope internal standard were monitored by multiple reaction-monitoring with mass transitions: m/z 85→68/43 and m/z 89→71/45 in the electrospray positive ion mode. For sample preparation of the infant formula, a diluted/filtered procedure was developed for this assay. The calculated LOD and LOQ values were 0.01 or 0.05ng/mL for the standard solution, respectively. The averaged recovery and precision were 110.8% and 7.4%, respectively. This assay was applied to monitor 23 infant formulas, and the dicyandiamide contamination in one sample was detected and quantified at 79.1±1.2ng/g (ppb) powder. We suggest that it is necessary to cautiously monitor the DCD in common products from international countries.

Use of chiral derivatization for the determination of dichlorprop in tea samples by ultra performance LC with fluorescence detection.

Dichlorprop is available for agricultural use as a chiral pesticide. In this study, the stereoselective determination of dichlorprop enantiomers in tea samples such as green, black, jasmine, and oolong was developed by ultra performance LC with fluorescence spectrometry after covalent chiral derivatization. The separation was achieved on an Acquity BEH C18 column with the mobile phase consisting of 0.1% formic acid in acetonitrile/water at a flow rate of 0.4 mL/min. In the covalent chiral derivatization using (S)-(+)-4-(N,N-dimethylaminosulfonyl)-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole, the peak resolution between the S and R-dichlorprop enantiomers was 2.6. LODs and LOQs values were 10 and 50 ng/mL standard solution. The linearity of the calibration curves yielded the coefficients (r(2) > 0.99, ranging from 0.05 to 5 µg/mL) of determination of each of the dichlorprop enantiomers. SPE extraction was used for the sample preparation of dichlorprop in various tea samples. Recoveries were in the range of 82.4-97.6% with associated precision values (within-day: 82.4-95.8%, n = 6, and between-day: 83.7-97.6% for 3 days) for repeatability and reproducibility. Based on this result, our method has been proven to be highly efficient and suitable for the routine assay of dichlorprop enantiomers in various tea samples. We propose that the ultra performance LC assay after covalent chiral derivatization would be the renewed tools in the era of chiral stationary platform for chiral pesticide residues in foods.

Development of a stable isotope dilution UPLC-MS/MS method for quantification of dexmedetomidine in a small amount of human plasma.

Dexmedetomidine (Dex) is a selective central α2-agonist with anesthetic properties and has been used in clinical practice for sedation in the intensive care unit (ICU) after operations. In this study, an analytical assay for the determination of Dex in a small amount of plasma was developed for the application to pediatric ICU trials. The quantification of Dex was constructed using the original stable isotope Dex-d3 for electrospray ionization-tandem mass spectrometry (ESI-MS/MS) in the selected reaction monitoring mode. A rapid ultra-performance liquid chromatography technique was adopted using ESI-MS/MS with a runtime of 3 min. Efficacious concentration levels (50 pg/mL to 5 ng/mL) could be evaluated using a very small amount of plasma (10 µL) from patients. The lower limit of the quantification was 5 pg/mL in the plasma (100 µL). For sample preparation, a solid-phase extraction was used along with the OASIS-HLB cartridge type. Recovery values ranged from 98.8 to 100.3% for the intra- [relative standard deviation (RSD), 0.9-1.3%] and inter- (RSD, 0.9-1.5%) day assays. A stable test had recovery values that ranged from 97.8 to 99.7% with an RSD of 1.0-1.9% for the process/wet extract, bench-top, freeze-thaw and long-term tests. This method was used to measure the Dex levels in plasma from pediatric ICU patients. In the clinical ICU trial, the small amount of blood (approximate plasma volume, 200 µL) remaining from blood gas analysis was reused and targeted for the clinical analysis of Dex in plasma.

A comparison between dosages and plasma concentrations of dexmedetomidine in clinically ill patients: a prospective, observational, cohort study in Japan.

BACKGROUND: Dexmedetomidine is a highly selective central α2-agonist with anesthetic and analgesic properties for patients in intensive care units. There is little information about the relationship between dosage and plasma concentration during long drug infusions of dexmedetomidine in critically ill patients, especially in Asians. In addition, the administration of dexmedetomidine with a dosage of 0.2-0.7 µg/kg/h in Japan is different from that with a dosage of 0.2-1.4 µg/kg/h in European countries and the USA. There has been concern about obtaining an effective concentration with a small dosage and estimating the relationship between dosage and plasma concentration. We conducted a prospective, observational, cohort study measuring plasma dexmedetomidine concentrations. METHODS: Plasma dexmedetomidine concentrations of 67 samples from 34 patients in an intensive care unit for 2 months were measured by ultra performance liquid chromatography coupled with tandem mass spectrometry using single-blind method, and the correlation coefficient between dosages and plasma concentrations was estimated. Exclusion criteria included young patients (<16 years) and samples obtained from patients in which the dosage of dexmedetomidine was changed within 3 h. RESULTS: Among the patients, 20 (58.8%) of the 34 received dexmedetomidine at 0.20-0.83 µg/kg/h, and in 40 of the 67 samples for which dexmedetomidine had been administered, this occurred for a median duration of 18.5 h (range, 3-87 h). The range of the dexmedetomidine plasma concentration was 0.22-2.50 ng/ml. By comparison with other studies, with a dosage of 0.2-0.7 µg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration. The plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). The approximate linear equation was y = 0.171x + 0.254. The range of Richmond Agitation-Sedation Scale was 0 to -5. CONCLUSIONS: We concluded that, with a dosage of 0.2-0.83 µg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration of 0.22-2.50 ng/ml. In addition, the plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000009115.

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids.

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.