Maximal flow rates and sieving coefficients in different plasmafilters: Effects of increased membrane surfaces and effective length under standardized in vitro conditions

Abstract Background To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Methods Apixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was utilized to provide dosing estimations for flow rates from 0.5–5 L/h. Results Mean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 2.5–7.5 mg twice daily (BID) may be needed for flow rates ranging from 0.5–5 L/h, respectively. Conclusion For CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

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Phosphoinositides Regulate Membrane-dependent Actin Assembly by Latex Bead Phagosomes

Molecular Biology of the Cell ◽

10.1091/mbc.01-06-0314 ◽

2002 ◽

Vol 13 (4) ◽

pp. 1190-1202 ◽

Cited By ~ 51

Author(s):

Hélène Defacque ◽

Evelyne Bos ◽

Boyan Garvalov ◽

Cécile Barret ◽

Christian Roy ◽

...

Keyword(s):

Binding Sites ◽

Kinase Activity ◽

Kinase Inhibitors ◽

Membrane Surface ◽

Latex Bead ◽

Actin Assembly ◽

Wild Type ◽

Membrane Surfaces ◽

Organelle Membrane

Actin assembly on membrane surfaces is an elusive process in which several phosphoinositides (PIPs) have been implicated. We have reconstituted actin assembly using a defined membrane surface, the latex bead phagosome (LBP), and shown that the PI(4,5)P2-binding proteins ezrin and/or moesin were essential for this process ( Defacque et al., 2000b ). Here, we provide several lines of evidence that both preexisting and newly synthesized PI(4,5)P2, and probably PI(4)P, are essential for phagosomal actin assembly; only these PIPs were routinely synthesized from ATP during in vitro actin assembly. Treatment of LBP with phospholipase C or with adenosine, an inhibitor of type II PI 4-kinase, as well as preincubation with anti-PI(4)P or anti-PI(4,5)P2 antibodies all inhibited this process. Incorporation of extra PI(4)P or PI(4,5)P2 into the LBP membrane led to a fivefold increase in the number of phagosomes that assemble actin. An ezrin mutant mutated in the PI(4,5)P2-binding sites was less efficient in binding to LBPs and in reconstituting actin assembly than wild-type ezrin. Our data show that PI 4- and PI 5-kinase, and under some conditions also PI 3-kinase, activities are present on LBPs and can be activated by ATP, even in the absence of GTP or cytosolic components. However, PI 3-kinase activity is not required for actin assembly, because the process was not affected by PI 3-kinase inhibitors. We suggest that the ezrin-dependent actin assembly on the LBP membrane may require active turnover of D4 and D5 PIPs on the organelle membrane.

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Assessment of Possible Thermal Damage of Tissue due to Atherectomy by Means of a Mechanical Debulking Device

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-191982 ◽

2008 ◽

Cited By ~ 4

Author(s):

Ryang D. Lovik ◽

John P. Abraham ◽

Eph M. Sparrow

Keyword(s):

Numerical Simulations ◽

Thermal Injury ◽

Thermal Damage ◽

Threshold Value ◽

Posterior Tibial Artery ◽

Artery Wall ◽

Flow Rates ◽

Injury Index ◽

Orbital Atherectomy

In vitro and cadaver experiments, coupled with numerical simulations, were performed to assess the possibility that orbital atherectomy might cause thermal damage of tissue. The experiments involved debulking operations on a surrogate artery and on the plaque-lined posterior tibial artery of a cadaver. Temperatures and coolant flow rates measured during these experiments enabled a numerical simulation of the debulking of a plaque-lined artery in a living human. The temperature variations from the numerical simulations were used to evaluate a thermal injury index. The resulting values of the index were found to be several orders of magnitude below the threshold value for thermal injury. It is concluded that it is extremely unlikely that the use of an orbital debulking device, the Diamondback 360°™ (Cardiovascular Systems, Inc.), can lead to thermal injury of the artery wall.

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In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model

Frontiers in Pharmacology ◽

10.3389/fphar.2021.702455 ◽

2021 ◽

Vol 12 ◽

Author(s):

M G Vossen ◽

S Pferschy ◽

C Milacek ◽

M Haidinger ◽

Mario Karolyi ◽

...

Keyword(s):

Blood Flow ◽

Renal Replacement Therapy ◽

Protein Binding ◽

Replacement Therapy ◽

Flow Rate ◽

Blood Flow Rate ◽

Bovine Blood ◽

Flow Rates ◽

Dialysate Flow Rate

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy.Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma.Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min.Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

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Co-Administration of Drugs and Parenteral Nutrition: In Vitro Compatibility Studies of Loop Diuretics for Safer Clinical Practice

Pharmaceutics ◽

10.3390/pharmaceutics12111092 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1092

Author(s):

Szymon Tomczak ◽

Maciej Stawny ◽

Anna Jelińska

Keyword(s):

