Circulating and muscle glutathione turnover in human endotoxaemia

2009 ◽  
Vol 117 (9) ◽  
pp. 313-319 ◽  
Author(s):  
Urban B. Fläring ◽  
Christina Hebert ◽  
Jan Wernerman ◽  
Folke Hammarqvist ◽  
Olav E. Rooyackers
Keyword(s):  
Skeletal Muscle ◽  
Healthy Volunteers ◽  
Whole Blood ◽  
Initial Phase ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Synthesis Rate ◽  
Total Glutathione ◽  
Endotoxin Challenge ◽  
Glutathione Status

Patients with septic shock have high plasma glutathione concentrations, whereas intracellular concentrations in erythrocytes and muscle are low. In the present study, we investigated the temporal pattern of glutathione status and glutathione kinetics in healthy volunteers during the initial phase of sepsis using a human endotoxin model. The present study was a descriptive pilot study in healthy male volunteers (n=8) before and after an endotoxin challenge. The glutathione status was determined in plasma and whole blood at baseline and hourly for 4 h after intravenous endotoxin injection and in skeletal muscle at baseline and at 2 and 4 h after endotoxin injection. In plasma, the concentration of total glutathione decreased 24% (P<0.05) at 3 h after endotoxin injection and 32% (P<0.001) at 4 h. In whole blood and skeletal muscle, the concentrations of both GSH and total glutathione as well as the redox status remained unaltered during the initial 4 h after the endotoxin challenge. The FSR (fractional synthesis rate) of glutathione in whole blood was 38±20%/day before and 59±22%/day 4 h after the endotoxin challenge (P=0.088) and in skeletal muscle this was 41±25 and 46±18%/day (P=0.68) respectively. During the initial phase of sepsis, as represented by an intravenous endotoxin challenge to healthy volunteers, plasma concentrations of total glutathione decreased, whereas glutathione status and synthesis rate in skeletal muscle and whole blood remained unaltered. However, due to the variation in the synthesis measurements, larger studies are needed to confirm these findings.

Changes in manganese content of mononuclear blood cells in patients receiving total parenteral nutrition

1994 ◽  
Vol 40 (5) ◽  
pp. 829-832 ◽  
Author(s):  
A Matsuda ◽  
M Kimura ◽  
T Takeda ◽  
M Kataoka ◽  
M Sato ◽  
...  
Keyword(s):  
Parenteral Nutrition ◽  
Healthy Volunteers ◽  
Total Parenteral Nutrition ◽  
Whole Blood ◽  
Blood Cells ◽  
Manganese Content ◽  
Plasma Concentrations ◽  
Manganese Concentration ◽  
Mononuclear Blood Cells ◽  
Manganese Concentrations

Abstract We measured the manganese content of mononuclear blood cells and the manganese concentrations in whole blood and plasma from 31 healthy volunteers and 25 patients receiving total parenteral nutrition (TPN) (i.e., no dietary manganese). The manganese content (mean +/- 2 SD) of mononuclear blood cells and the manganese concentration in whole blood and plasma in the healthy volunteers were 8.84 +/- 4.18 ng/10(8) cells, 11.21 +/- 4.68 micrograms/L, and 1.21 +/- 0.72 micrograms/L, respectively. The manganese content of mononuclear blood cells from patients receiving TPN gradually decreased, falling below the lowest limit of the normal range by 21 weeks (95% confidence limits, 13-30 weeks) after starting TPN. Manganese concentrations in whole blood and plasma were within normal limits during our study period. These results suggest that the manganese content of mononuclear blood cells may better indicate manganese nutritional status than whole-blood or plasma concentrations.

Amino acid metabolism in leg muscle after an endotoxin injection in healthy volunteers

2005 ◽  
Vol 288 (2) ◽  
pp. E360-E364 ◽  
Author(s):  
Rokhsareh F. Vesali ◽  
Maria Klaude ◽  
Olav Rooyackers ◽  
Jan Wernerman
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Healthy Volunteers ◽  
Initial Phase ◽  
Plasma Amino Acid ◽  
Human Model ◽  
Endotoxin Administration ◽  
Leg Muscle ◽  
Amino Acid Concentrations

Decreased plasma amino acid concentrations and increased net release of amino acids from skeletal muscle, especially for glutamine, are common features in critically ill patients. A low dose of endotoxin administered to healthy volunteers was used as a human model for the initial phase of sepsis to study the early metabolic response to sepsis. Six healthy male volunteers were studied in the postabsorptive state. Blood samples from the forearm artery and femoral vein were taken during 4 h before and 4 h after an intravenous endotoxin injection (4 ng/kg body wt). In addition, muscle biopsies from the leg muscle were taken. Plasma concentration of the total sum of amino acids decreased by 19% ( P = 0.001) and of glutamine by 25% ( P = 0.004) the 3rd h after endotoxin administration. At the same time, muscle concentrations of the sum of amino acids and glutamine decreased by 11% ( P = 0.05) and 9% ( P = 0.09), respectively. In parallel, the efflux from the leg increased by 35% ( P = 0.004) for the total sum of amino acids and by 43% ( P = 0.05) for glutamine. In conclusion, intravenous endotoxin administration to healthy volunteers, used as a model for the initial phase of sepsis, resulted in a decrease in plasma amino acid concentrations. At the same time, amino acid concentrations in muscle tissue decreased, whereas the efflux of amino acids from leg skeletal muscle increased.

