1,720,985 research outputs found
Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: Implications for therapeutic drug monitoring
No full textThe need for mycophenolic acid (MPA) monitoring is still under discussion. Key issues for the PK/PD relationships of this drug are: the role of metabolites, the usefulness of AUC versus predose levels, and the need to monitor the free concentration of MPA (f-MPA). Recent advances have revealed that, in addition to 7-O-MPAG, three additional MPA metabolites are present in the plasma of transplant recipients. One of these metabolites (M-2), identified as an acyl glucuronide of MPA, was found to inhibit IMPDH-II in vitro. This active metabolite was also found to cross-react in the Emit assay for MPA. In an ongoing multicenter study, the authors are evaluating the relevance of monitoring total (t-MPA) and free mycophenolic acid (f-MPA) in pediatric renal transplant recipients. As in adults, a time-dependant increase of t-MPA-AUC(0-12h) within the first 3 months posttransplant (35 versus 64 mg x L/h, 3 weeks versus 3 months respectively; daily dosage: 0.6 g/m(2) bid) was seen. Receiver operating characteristics curve analyses were used to test the ability of predose levels or AUC(0-12h) to discriminate between cases with no complications and those with acute rejection, adverse events (severe infections, leukopenia), or gastrointestinal disorders observed during the early posttransplant course, In agreement with observations in adults, a significant (p = 0.001) association was observed between AUC(0-12h) and acute rejection. A t-MPA-AUC(0-12h) of approximately 30-60 mg x L/h, as determined by HPLC, seems to be a reasonable target for the early posttransplant period. It remains to be elucidated whether regular predose level monitoring may be of more practical value. A higher incidence of rejection was observed at predose MPA concentrations less than or equal to 1 mg/L, as measured by HPLC. In contrast to t-MPA, f-MPA-AUC(0-12h) was significantly related to seven infections and leukopenia. The risk for severe adverse events was increased at f-MPA- AUC(0-12h) values greater than or equal to 600 mu g x Uh. On the basis of these data and the observed variability in the pharmacokinetics of MPA, the development of monitoring strategies for this drug appears to he promising
Immunosuppressive drug monitoring of sirolimus and cyclosporine in pediatric patients
No full textSirolimus is primarily used as a rescue agent in pediatric transplant recipients, particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data indicate a higher apparent oral clearance in younger children (4-10 years of age). Various drug interactions have been described between sirolimus and drugs that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein transporter. Close monitoring of trough sirolimus blood levels is therefore recommended for pediatric transplant recipients. In de novo adult kidney transplant recipients on triple therapy with cyclosporine, corticosteroids and sirolimus, a therapeutic window of 4-12 mug/l is recommended for sirolimus trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult patients after conversion to a calcineurin inhibitor-free regimen, sirofirmis trough concentrations of 5-10 mug/l are proposed in combination with mycophenolate mofetil. These therapeutic ranges may also serve as a guide for pediatric renal transplant recipients. The concept Of C-2 monitoring still needs to be critically evaluated in pediatric patients. The crucial importance of achieving an adequate cyclosporine exposure early after transplantation has been demonstrated for adult transplant recipients. A cyclosporine concentration taken 2 h after dosing is a good surrogate marker of the AUC(0-4h) in adults. Various clinical studies have shown that in pediatric patients, the C-2 concentration shows a substantially better correlation with cyclosporine exposure compared to the trough level (CO). In an outcome study with pediatric renal transplant recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute rejection in the first 3 weeks after transplantation, whereas C-2 levels showed no significant association. Abbreviated AUC strategies may be preferable for optimization of CsA exposure in pediatric patients. (C) 2004 The Canadian Society of Clinical Chemists. All rights reserved
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Pharmacokinetics and protein adduct formation of the pharmacologically active acyl glucuronide metabolite of mycophenolic acid in pediatric renal transplant recipients
No full textThe acyl glucuronide metabolite (AcMPAG) of mycophenolic acid (MPA) has been found to possess both immunosuppressive and pro-inflammatory activity in vitro. In this study its pharmacokinetics were determined in pediatric renal transplant recipients receiving cyclosporine, steroids, and mycophenolate mofetil. Twelve-hour concentration-time profiles for AcMPAG, MPA, and the phenolic glucuronide (MPAG) were determined by high-performance liquid chromatography (HPLC) in the initial (1-3 wk; n=16) and stable (3-12 mo; n=22) phase,, after transplantation. In addition, the formation of covalent adducts between AcMPAG and plasma albumin (AcMPAG-Alb) was investigated using Western Blot analysis. AcMPAG-AUC(12h) showed significant (p<0.05) correlations with MPA-AUC(12h) (r=0.78) and MPAG-AUC(12h) (r=0.78). In molar equivalents the median AcMPAG-AUC(12h) was 10.3% (range, 4.6%-45.5%) of MPA-AUC(12h). Values (median [range]) of AcMPAG-AUC(12h) (10.1 [3.30-30.1] mg.h/L), AcMPAG-C-0 (0.48 [0.08-1.43] mg/L), and AcMPAG-C-max (1.95 [0.88-5.35] mg/L) were significantly (p<0.05) higher in the stable phase than in the initial phase: 3.54 [2.07-20.0] mg.h/L for AUC(12h); 0.25 [<0.04-0.97] mg/L for C-0, and 1.12 [0.32-2.44] mg/L for C-max. The increases in the AcMPAG pharmacokinetic variables were paralleled by significant increases in the corresponding MPA variables. In addition, a strong negative correlation (r=-0.69; p<0.05) was found between AcMPAG concentrations and the creatinine clearance. AcMPAG-Alb adducts were detected in all patient samples. They showed considerable interindividual variation and increased significantly with time from the initial phase to the stable phase. AcMPAG-Alb correlated significantly (p<0.05) with AcMPAG-AUC(12h) (r=0.70) and plasma albumin (r=0.40). AcMPAG plasma concentrations are dependent on renal function, MPA disposition, and glucuronidation. The pharmacokinetics of AcMPAG is characterized by broad interindividual variation. In some patients AcMPAG may significantly contribute to the immunosuppression during mycophenolate mofetil therapy. AcMPAG-Alb adduct formation may serve as a marker for extended AcMPAG exposure. The association of AcMPAG with adverse effects must be further investigated
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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