Clinical Practice ◽

Zeta Potential ◽

Parenteral Nutrition ◽

Lipid Emulsion ◽

Droplet Diameter ◽

Loop Diuretics ◽

Compatibility Studies ◽

Emulsion Droplet ◽

Flow Rates

Parenteral nutrition (PN) admixtures are prone to interacting with drugs administered intravenously via a common catheter. This may cause a threat to a patient’s health and life. The literature that has been reported on the compatibility of loop diuretics with PN presents conflicting results. This work aimed to study the compatibility of furosemide and torsemide with PN used in clinical practice. Undiluted solutions of drugs were mixed with PN at various ratios determined by flow rates. In order to assess compatibility, visual control was followed by pH measurement, osmolality, mean emulsion droplet diameter (MDD), and zeta potential upon mixing and at 4 h of storage. No macroscopic changes that indicated lipid emulsion degradation were observed. After the addition of the drugs, the value of pH ranged from 6.37 ± 0.01 to 7.38 ± 0.01. The zeta potential was in reverse proportion to the drug concentration. The addition of the drugs did not affect the MDD. It may be suggested that the co-administration of furosemide or torsemide and PN caused no interaction. The absence of such signs of unwanted interactions allowed for the co-administration of the mentioned loop diuretics and PN at each of the studied ratios.

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Clearance of Levofloxacin by an in Vitro Model of Continuous Venovenous Hemodialysis (CVVHD)

The International Journal of Artificial Organs ◽

10.1177/039139880703001005 ◽

2007 ◽

Vol 30 (10) ◽

pp. 889-895 ◽

Cited By ~ 2

Author(s):

S. Siewert ◽

B. Drewelow ◽

S.C. Mueller

Keyword(s):

In Vitro Model ◽

Urea Clearance ◽

Flow Rates ◽

Dialysate Flow ◽

Dialysate Flow Rate ◽

Continuous Venovenous Hemodialysis ◽

Vitro Model ◽

Positive Correlations

Information about the elimination and the adequate dosing of levofloxacin during renal replacement therapy is scarce. The aim of this study was to characterize in vitro the elimination of levofloxacin during continuous venovenous hemodialysis (CVVHD) and to investigate whether the CVVHD clearances of creatinine and urea are correlated with the levofloxacin clearance in order to facilitate dosage adjustments. An in vitro model of CVVHD was established using five dialyzer membranes at varying dialysate flow rates applied in the clinical setting (8, 16, 25, 33 and 41 ml/min). Plasma and dialysate samples were drawn for determination of levofloxacin, creatinine and urea concentrations to evaluate clearances by CVVHD. During CVVHD, the clearance of levofloxacin varied between 9.02 and 33.30 ml/min, depending on the chosen setup. Positive correlations (p<0.001) were received for: dialysate flow rate (QD) and creatinine/urea clearances (R>0.93); QD and levofloxacin clearance (R 0.59–0.71); levofloxacin and creatinine clearance (R 0.69–0.75); and levofloxacin and urea clearance (R 0.56–0.75) as well. When dosing critically ill patients, therefore, extracorporeal as well as total clearance of levofloxacin should be considered.

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CFD Challenge: Solutions Using the In-House Finite-Element-Based Solver NEWTETR

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80509 ◽

2012 ◽

Author(s):

Yiemeng Hoi ◽

David A. Steinman

Keyword(s):

Steady State ◽

Pressure Measurements ◽

Surface Geometry ◽

Flow Rates ◽

Pressure Drops ◽

Or Groups ◽

Giant Cerebral Aneurysm ◽

Pulsatile Pressure ◽

Nominal Surface

Briefly, this Challenge aims to test the sensitivity of steady and pulsatile pressure drops as predicted by different CFD solvers or groups, and ultimately against in vitro pressure measurements. The current study focuses on the Phase I of the Challenge. We simulated steady state and pulsatile pressure drops based on the nominal surface geometry and specific inlet flow rates on a giant cerebral aneurysm with proximal stenosis.

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Variability in Infusion Pressure and Continuous Flow Rate Delivered from Pressurized Bag Pump Flush Systems

Anaesthesia and Intensive Care ◽

10.1177/0310057x0203000313 ◽

2002 ◽

Vol 30 (3) ◽

pp. 341-347 ◽

Cited By ~ 1

Author(s):

M. I. Hug ◽

V. Buettiker ◽

A. Cornelius ◽

M. Weiss

Keyword(s):

Continuous Flow ◽

Fluid Overload ◽

Flow Rates ◽

Small Children ◽

In Vitro Experiment ◽

Arterial Circulation ◽

Infusion Pressure ◽

Considerable Impact ◽

Vertical Level

Using 10 different infusion bag pressure pumps, indicated manometer pressures were compared with measured infusion pressures proximal to the flow-regulating device in an in vitro experiment. Flow rates delivered through the flow-regulating device were gravimetrically measured at different monitored pressure levels. Significant differences were found between manometer and measured infusion pressures among the tested pressure bag pumps (e.g. 500 ml bag volume pressurized to 300mmHg manometer pressure: 219.6±7.8 to 407.2±2.7 mmHg). The infusion pressures were additionally affected by the vertical level of the infusion bag pump and by the volume of the infusion bag. Flow rates delivered through the flow-regulating device were directly correlated to the measured infusion pressure (r 2 =0.9926). Differences in flow rates can have a considerable impact on maintaining catheter patency and avoidance of fluid overload and retrograde flushing into the central arterial circulation in neonates and small children. A simple manoeuvre using the invasive pressure transducer allows monitoring and adjustment of the infusion pressure in the clinical setting.

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