scholarly journals Intra- and Intersubject Whole Blood/Plasma Cannabinoid Ratios Determined by 2-Dimensional, Electron Impact GC-MS with Cryofocusing

2009 ◽  
Vol 55 (6) ◽  
pp. 1188-1195 ◽  
Author(s):  
Eugene W Schwilke ◽  
Erin L Karschner ◽  
Ross H Lowe ◽  
Ann M Gordon ◽  
Jean Lud Cadet ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Whole Blood ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Research Unit ◽  
Scientific Data ◽  
Intrasubject Variability ◽  
Blood Concentrations ◽  
The Mean ◽  
First Time

Abstract Background: Whole-blood concentrations of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) are approximately half of those in plasma due to high plasma protein binding and poor cannabinoid distribution into erythrocytes. Whole blood is frequently the only specimen available in forensic investigations; controlled cannabinoid administration studies provide scientific data for interpretation of cannabinoid tests but usually report plasma concentrations. Whole-blood/plasma cannabinoid ratios from simultaneously collected authentic specimens are rarely reported. Methods: We collected whole blood for 7 days from 32 individuals residing on a closed research unit. Part of the whole blood was processed to obtain plasma, and the whole blood and plasma were stored at −20 °C until analysis by validated 2-dimensional GC-MS methods. Results: We measured whole-blood/plasma cannabinoid ratios in 187 specimen pairs. Median (interquartile range) whole-blood/plasma ratios were 0.39 (0.28–0.48) for THC (n = 75), 0.56 (0.43–0.73) for 11-OH-THC (n = 17), and 0.37 (0.24–0.56) for THCCOOH (n = 187). Intrasubject variability was determined for the first time: 18.1%–56.6% CV (THC) and 10.8%–38.2% CV (THCCOOH). The mean whole-blood/plasma THC ratio was significantly lower than the THCCOOH ratio (P = 0.0001; 4 participants’ mean THCCOOH ratios were &gt;0.8). Conclusions: Intra- and intersubject whole-blood/plasma THC and THCCOOH ratios will aid interpretation of whole-blood cannabinoid data.

The effect of stress hormone infusion on protein synthesis rate in skeletal muscle and lymphocytes in healthy volunteers

1993 ◽  
Vol 12 ◽  
pp. 28 ◽  
Author(s):  
A. Sandgren ◽  
M.A. McNurlan ◽  
P. Essen ◽  
S.E. Anderson ◽  
J. Wernerman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Healthy Volunteers ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Stress Hormone

scholarly journals The novel polyclonal Ab preparation trimodulin attenuates ex vivo endotoxin-induced immune reactions in early hyperinflammation

2019 ◽  
Vol 25 (6) ◽  
pp. 374-388
Author(s):  
Celia Duerr ◽  
Annica Bacher ◽  
Angelika de Martin ◽  
Monika Sachet ◽  
Kambis Sadeghi ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Whole Blood ◽  
Ex Vivo ◽  
Early Stage ◽  
Lipoteichoic Acid ◽  
Laboratory Research ◽  
Endotoxin Challenge ◽  
Endotoxin Exposure ◽  
Tnf Α

Sepsis is a syndrome associated with excessive inflammation. Since mortality from sepsis remains high, more laboratory research is needed to provide insight into more effective ways to use novel, potentially more beneficial agents in sepsis. We investigated the ex vivo immunomodulatory effect of a novel polyclonal Ab preparation, trimodulin, containing IgM (∼23%), IgA (∼21%) and IgG (∼56%). Using whole blood and purified PBMCs from healthy volunteers and patients with sepsis, various ex vivo investigations upon endotoxin challenge and pre- and post-trimodulin treatment were performed. Endotoxin-induced TNF-α secretion was noticeably lower with than without trimodulin, implying attenuation of the hyper-responsive state. Trimodulin also lowered TLR2, TLR4, CD11b and CD64 detection on LPS/lipoteichoic acid-stimulated monocytes. These responses were observed in cells from healthy volunteers only shortly after ex vivo endotoxin stimulation and in whole blood from patients with early-stage sepsis. Furthermore, trimodulin markedly reduced lymphocyte proliferation and release of pro- and anti-inflammatory cytokines, but did not affect phagocytosis or oxidative-burst activities of endoxin-stimulated cells. Thus, trimodulin mitigated monocyte and lymphocyte hyperinflammatory responses early after endotoxin exposure. Determining whether early in vivo administration of trimodulin will elicit similar positive immunomodulatory effects and offer a clinical benefit warrants investigation.

scholarly journals Blood Plasma Quality Control by Plasma Glutathione Status

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 864
Author(s):  
Tamara Tomin ◽  
Natalie Bordag ◽  
Elmar Zügner ◽  
Abdullah Al-Baghdadi ◽  
Maximilian Schinagl ◽  
...  
Keyword(s):  
Quality Control ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Linear Increase ◽  
Clinical Parameters ◽  
Clinical Environment ◽  
Lactate Dehydrogenase Activity ◽  
Glutathione Status ◽  
Potential Marker ◽  
Downstream Analysis

