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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  54. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds); 20090907-20090910; Essen; DOC09gmds051 /20090831/
    Publication Date: 2009-08-31
    Keywords: personal exposure ; UFP ; microenvironments ; air pollution ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    ISSN: 1432-1041
    Keywords: valnoctamide ; valpromide ; valproic acid ; pharmacokinetics ; healthy subjects ; tranquiliser
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a prodrug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.
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  • 3
    ISSN: 1432-1041
    Keywords: primidone ; viral hepatitis ; single-dose kinetics ; primidone metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of primidone (PRM) after oral administration of a single 500 mg dose was studied in 7 patients with acute viral hepatitis and 7 healthy control subjects. The elimination half-life and the apparent clearance of unchanged PRM in the patients were 18.0±3.1 h and 42±14 ml·h−1·kg−1, respectively (mean ± SD) and did not differ significantly from the values in the controls (half-life 17.0±2.4 h; clearance 35±8 ml·h−1·kg−1). The metabolite phenylethylmalonamide (PEMA) was detected in the serum of all normal subjects within 2–24 h. By contrast, serum levels of this metabolite were undetectable (〈2 umol/l) in all but one of the patients. Serum levels of phenobarbital (PB) remained below the limit of detection (〈2 µmol/l) in all subjects. The findings indicate that accumulation of PRM with its attendant toxicity is unlikely to occur in epileptic patients who develop acute viral hepatitis, despite evidence that the metabolism of the drug is affected by this condition. The possibility of impaired conversion to PB and its implications are discussed.
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  • 4
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; Immunosuppression ; Prednisone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Prednisone has been commonly considered the mainstay of immunosuppressive therapy after liver transplantation. Recent data suggest that prednisone withdrawal late after transplant reduces complications without affecting graft function. We report here the preliminary results of an open-label, randomized study aimed at investigating whether prednisone therapy can be completely avoided during the first 3 months after transplantation. Twenty-seven consecutive patients were randomized to receive double (group A: cyclosporine and azathioprine) or triple (group B: prednisone, cyclosporine, and azathioprine) immunosuppressive therapy after liver transplantation. Six patients died within the first 3 weeks in each group and were excluded from the calculations. The present results refer to 10 patients in group A and 11 in group B. The actuarial 1-year survival did not differ between the two groups (90.9 % vs 88.8 %). There were no differences with respect to infectious complications or episodes of histological acute graft rejections. Only one severe acute rejection occurred in group A and two in group B. During the first month after transplant, liver and kidney functions tended to be better in the group of patients treated without prednisone, although there were no differences in the mean cyclosporine blood levels. These data, though preliminary, indicate that early immunosuppression without the use of prednisone is safe and tends to be associated with improved liver and renal functions compared to conventional triple therapy.
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  • 5
    ISSN: 1432-2277
    Keywords: Key words Kidney transplantation immunology ; Kidney transplantation monitoring ; Flow cytometry crossmatch ; Donor-specific antibodies ; Class I histocompatibility antigens immunology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study was designed to investigate the clinical relevance of donor-specific antibodies (DS-Abs) and their influence on graft survival. Among 106 patients who underwent cadaveric kidney donor transplantation and were monitored by flow cytometry crossmatch (FCXM) during the 1st posttransplantation year, 25 (23.6 %) resulted positive for DS-Ab production. During a 2-year follow up only 12 of the 81 FCXM-negative patients (14.8 %) suffered rejection vs 17 of 25 FCXM-positive patients (68 %; P = 0.00 001). Correlating graft loss to DS-Ab production, 9 FCXM-positive patients lost the graft vs only 1 among the FCXM-negative patients. A worse graft function was evidenced in FCXM-positive subjects who had also suffered rejection episodes than in those which had acute rejection but did not produce DS-Abs. A high incidence of HLA-AB mismatches was found in FCXM-positive subjects which produced anti-class I antibodies. FCXM appears useful in estimating posttransplant alloimmune response. Moreover our findings confirm the harmful effects of anti-class I DS-Abs on long-term graft survival.
