scholarly journals Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

Author(s):  
David Busse ◽  
Philipp Simon ◽  
Lisa Schmitt ◽  
David Petroff ◽  
Christoph Dorn ◽  
...  
2020 ◽  
Vol 40 (4) ◽  
pp. 929-942 ◽  
Author(s):  
Nicolas Tessandier ◽  
Imene Melki ◽  
Nathalie Cloutier ◽  
Isabelle Allaeys ◽  
Adam Miszta ◽  
...  

Objective: The lymphatic system is a circulatory system that unidirectionally drains the interstitial tissue fluid back to blood circulation. Although lymph is utilized by leukocytes for immune surveillance, it remains inaccessible to platelets and erythrocytes. Activated cells release submicron extracellular vesicles (EV) that transport molecules from the donor cell. In rheumatoid arthritis, EV accumulate in the joint where they can interact with numerous cellular lineages. However, whether EV can exit the inflamed tissue to recirculate is unknown. Here, we investigated whether vascular leakage that occurs during inflammation could favor EV access to the lymphatic system. Approach and Results: Using an in vivo model of autoimmune inflammatory arthritis, we show that there is an influx of platelet EV, but not EV from erythrocytes or leukocytes, in joint-draining lymph. In contrast to blood platelet EV, lymph platelet EV lacked mitochondrial organelles and failed to promote coagulation. Platelet EV influx in lymph was consistent with joint vascular leakage and implicated the fibrinogen receptor α2bβ 3 and platelet-derived serotonin. Conclusions: These findings show that platelets can disseminate their EV in fluid that is inaccessible to platelets and beyond the joint in this disease.


BMJ ◽  
1973 ◽  
Vol 1 (5853) ◽  
pp. 569-573 ◽  
Author(s):  
G. D. Chisholm ◽  
P. M. Waterworth ◽  
J. S. Calnan ◽  
L. P. Garrod

1950 ◽  
Vol 33 (5) ◽  
pp. 525-534 ◽  
Author(s):  
Max Kleiber ◽  
Arthur H. Smith ◽  
N. P. Ralston

Radiophosphate was injected into the left jugular vein of dairy cows. Blood samples were taken frequently from the right jugular vein during the first hour after injection. Between 20 minutes and 1 hour after injection, the decrease in plasma radioactivity could be formulated as a first order process, designated as "process 3," with a turnover time of 50 minutes. From 5 to 20 minutes after injection the decrease in plasma activity could be interpreted as the result of mixing plasma phosphate with another phosphate pool, designated as the second pool. The capacity of this second pool was derived as a constant in a kinetic equation, so chosen that the resulting mixing rates were independent of time. For two cows the capacity of the second pool was 5 and 8 times, respectively. the phosphate content of the plasma. This result led to the working hypothesis that the major part of the second pool was the phosphate in the interstitial tissue fluid. The turnover time of the plasma phosphate in the mixing process with the second pool amounted to an average of 14 minutes for 5 lactating cows, and an average of 21 minutes for 2 dry cows. This result was obtained under the assumption that the slow first order process 3 is parallel to the mixing process. The assumption that the slower first order process is in series with the mixing process reduces the resulting mixing time to about four-fifths of that reported above. The calculation of process 2 which deviates from first order may be applicable to numerous turnover processes in which both exchange pools have a limited capacity.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1380
Author(s):  
David Busse ◽  
Philipp Simon ◽  
David Petroff ◽  
Christoph Dorn ◽  
Lisa Schmitt ◽  
...  

Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3–4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%fT>MIC). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %fT>2×MIC instead of %fT>4×MIC during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %fT>MIC = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %fT>MIC = 98) of piperacillin/tazobactam.


Infection ◽  
1976 ◽  
Vol 4 (S2) ◽  
pp. S123-S130 ◽  
Author(s):  
G. D. Chisholm ◽  
C. B. Smith ◽  
Pamela M. Waterworth ◽  
J. S. Calnan

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 785 ◽  
Author(s):  
Rhonda Flores ◽  
Xueting Jin ◽  
Janet Chang ◽  
Connie Zhang ◽  
David G. Cogan ◽  
...  

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular connective tissue matrix of the cornea stroma in individuals with genetic deficiency of LCAT. LCAT can be activated by apolipoproteins (Apo) including ApoD and ApoA1. ApoA1 also mediates cellular synthesis of HDL. This study examined the expression of LCAT by epithelial cells, keratocytes, and endothelial cells, the cell types that comprise from anterior to posterior the three layers of the cornea. LCAT and ApoD were immunolocalized to all three cell types within the cornea, while ApoA1 was immunolocalized to keratocytes and endothelium but not epithelium. In situ hybridization was used to detect LCAT, ApoD, and ApoA1 mRNA to learn what cell types within the cornea synthesize these proteins. No corneal cells showed mRNA for ApoA1. Keratocytes and endothelium both showed ApoD mRNA, but epithelium did not. Epithelium and endothelium both showed LCAT mRNA, but despite the presence of LCAT protein in keratocytes, keratocytes did not show LCAT mRNA. RNA sequencing analysis of serum-cultured dedifferentiated keratocytes (commonly referred to as corneal stromal fibroblasts) revealed the presence of both LCAT and ApoD (but not ApoA1) mRNA, which was accompanied by their respective proteins detected by immunolabeling of the cultured keratocytes and Western blot analysis of keratocyte lysates. The results indicate that keratocytes in vivo show both ApoA1 and LCAT proteins, but do not synthesize these proteins. Rather, keratocytes in vivo must take up ApoA1 and LCAT from the corneal interstitial tissue fluid.


Chemotherapy ◽  
1979 ◽  
Vol 25 (6) ◽  
pp. 329-335 ◽  
Author(s):  
M.V. Vicente ◽  
T. Olay ◽  
M.C.R. Quecedo ◽  
A. Rodríguez

1983 ◽  
Vol 25 (3) ◽  
pp. 333-338 ◽  
Author(s):  
C. Fernandez Lastra ◽  
E. L. Mari�o ◽  
A. Dominguez-Gil ◽  
J. M. Tabernero ◽  
A. Gonzalez Lopez ◽  
...  

Author(s):  
Toichiro Kuwabara

Although scanning electron microscopy has a great potential in biological application, there are certain limitations in visualization of the biological structure. Satisfactory techniques to demonstrate natural surfaces of the tissue and the cell have been reported by several investigators. However, it is commonly found that the surface cell membrane is covered with a minute amount of mucin, secretory substance or tissue fluid as physiological, pathological or artefactual condition. These substances give a false surface appearance, especially when the tissue is fixed with strong fixatives. It seems important to remove these coating substances from the surface of the cell for demonstration of the true structure.


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