Timely centrifugation of blood for plasma preparation is a key step to ensure high plasma quality for analytics. Delays during preparation can significantly influence readouts of key clinical parameters. However, in a routine clinical environment, a strictly controlled timeline is often not feasible. The next best approach is to control for sample preparation delays by a marker that provides a readout of the time-dependent degradation of the sample. In this study, we explored the usefulness of glutathione status as potential marker of plasma preparation delay. As the concentration of glutathione in erythrocytes is at least two orders of magnitude higher than in plasma, even the slightest leakage of glutathione from the cells can be readily observed. Over the 3 h observation period employed in this study, we observed a linear increase of plasma concentrations of both reduced (GSH) and oxidized glutathione (GSSG). Artificial oxidation of GSH is prevented by rapid alkylation with N-ethylmaleimide directly in the blood sampling vessel as recently published. The observed relative leakage of GSH was significantly higher than that of GSSG. A direct comparison with plasma lactate dehydrogenase activity, a widely employed hemolysis marker, clearly demonstrated the superiority of our approach for quality control. Moreover, we show that the addition of the thiol alkylating reagent NEM directly to the blood tubes does not influence downstream analysis of other clinical parameters. In conclusion, we report that GSH gives an excellent readout of the duration of plasma preparation and the associated pre-analytical errors.

Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

1986 ◽  
Vol 56 (01) ◽  
pp. 001-005 ◽  
Author(s):  
M Verstraete ◽  
C A P F Su ◽  
P Tanswell ◽  
W Feuerer ◽  
D Collen
Keyword(s):  
Healthy Volunteers ◽  
Plasminogen Activator ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
State Level ◽  
Compartment Model ◽  
Tissue Type ◽  
Maximum Plasma ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t½α = 5.7 min, a t½β = 1.3 h and a total clearance of 380 ml/min.Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and α2-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

scholarly journals Viscoelastometry for detecting oral anticoagulants

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Philipp Groene ◽  
Daniela Wagner ◽  
Tobias Kammerer ◽  
Lars Kellert ◽  
Andreas Giebl ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Prospective Observational Study ◽  
Oral Anticoagulants ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Clotting Time ◽  
Emergency Situations ◽  
Tissue Plasminogen ◽  
The Impact

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. Conclusions In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. Trial registration German clinical trials database ID: DRKS00015302.

Women with high plasma levels of PBDE-47 are at increased risk of preterm birth

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Morgan R. Peltier ◽  
Michael J. Fassett ◽  
Yuko Arita ◽  
Vicki Y. Chiu ◽  
Jiaxiao M. Shi ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Los Angeles ◽  
Polybrominated Diphenyl Ethers ◽  
Flame Retardants ◽  
Plasma Concentrations ◽  
First Trimester ◽  
High Plasma ◽  
Thyroid Stimulating Hormone ◽  
Spontaneous Preterm Birth ◽  
Increased Risk

Abstract Objectives Nearly 100% of North American women have detectable levels of flame retardants such as polybrominated diphenyl ethers (PBDEs) in their plasma. These molecules have structural homology to thyroid hormones and may function as endocrine disruptors. Thyroid dysfunction has previously been associated with increased risk for preterm birth. Therefore, we conducted a multi-center, case-cohort study to evaluate if high plasma concentrations of a common PBDE congener in the first trimester increases the risk of preterm birth and its subtypes. Methods Pregnant women were recruited at the onset of initiation of prenatal care at Kaiser-Permanente Southern California (KPSC)-West Los Angeles and KPSC-San Diego medical centers. Plasma samples from women whose pregnancies ended preterm and random subset of those delivering at term were assayed for PBDE-47 and thyroid-stimulating hormone (TSH) by immunoassay. Quartile cutoffs were calculated for the patients at term and used to determine if women with exposures in the 4th quartile are at increased risk for preterm birth using logistic regression. Results We found that high concentrations of PBDE-47 in the first trimester significantly increased the odds of both indicated (adjusted odds ratio, adjOR=2.35, 95% confidence interval [CI]: 1.31, 4.21) and spontaneous (adjOR=1.76, 95% CI: 1.02, 3.03) preterm birth. Regardless of pregnancy outcome, TSH concentrations did not differ between women with high and low concentrations of PBDE-47. Conclusions These results suggest that high plasma concentrations of PBDE-47 in the first trimester, increases the risk of indicated and spontaneous preterm birth.

scholarly journals Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 278
Author(s):  
Jennifer Lagoutte-Renosi ◽  
Bernard Royer ◽  
Vahideh Rabani ◽  
Siamak Davani
Keyword(s):  
Active Metabolite ◽  
Plasma Concentrations ◽  
Antiplatelet Agent ◽  
High Plasma ◽  
Therapeutic Drug ◽  
Routine Practice ◽  
Daily Routine ◽  
Limit Of Quantification ◽  
Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

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