CAHP-210 dialyzer influence on intra-dialytic vancomycin removal.

BACKGROUND: Vancomycin is often administered during the last hour of haemodialysis because it was not removed significantly by older hemodialyzers. However, newer higher permeability hemodialyzers remove vancomycin, although the amount removed varies considerably between dialyzers. The purpose of this study was to determine the apparent amount of vancomycin removed during the last hour of haemodialysis with a CAHP-210 hemodialyzer. METHODS: Eight subjects with end-stage renal disease (ESRD) received i.v. vancomycin 15 mg/kg after their regular haemodialysis session ended. Serum samples for the determination of vancomycin concentrations were obtained serially for 44 h. After a 3-week washout, the study was repeated with the vancomycin infused during the last hour of their regular haemodialysis session using a CAHP-210 hemodialyzer. Vancomycin concentrations were determined by the Enzyme Multiplied Immunoassay Technique. Differential equations describing a two-compartment open infusion model were fitted to the serum concentration vs time data and pharmacokinetic parameters and apparent vancomycin removal was estimated. RESULTS: The median age and weight of the subjects were 52 years (range 37-71) and 75.6 kg (range 37.6-89.8), respectively. The apparent vancomycin intra-dialytic removal was 0.24 (range -0.07-0.35), which was statistically significantly different from zero. CONCLUSIONS: Vancomycin administered during the last hour of CAHP-210 dialysis results in 24% less vancomycin exposure than when administered post-haemodialysis. This intra-dialytic drug loss should be accounted for when dosing vancomycin in this manner.     

Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia

Background  

Community-acquired pneumonia (CAP) is the most frequent infection-related cause of death. The reference standard to diagnose CAP is a new infiltrate on chest radiograph in the presence of recently acquired respiratory signs and symptoms. This study aims to evaluate the diagnostic and prognostic accuracy of clinical signs and symptoms and laboratory biomarkers for CAP.     

Improved Dose Linearity of Cyclosporine Pharmacokinetics from a Microemulsion Formulation

The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) were compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radio-immunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neoral at all dose levels investigated. The area under the curve for Sandimmune increased in a less than proportional manner with respect to dose, whereas that for Sandimmune Neoral was consistent with linear pharmacokinetics. Because of this difference, no global assessment of relative bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compared to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after administration as Sandimmune Neoral should facilitate more accurate dosage titration in the clinical setting.     

Band 3 Memphis: a widespread polymorphism with abnormal electrophoretic mobility of erythrocyte band 3 protein caused by substitution AAG----GAG (Lys----Glu) in codon 56.

Band 3 Memphis (b3M) is a variant of the erythrocyte band 3 protein detected in individuals of virtually all ethnic groups and characterized by a reduced mobility of proteolytic fragments derived from the N-terminus of the cytoplasmic domain of band 3 (cdb3). We have sequenced band 3 cDNA corresponding to cdb3 in 12 heterozygotes for the b3M polymorphism including one white, one black, one Chinese, one Philippino, one Malay, and seven Melanesian subjects. In all individuals, we found a single-base substitution in codon 56 of one band 3 allele changing lysine to glutamic acid (AAG----GAG) which, in some of them, was linked with an additional mutation in cdb3. Since the change of codon 56 from AAG to GAG was the only mutation in the studied individuals found within the cDNA segment coding for the abnormally migrating fragment of cdb3, we conclude that it represents the underlying molecular basis of the b3M polymorphism. We further support this conclusion by showing that electrophoresis in the presence of 4 mol/L urea abolished the difference in migration between proteolytic products of b3M and normal band 3, and that a fusion protein prepared from cDNA coding for the b3M allele again exhibits reduced electrophoretic mobility compared with the normal fusion protein. Finally, since most of the previously cloned mouse, rat, and chicken band 3 and band 3-related proteins contain glutamic acid in the position corresponding to amino acid 56 in the human band 3, we propose that the Memphis variant is the evolutionarily older form of band 3.     

