Development and validation of an HPLC/MS/MS method for the determination of sufentanil and morphine in human plasma.

A sensitive and fast HPLC/MS/MS method for measurement of sufentanil and morphine in plasma was developed and validated. A single liquid-liquid extraction in alkaline medium was used for the cleanup of plasma, and fentanyl was added as an internal standard (IS). The analyses were carried out using a C18 column and the mobile phase acetonitrile-5 mM ammonium acetate + 0.25% formic acid (70 + 30, v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source in positive mode was set up in the selective reaction monitoring mode to detect precursor --> product ion transition 387.0 > 238.0, 285.7 > 165.1, and 337.0 > 188.0 for sufentanil, morphine, and IS, respectively. The method was linear in the 0.05 (LOQ) - 500 ng/mL range for sufentanil and 10 (LOQ) - 1000 ng/mL range for morphine. Good selectivity, linearity, precision, accuracy, and robustness were obtained for the HPLC/MS/MS method. The proposed method was successfully applied for the determination of sufentanil and morphine in patients undergoing cardiac surgery.

Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.

Unpredictable pharmacokinetics (PK) in burn patients may result in plasma concentrations below concentrations that are effective against common pathogens. The present study evaluated the imipenem PK profile and pharmacokinetic/pharmacodynamics (PK/PD) correlation in burn patients. Fifty-one burn patients, 38.7 years of age (mean), 68.0 kg, 36.3% total burn surface area (TBSA), of whom 84% (43/51) exhibited thermal injury, 63% inhalation injury and 16% electrical injury (8/51), all of whom were receiving imipenem treatment were investigated. Drug plasma monitoring, PK study (120 sets of plasma levels) and PK/PD correlation were performed in a series of blood samples. Only 250 µl of plasma samples were required for drug plasma measurements using the ultra filtration technique for the purification of biological matrix and quantification using liquid chromatography. Probability of target attainment (PTA) was calculated using a PD target of 40% free drug concentrations above the minimum inhibitory concentration (40%fT>MIC). Significant differences in PK parameters (medians), such as biological half-life (2.2 vs 5.5 h), plasma clearance (16.2 vs 1.4 l h(-1)) and volume of distribution (0.86 vs 0.19 l kg(-1)), were registered in burn patients via comparisons of set periods with normal renal function against periods of renal failure. Correlations between creatinine clearance and total body plasma clearance were also obtained. In addition, the PK profile did not change according to TBSA during sets when renal function was preserved. PTA was >89% for MIC values up to 4 mg l(-1). In conclusion, imipenem efficacy for the control of hospital infection on the basis of PK/PD correlation was guaranteed for burn in patients at the recommended dose regimens for normal renal function (31.1±9.7 mg kg(-1) daily), but the daily dose must be reduced to 17.2±9.7 mg kg(-1) during renal failure to avoid neurotoxicity.

Individualised vancomycin doses for paediatric burn patients to achieve PK/PD targets.

BACKGROUND: The objective of the study was to investigate vancomycin dose adjustment in pediatric burn patients by evaluating trough drug concentrations and the pharmacokinetic and pharmacodynamic (PK/PD) correlation. METHODS: Study subjects included 13 patients who were 6.0 years old, 25 kg (median). with normal renal function. These had at least a 30% total burn surface area and inhalation injury were present in 7/13 patients. The patients were investigated prospectively. Plasma monitoring and PK assessments were performed by serial blood sample collections (30 sets). Only 0.2 mL of each plasma sample was required for our plasma measurements, which were made by high performance liquid chromatography. The vancomycin PK/PD target was set at AUC0-24(ss)/MIC>400. RESULTS: Trough values less than 10 µg/mL were obtained in 16/30 sets (53%) as a consequence of increased plasma clearance and the apparent volume of distribution. The daily dose was subsequently increased from 43.4 ± 9.0mg/kg (mean ± SD) to 98.0 ± 17.9 mg/kg, p<0.05. The PK/PD target was reached for pathogens with 0.5mg/L, 1mg/L, 2mg/L and 4 mg/L MIC in 93.3% (28/30), 66.7% (20/30), 33.3% (10/30) and 3.3% (1/30) of the sets, respectively. CONCLUSIONS: To more rapidly achieve the PK/PD targets in pediatric burn patients with normal renal function, an initial dose of approximately 90-100mg/kg/day is recommended; however, this higher dosage regimen should be further evaluated in this population in terms of efficacy and toxicity as well as in terms of achieving pharmacodynamic goals.