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  • 6
    ISSN: 1433-4909
    Keywords: Key wordsSulfolobus solfataricus ; DNA replication ; DNA polymerase ; 3′-5′ Exonuclease ; Modular organization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract DNA polymerase from Sulfolobus solfataricus, strain MT4 (Sso DNA pol), was one of the first archaeal DNA polymerases to be isolated and characterized. Its encoding gene was cloned and sequenced, indicating that Sso DNA pol belongs to family B of DNA polymerases. By limited proteolysis experiments carried out on the recombinant homogeneous protein, we were able to demonstrate that the enzyme has a modular organization of its associated catalytic functions (DNA polymerase and 3′-5′ exonuclease). Indeed, the synthetic function was ascribed to the enzyme C-terminal portion, whereas the N-terminal half was found to be responsible for the exonucleolytic activity. In addition, partial proteolysis studies were utilized to map conformational changes on DNA binding by comparing the cleavage map in the absence or presence of nucleic acid ligands. This analysis allowed us to identify two segments of the Sso DNA pol amino acid chain affected by structural modifications following nucleic acid binding: region 1 and region 2, in the middle and at the C-terminal end of the protein chain, respectively. Site-directed mutagenesis studies will be performed to better investigate the role of these two protein segments in DNA substrate interaction.
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  • 7
    ISSN: 1432-0584
    Keywords: Key words AML ; ATRA ; bcl-2 ; CD34
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Using flow cytometry, we have investigated the effects of 0.5 μM all-trans–retinoic acid (ATRA) on bcl-2 expression in the blast cells of 25 acute myeloblastic leukemia (AML) patients and the HL-60 cell line after incubation for 6 days. We observed a significant decrease of bcl-2 expression after treatment with ATRA in 12 of 25 AML samples and the HL-60 cells. The mean fluorescence intensity (MFI) ratio for the bcl-2 levels of the ATRA responders (n=12) was reduced to 7.9±4.8 following incubation with ATRA compared with 10.9±6.5 (mean±SD) for control samples incubated without ATRA (p=0.011). There was no significant difference between the baseline bcl-2 MFI ratio in the ATRA responders (11.14±7, n=12) and the non responders (14.18±11.3, n=13;p=0.432). The down-regulation of bcl-2 expression by ATRA was not significantly associated with CD34-negative or -positive AML. There was no correlation between AML subtypes and regulation of bcl-2 expression by ATRA. Complete remission and overall survival were not significantly improved in bcl-2 down-regulated cases. Our data confirm that ATRA can down-regulate the bcl-2 expression in AML blasts. Because many chemotherapeutic agents also operate through the activation of programmed cell death and bcl-2 levels are positively associated with resistance to apoptosis, ATRA can be used in combination chemotherapy to increase the chemosensitivity of some patients with AML.
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  • 8
    ISSN: 0392-6737
    Keywords: Plasma interactions ; Radio-frequency and microwave measurements ; Diffraction and scattering
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Summary A microwave coherent backscattering experiment has been carried out on Mirabelle, a weakly ionised plasma device, with the objective of measuring the electron density fluctuation level. The experiment is a preliminary step in order to prepare the detection system for a microwave stimulated backscattering experiment. The incident electromagnetic wave is focused in front of a plane grid which excites ion acoustic or electron Bernstein waves inducing fluctuations in the plasma. The backscattering signal is collected by the launching circuit and detected by homodyne mixing. The typical ratio of the scattered power to the incident power is about 10−12 and the relative density fluctuations are of the order of δn e/n e=10−3 against a background electron density ofn e=1–5·109 cm−3. The backscattering measurement is compared with Langmuir probe measurements. The spectral width of the backscattered signal has also been studied, by taking into account effects due to the incident wave focusing and plasma wave damping.