Benefit of Kupffer cell modulation with glycine versus Kupffer cell depletion after liver transplantation in the rat: effects on postischemic reperfusion injury, apoptotic cell death graft regeneration and survival.

Inhibition or destruction of Kupffer cells (KC) may protect against ischemia-reperfusion (IR) induced primary graft nonfunction (PNF) in liver transplantation. Besides KC activation, PNF is characterized by microvascular perfusion failure, intrahepatic leukocyte accumulation, cell death and hepatocellular dysfunction. KCs can be inactivated by different agents including gadolinium chloride (GdCl3), methyl palmitate (MP) and glycine. The effects of three KC inactivators on IR-injury after rat liver transplantation were compared in the present study. Lewis liver donors were treated with GdCl3, MP, glycine or saline (control). Liver grafts were transplanted following 24 h storage (UW solution). KC populations and IR damage were assessed by histologic analysis, quantitative real-time polymerase chain reaction (RT-PCR) and intravital microscopy. The number of hepatic ED-1 positive macrophages was diminished after GdCl3 (114.8+/-4.4/mm2 liver tissue) and MP treatment (176.0+/-5.0), versus the glycine (263.9+/-5.5) and control (272.1+/-5.6) groups. All three treatment modalities downregulated phagocytic activity for latex particles, paralleled by reduced microvascular injury (acinar perfusion index, GdCl3: 0.75+/-0.03; MP: 0.83+/-.03; glycine: 0.84+/-0.03; 0.63+/-0.03). Quantitative RT-PCR revealed elevated myeloperoxidase mRNA after glycine versus GdCl3 and MP pretreatment (3.2- and 3.4-fold, P=0.011, respectively), without difference to controls (2.9-fold of glycine). TNFalpha-mRNA was reduced after glycine- (5.2-fold), GdCl3- (19.7-fold), MP-treatment (39.5-fold) compared with controls. However, profound prevention of intrahepatic cell death and liver graft failure was solely achieved with glycine preconditioning. Different than GdCl3 and MP, glycine modulates rather than destroys KCs. Glycine appears to preserve cell viability and to TNFalpha/leukocyte dependent organ regeneration capacity, which is related to increase graft survival following liver transplantation.     

Reliability, dependability, and precision of anthropometric measurements. The Second National Health and Nutrition Examination Survey 1976-1980

The components of reliability for eight anthropometric measures were studied in 95 male and 134 female subjects from the Second National Health and Nutrition Examination Survey (NHANES II). The contributions to unreliability variance (Sr2) that occur as a result of measuring errors (Sp2, imprecision variance) and of intrasubject fluctuations in a measurement due to physiologic factors (Sd2, undependability) were estimated (Sr2 = Sp2 + Sd2). Unreliability was then related to the between-subject variance (S2) to estimate the reliability (R = 1 - (Sr2/S2)) of the measurement. Four of the anthropometric measurements (weight, height, sitting height, and arm circumference) had reliabilities in excess of R = 0.97. In the first three of these, measurement imprecision made up two thirds or less of unreliability, and undependability (Sd2) was stable by two weeks. Lesser but still acceptable reliabilities were obtained for triceps and subscapular skinfolds, bitrochanteric breadth, and elbow breadth (R = 0.81-0.95). For these variables imprecision (Sp2) was the major source of error. Furthermore, the unreliability (Sr2) between observers was twice as high or more than the unreliability within observers for these variables, evidence that imprecision (Sp2) is the single most important source of unreliability in these anthropometric measurements. Unreliability standard deviations of skinfolds increased in a linear manner with skinfold thickness corresponding to an unreliability coefficient of variation of 13-19 per cent. None of the other measurements showed such scale effects. Analyses of the kind suggested will help epidemiologists decide whether reliability can be increased by improving precision, and whether there is a need to improve reliability in the first place. Reliability appears to be adequate for all anthropometry in the NHANES II.     

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