Avaliaçäo experimental das variaçöes dos níveis de glicogênio, lípides totais, triglicérides e água no miocárdio submetido a parada anóxica hipotérmica / Experimental evaluation of the variations of glycogen, total lipids, triglycerides and water levels in the myocardium subjected to anoxic hypothermic arrest

Analisam-se as variaçöes tissulares miocárdicas de glicogênio, lípides, triglicérides e teores de água que ocorreram em dois grupos de cäes submetidos a parada cardíaca anóxica sob circulaçäo extracorpórea, respectivamente em normotermia e hipotermia sistêmica de 28-C. Houve quedas dos níveis de glicogênio nos dois grupos sem diferenças significativas entre eles. Os níveis miocárdicos de lípideos totais apresentaram-se relativamente estáveis nos cäes a 28-C e apresentaram quedas expressivas no grupo sob normotermia. Os níveis de triglicérides mantiveram-se relativamente estáveis nos primeiros 30 minutos de anóxia, apresentando a partir daí quedas expressivas. Os teores de água decresceram em ambos os grupos, particularmente nos cäes operados sob normotermia

Vancomycin monitoring in term newborns: comparison of peak and trough serum concentrations determined by high performance liquid chromatography and fluorescence polarization immunoassay

INTRODUCTION: Peak and trough serum concentrations of vancomycin were determined in term newborn infants with confirmed or suspected Staphylococcus sp sepsis by high performance liquid chromatography and flourescence polarization immunoassay. OBJECTIVE: To statistically compare the results of the high performance liquid chromatography and flourescence polarization immunoassay techniques for measuring serum vancomycin concentrations. METHODS: Eighteen peak and 20 trough serum samples were assayed for vancomycin concentrations using high performance liquid chromatography and flourescence polarization immunoassay from October 1995 to October 1997. RESULTS: The linear correlation coefficients for high performance liquid chromatography and flourescence polarization immunoassay were 0.27 (peak, P = 0.110) and 0.26 (trough, P = 0.1045) respectively, which were not statistically significant. CONCLUSION: There was wide variation in serum vancomycin concentrations determined by high performance liquid chromatography as compared with those determined by flourescence polarization immunoassay. There was no recognizable pattern in the variability; in an apparently random fashion, the high performance liquid chromatography measurement was sometimes substantially higher than the flourescence polarization immunoassay measurement, and at other times it was substantially lower

Níveis séricos de teofilina e velocidade de administraçäo por vía endovenosa / Serum theophylline levels and intravenous administration velocity

Com o objetivo de avaliar a influência da velocidade de administraçäo de aminofilina por via endovenosa sobre a concentraçäo sanguínea inicial de teofilina, foram avaliados 21 voluntários normais divididos em dois grupos. Grupo I - Dez indivíduos quais foi administrada aminofilina (5,6 mg/kg) diluída em 100ml de soro fisiológico em 20 minutos. Grupo II - Onze voluntários em que a mesma dose foi injetada diluída em 10ml de soro, em cinco minutos. Amostras sanguíneas para dosagem da teofilina sérica foram colhidas imediatamente após a injeçäo (tempo 0) e após 3 e 5 minutos. Os valores médios obtidos nos grupos I e II, foram respectivamente (microng/ml): 0' - 9,70 ñ 2,07 e 33,87 ñ 13,09; 3' - 9,41 ñ 2,45 e 22,39 ñ 8,03; 5' - 8,82 ñ 2,21 e 18.01 ñ 6,02. O nível máximo de teofilinemia no grupo I foi de 13,7 microng/ml e no grupo II 57,1 microng/ml. Somente em dois indivíduos deste grupo os níveis foram inferiores a 20microng/ml no tempo zero. Como a distribuiçäo da teofilina do compartimento vascular para o extravascular é rápida, pode-se assumir que a concentraçäo sanguínea reflita os valores teciduais. Assim a administraçäo endovenosa rápida coloca os pacientes por um curto período sob risco de efeitos colaterais potencialmente graves. Concluímos que a dose de ataque de aminofilina deve ser administrada por via endovenosa em 20 minutos, eliminando-se o perigoso hábito das injeçöes rápidas