Population pharmacokinetics of four β-lactams in critically ill septic patients comedicated with amikacin

ObjectivesThe study aimed to characterize the pharmacokinetics (PK) of four β-lactams (piperacillin, ceftazidime, cefepime, and meropenem) in patients comedicated with amikacin (AMK), and to confirm the predictive performance of AMK data, obtained from therapeutic drug monitoring (TDM), on these PK, using a population modeling approach.Design and methodsSerum samples were collected in 88 critically ill septic patients. For each β-lactam, the covariate model was optimized using renal function. Furthermore, predictive performance of AMK concentrations and PK parameters was assessed on β-lactam PK.ResultsA two-compartment model with first-order elimination best fitted the β-lactam data. Results supported the superiority of AMK concentrations, over renal function and AMK PK parameters, to assess the β-lactam PK.ConclusionThe study confirmed the significant link between the exposure to AMK and to β-lactams, and presented population models able to guide β-lactam dosage adjustments using renal biomarkers or TDM-related aminoglycoside data.     

Dialysis arteriovenous fistulas: the critical role of color doppler ultrasound

Despite being time-consuming and observer-dependent, CDUS is a method of choice for performing and controlling dialysis shunts. It contributes to increasing the number of native AVFs and enables early detection of lesions therefore allowing quick percutaneous or surgical therapy.     

Pipotiazine pharmacokinetics after p.o. and i.v. administration in man. Correlation between blood levels and effect on the handwriting area.

Plasma kinetics of pipotiazine, a phenothiazine neuroleptic, have been studied in five chronic schizophrenic patients after both oral (25 mg) and i.v. (5 mg) administration of pipotiazine tritiated in the 3- and 4-positions of the piperidine ring. Peak plasma concentrations of unchanged pipotiazine were reached between 1 and 2 h after oral administration and showed a five-fold inter-individual variation. The mean terminal elimination half-life was 11.2 h. After i.v. administration plasma concentration declined bi-exponentially with mean half-life values of 2.7 and 8.8 h. Data indicate that biotranformation of the drug was not dependent on the route of administration and that there were no qualitative differences in biotransformation between individuals. The large apparent distribution volumes (mean value 545 l) indicated extensive binding to tissue components. After 25 mg p.o. effect on the handwriting area was manifest from 8 to 48 h after administration and reached maximum intensity between 24 and 36 h. This is consistent with rather a large duration of action observed clinically.     

Conversion of octacalcium phosphate in calcium phosphate cements

This study investigated the in vitro conversion reaction in calcium phosphate cements (CPCs) containing octacalcium phosphate (OCP) as one of the reagents. OCP is known to be a precursor for apatite formation in vivo. The reaction products were characterized using infrared spectroscopy and X-ray diffraction. Although the conversion of OCP into hydroxyapatite is thermodynamically favorable, OCP only yields apatite formation in CPC provided it is combined with a highly soluble Ca(2+) and OH(-) releasing reaction partner. In this respect, tetracalcium phosphate is a promising compound. Adding small amounts of monocalcium phosphate monohydrate can stimulate the setting through intermediate brushite formation. The preparation method of OCP might drastically affect the performance of the cement. The reaction path of the setting of these CPC probably does not conform to the singular point principle described in the literature, and an in situ hydrolysis of OCP to apatite is conceivable. Simulation of apatite formation using OCP as the precursor and/or seed in CPC might be beneficial for some biomedical applications.     

Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up

OBJECTIVES: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. METHODS: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG-IUS, releasing 20 microg LNG/day. The study is a non-comparative study with long-term follow-up (range 14-90 months). RESULTS: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (< 4 mm) endometrium. CONCLUSION: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG-IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression.     

Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains

Copy number gains at Xq28 are a frequent cause of X‐linked intellectual disability (XLID). Here, we report on a recurrent 0.5 Mb tandem copy number gain at distal Xq28 not including MECP2, in four male patients with nonsyndromic mild ID and behavioral problems. The genomic region is duplicated in two families and triplicated in a third reflected by more distinctive clinical features. The X‐inactivation patterns in carrier females correspond well with their clinical symptoms. Our mapping data confirm that this recurrent gain is likely mediated by nonallelic homologous recombination between two directly oriented Int22h repeats. The affected region harbors eight genes of which RAB39B encoding a small GTPase, was the prime candidate since loss‐of‐function mutations had been linked to ID. RAB39B is expressed at stable levels in lymphocytes from control individuals, suggesting a tight regulation. mRNA levels in our patients were almost two‐fold increased. Overexpression of Rab39b in mouse primary hippocampal neurons demonstrated a significant decrease in neuronal branching as well as in the number of synapses when compared with the control neurons. Taken together, we provide evidence that the increased dosage of RAB39B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain.     

Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition

A simultaneous brain and blood microdialysis system was developed to study the passage of colchicine through the blood–brain barrier in the mouse. Colchicine was administered as a bolus in the jugular vein (1.5 mg kg⁻¹) and its hippocampal extracellular fluid (ECF) and blood kinetics were determined over a 4 h period using two microdialysis probes, one in the dorsal hippocampus, the other in the inferior vena cava. Colchicine rapidly diffused into the hippocampus (maximum concentration in the first dialysate sample) and brain and blood concentrations declined in parallel, suggesting rapid equilibration between these two compartments. However, only 6.7% of total blood colchicine, 14% of unbound colchicine was present in the hippocampus suggesting that the P-glycoprotein efflux pump limits colchicine uptake by the brain. We also found, using conventional tissue homogenate analysis in parallel, that the concentration of colchicine in the hippocampal ECF was 10 times less than that in the intracellular space and that the hippocampus colchicine concentration was 2.8 times higher than that of the rest of the brain. This study shows that the simultaneous brain and blood microdialysis can be used to measure the passage of colchicine through the blood–brain barrier and to estimate the brain extra- and intracellular distribution of colchicine.