Empirical models for dosage optimization of four β-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin

ObjectivesThe study aims to develop empirical models able to predict the pharmacokinetics (PK) of four β-lactams using the amikacin (AMK) therapeutic drug monitoring (TDM), in order to optimize their dosage regimens.Design and methods69 critically ill septic patients were included. All received a first dose of AMK combined with piperacillin/tazobactam, ceftazidime, cefepime or meropenem. A multivariate analysis was performed to predict the β-lactam PK using AMK PK parameters estimated from TDM and using pathophysiological variables.ResultsAn optimal prediction model was identified for each PK parameter of each β-lactam. The best predictor of each model was one of the AMK PK parameters estimated from TDM. Other variables included colloid solution, renal and hepatic biomarkers, age and body weight.ConclusionPK of the four β-lactams could be easily and rapidly predicted in critically ill septic patients using the AMK TDM. These predictions could improve the β-lactam dosages in clinical practice.     

Detection of perinatal cytomegalovirus infection and sensorineural hearing loss in belgian infants by measurement of automated auditory brainstem response

Since auditory disability causes serious problems in the development of speech and in the total development of a child, it is crucial to diagnose possible hearing impairment as soon as possible after birth. This study evaluates the neonatal hearing screening program in Flanders, Belgium. The auditory ability of 118,438 babies was tested using the automated auditory brainstem response. We selected 194 babies with indicative hearing impairment and 332 matched controls to investigate the association between the presence of human cytomegalovirus (HCMV) in urine samples and sensorineural hearing loss and to analyze the sensibility and specificity of a cell culture assay and a quantitative PCR detection method. Our results indicate that significantly more babies with confirmed hearing impairment were HCMV positive after birth. Further, based on the results of our study, babies with HCMV viral loads above 4.5 log copies/ml urine seem to be 1.4 times more likely to have confirmed hearing impairment. Our follow-up study suggests that the hearing impairment of children infected with HCMV after birth is less likely to improve than that of HCMV-negative infants. Our results confirm that the presence of HCMV before or shortly after birth influences the outcome of hearing impairment.     

Extrahepatic Metabolism of Sevoflurane in Children Undergoing Orthotopic Liver Transplantation

Background: Sevoflurane is metabolized by cytochrome P450 and produces inorganic fluoride. The anhepatic phase of liver transplantation provides a useful tool to study the extrahepatic metabolism of drugs. The authors therefore studied the extrahepatic metabolism of sevoflurane by measuring the fluoride production in children receiving sevoflurane solely during the anhepatic phase of orthotopic liver transplantation.

Methods: Children with end-stage liver disease undergoing orthotopic liver transplantation were studied. Anesthesia was provided with isoflurane, sufentanil, and pancuronium. In one group, isoflurane was replaced by sevoflurane as soon as the liver was removed from the patient and maintained until reperfusion of the new liver. Arterial blood samples were drawn at induction, before removal of the liver, 15 min and 30 min after the beginning of the anhepatic phase, at the unclamping of the new liver, and finally 60 and 120 min after the unclamping. Plasma fluoride concentrations were determined by ion-selective electrode.

Results: No differences between the two groups (n = 10) regarding age, weight, duration of the anhepatic phase, or basal level of inorganic fluoride were found. The fluoride concentration increased significantly as soon as sevoflurane was introduced; it remained stable in the group receiving isoflurane. The peak fluoride concentration was also significantly higher in the first group (mean +/- SD: 5.5 +/- 0.8 [mu]M (sevoflurane group) versus 1.4 +/- 0.5 [mu]M (isoflurane group) P < 0.05).     

Local Burr distribution estimator for speckle statistics

Speckle statistics in ultrasound and optical coherence tomography have been studied using various distributions, including the Rayleigh, the K, and the more recently proposed Burr distribution. In this paper, we expand on the utility of the Burr distribution by first validating its theoretical framework with numerical simulations and then introducing a new local estimator to characterize sample tissues of liver, brain, and skin using optical coherence tomography. The spatially local estimates of the Burr distribution’s power-law or exponent parameter enable a new type of parametric image. The simulation and experimental results confirm the potential for various applications of the Burr distribution in both basic science and clinical realms.     

Quantitation of replication of the HCV genome in human livers with end‐stage cirrhosis by strand‐specific real‐time RT‐PCR assays: Methods and clinical relevance

HCV replicates in liver via an intermediate negative strand RNA. To study the relevance of HCV genome replication, quantitative strand‐specific HCV real‐time RT‐PCR assays were developed and applied to livers explanted because of end‐stage cirrhosis. The assays have broad ranges of determination and a high reproducibility and accuracy. Analysis of five different samples showed an even distribution of HCV genomes in four livers. Hepatic concentrations of positive (PS)‐ and negative (NS)‐strand RNA did correlate with each other, with PS/NS ratios ranging between 3 and 340. Hepatic concentrations of HCV‐PS or ‐NS RNA did not correlate with serum HCV‐RNA levels or with genotypes. A high HCV envelope‐2 protein expression correlated with a low NS concentration. HCV‐PS and ‐NS levels, E2 protein expression and genotype did not correlate with biochemical tests or with histological changes in the explanted liver, but the ratio NS/PS, a marker of viral replication, correlated with the severity of the recurrent post‐transplant hepatitis caused by HCV. This suggests the existence of an extra‐hepatic location of HCV with comparable viral replication rate being responsible for the infection of the newly transplanted liver. J. Med. Virol. 81:1569–1575, 2009. © 2009 Wiley‐Liss, Inc.     

Low-voltage coagulation for welding sutures watertight: an experimental study

Summary A rat model was developed to test the watertightness of sutures. In this model it was proved that welding by use of low-voltage coagulation current did not improve on the watertightness obtained with conventional skin suturing. The mean leak pressure after welding was about 4.2 cm H₂O, i.e. statistically significantly lower than the mean leak pressure of the conventional suture, which is 14.1 cm H₂O. Neither addition of protein solder nor an additional conventional suture improved these results. It is therefore concluded that low-voltage coagulation is unsuitable for welding tissues.     

Effect of aluminum hydroxide on diflunisal absorption.

1 The effect of aluminum hydroxide on the oral absorption of diflunisal was studied in healthy subjects. 2 Relative bioavailability of the oral diflunisal dose (500 mg) was estimated by comparison of the areas under plasma concentration versus time curves, and comparison of the amount of drug (unchanged + glucuronides) excreted in the urine. 3 From the AUC-method, a relative bioavailability of 0.60 was calculated. A similar value (F = 0.63) was obtained from the urinary excretion data. 4 The results indicate that co-administration of aluminum hydroxide reduces the bioavailability of oral diflusinal by about 40%.     

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: Effect of cimetidine

Summary The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). t_lag, C_max, t_max, t_1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 µg·h·ml^–1) as compared to single dose administration (19.0 µg·h· ml^–1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery.The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.