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  • 9
    ISSN: 1590-3478
    Keywords: Epidemiology ; Clinical ; Impact ; Antiepiletic drug interation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Sommario Il presente studio è stato condotto al fine di valutare, in condizioni cliniche rutinarie, i possibili effetti delle interazioni farmacocinetiche degli anticonvulsivanti su: (I) le prescrizioni delle dosi giornaliere e (II) la variabilità dei livelli plasmatici dei singoli farmaci. La casistica comprende 848 pazienti epilettici sottoposti, per la prima volta ad un dosaggio ematico e trattati cronicamente con uno o due dei seguenti farmaci: fenitoina (PHT), fenobarbital (PB), carbamazepina (CBZ) e valproato (VPA). Nessuna differenza significativa è stata osservata nelle prescrizioni delle dosi giornaliere tra i gruppi in monoterapia e quelli in biterapia. Per quanto riguarda la variabilità dei livelli ematici, sono state osservate le seguenti differenze statisticamente significative: (I) una più alta percentuale di pazienti con livelli di CBE e VPA al di sotto dei «ranges» tereapeutici nei gruppi che assumevano tali farmaci in associazione con uno degli altri considerati, rispetto ai gruppi in monoterapia; (II) una percentuale più alta di pazienti con livelli di PB al di sopra del «range» nel gruppo trattato con PB e PHT in associazione, rispetto agli altri gruppi considerati. Le implicazioni cliniche di tali dati vengono, quindi, discusse.
    Notes: Abstract The impact of pharmacokinetic anticonvulsant drug interactions on prescribing patterns and serum drug level distribution in a routine clinical setting was evaluated in a population of 848 patients chronically treated with phenytoin, phenobarbital, carbamazepine and valproic acid (either alone or as two-drug combinations) and referred for therapeutic drug monitoring for the first time. While dosages of each drug did not differ significantly between monotherapy and polytherapy patients, significant differences in serum level distribution were found. The proportion of patients with suboptimal serum carbamazepine and valproic acid levels (〈4 and 〈50μg/ml, respectively) was much greater in the polytherapy than in the monotherapy groups, probably as a consequence of induction of carbamazepine and valproic acid metabolism by combined anticonvulsants. Conversely, the proportion of phenobarbital levels above the upper limit of the optimal range (40μg/ml) was greater among patients receiving phenytoin in combination than among patients taking phenobarbital alone, presumably as a result of phenytoin-induced inhibition of barbiturate metabolism. The therapeutic implications of these findings are discussed.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Neurological sciences 1 (1979), S. 245-249 
    ISSN: 1590-3478
    Keywords: Dipropylacetamide ; Valproic acid ; Kinetic parameters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Sommario Alcuni aspetti di farmacocinetica della amide primaria dell'acido valproico, la dipropilacetamide, che nell'uomo viene rapidamente trasformata nell'acido corrispondente, sono stati studiati e confrontati con quelli ottenuti dopo somministrazione di valproato di sodio. In un gruppo di soggetti volontari e sani il picco di concentrazione di acido valproico è stato raggiunto entro 5–14 ore dopo somministrazione di dipropilacetamide ed entro 1–2 ore dopo somministrazione di valproato di sodio. L'emivita plasmatica è risultata 8–12 ore dopo assunzione di entrambi i composti, senza significative differenze. La biodisponibilità della dipropilacetamide è stata 81,2% in media rispetto al sale sodico. In un gruppo di pazienti epilettici nessuna correlazione è stata osservata tra livelli plasmatici di acido valproico e dose giornaliera di valproato o amide; le fluttuazioni gionaliere delle concentrazioni ematiche del farmaco sono state meno ampie durante terapia con dipropilacetamide. Questo farmaco, dato il lento assorbimento presentato e la conseguente maggiore stabilità dei livelli plasmatici durante le 24 ore, sembra offrire qualche vantaggio di somministrazione rispetto al valproato di sodio.
    Notes: Abstract The kinetics of the primary amide of valproic acid (VPA), i.e. dipropylacetamide, rapidly transformed into the corresponding acid in humans, are investigated and compared with valproate kinetics. In a group of healthy volunteers peak VPA concentration was reached within 5–14 hours of dipropylacetamide and within 1–2 hours of valproate administration. The plasma half-life appeared to be 8–12 hours for both compounds without significant differences. The relative bioavailability of the amide was 81.2% of valproate on average. In epileptics no correlation between plasma VPA levels and daily valproate or amide dose was observed; daily plasma valproic acid level fluctuations were significantly less wide during dipropylacetamide therapy. This compound seems to offer some advantages over sodium valproate, namely: slower absorption, stabler plasma levels through the day, 2 instead of 3 or 4 daily doses and hence less risk of drug defaulting.
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