scholarly journals Early Phase Pharmacokinetics but Not Pharmacodynamics Are Influenced by Propofol Infusion Rate

2009 ◽  
Vol 111 (4) ◽  
pp. 805-817 ◽  
Author(s):  
Kenichi Masui ◽  
Marimo Kira ◽  
Tomiei Kazama ◽  
Satoshi Hagihira ◽  
Eric P. Mortier ◽  
...  
Keyword(s):  
Dose Rate ◽  
Rate Constant ◽  
Early Phase ◽  
Infusion Rate ◽  
Pharmacokinetic Model ◽  
Drug Effect ◽  
Lag Time ◽  
Time Shift ◽  
Pharmacokinetic Models ◽  
Arterial Blood

Background Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. Methods Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg . kg(-1). h(-1). Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. Results Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. Conclusions This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg . kg(-1). h(-1). The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.

Rates of insorption of sodium and potassium from upper small bowel of rats

1962 ◽  
Vol 203 (2) ◽  
pp. 225-228 ◽  
Author(s):  
Johann C. Moll ◽  
Charles F. Code
Keyword(s):  
Small Bowel ◽  
Rate Constant ◽  
Mean Values ◽  
Healthy Humans ◽  
Arterial Blood ◽  
Sodium And Potassium

Rates of insorption of radiosodium and radiopotassium from the unobstructed small bowel of rats were determined and compared with those obtained by others in healthy humans. Insorption of the isotopes under study was estimated by integration of their rates of appearance in the blood after placement in the small bowel and their rates of disappearance from blood after injection into the circulation. The rates of disappearance from arterial blood were determined during separate tests. They followed an exponential pattern similar though not identical with that reported from other species by other investigators. Radiosodium was insorbed more rapidly than radiopotassium. Mean values indicated that 50% of administered radiosodium was insorbed within 6–7 min, whereas 26–27 min were required for insorption of 50% of the radiopotassium. The rate constant during insorption of the first 76% of the Na22 was 10.8% per min and that for insorption of 58% of the K42 was 2.7% per min.

Semiparametric approach to pharmacokinetic-pharmacodynamic data

1989 ◽  
Vol 256 (4) ◽  
pp. R1005-R1010
Author(s):  
D. Verotta ◽  
S. L. Beal ◽  
L. B. Sheiner
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Drug Concentration ◽  
Venous Blood ◽  
Time Lag ◽  
Elimination Rate ◽  
Hysteresis Loops ◽  
Real Data ◽  
Elimination Rate Constant ◽  
Arterial Blood

A semiparametric model for analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non-steady-state experiments is presented. The model describes time lag between drug concentration in a sampling compartment, e.g., venous blood (Cv), and drug effect (E). If drug concentration at the effect site (Ce) equilibrates with arterial blood concentration (Ca) slower than with Cv, a non-steady-state experiment yields E vs. Cv data describing a counterclockwise hysteresis loop. If Ce equilibrates with Ca faster than with Cv, clockwise hysteresis is observed. To model hysteresis, a parametric model is proposed linking (unobserved) Ca to Cv with elimination rate constant kappa ov and also linking Ca to Ce with elimination rate constant kappa oe. When kappa oe is greater than (or less than) kappa ov clockwise (or counterclockwise) hysteresis occurs. Given kappa oe and kappa ov, numerical (constrained) deconvolution is used to obtain the disposition function of the arterial compartment (Ha), and convolution is used to calculate Ce given Ha. The values of kappa oe and kappa ov are chosen to collapse the hysteresis loops to single curves representing the Ce-E (steady-state) concentration-response curve. Simulations, and an application to real data, are reported.

Concentration–Effect Relation of Succinylcholine Chloride during Propofol Anesthesia

2002 ◽  
Vol 97 (5) ◽  
pp. 1082-1092 ◽  
Author(s):  
Julie J. Roy ◽  
François Donati ◽  
Daniel Boismenu ◽  
France Varin
Keyword(s):  
Rate Constant ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Quantitative Model ◽  
Concentration Effect ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Duration Of Action ◽  
Arterial Blood ◽  
Effect Relation

Background The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. Methods Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. Results The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. Conclusion Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

On the dose rate constant of the selectSeed I125 interstitial brachytherapy seed

2006 ◽  
Vol 33 (5) ◽  
pp. 1522-1523 ◽  
Author(s):  
Panagiotis Papagiannis ◽  
Loukas Sakelliou ◽  
Giorgos Anagnostopoulos ◽  
Dimos Baltas
Keyword(s):  
Dose Rate ◽  
Rate Constant ◽  
Interstitial Brachytherapy

Impact of the differential fluence distribution of brachytherapy sources on the spectroscopic dose-rate constant

2015 ◽  
Vol 42 (5) ◽  
pp. 2379-2388
Author(s):  
Martha J. Malin ◽  
Laura J. Bartol ◽  
Larry A. DeWerd
Keyword(s):  
Dose Rate ◽  
Rate Constant

Evaluating the clinical impact of a shortened infusion duration for ramucirumab: A population pharmacokinetic model-based approach.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 191-191
Author(s):  
Paolo Abada ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Study Data ◽  
Population Pharmacokinetic ◽  
Time Profiles ◽  
Concentration Time ◽  
Increased Risk ◽  
Grade 3 ◽  
Infusion Duration

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.

scholarly journals Perioperative metabolic acidosis: The Bradford Anaesthetic Department Acidosis Study

2018 ◽  
Vol 20 (1) ◽  
pp. 11-17 ◽  
Author(s):  
TO Lawton ◽  
A Quinn ◽  
SJ Fletcher
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Metabolic Acidosis ◽  
Early Phase ◽  
Time Course ◽  
Late Phase ◽  
Common Finding ◽  
Major Surgery ◽  
Arterial Blood ◽  
Early Fluid

Metabolic acidosis is considered deleterious but is common in post-surgical patients admitted to intensive care unit. We evaluated the prevalence and time course of metabolic acidosis in elective major surgery, and generated hypotheses about causes, by hourly arterial blood sampling in 92 patients. Metabolic acidosis began before incision and most had occurred by the next hour. Seventy-eight per cent of patients had a significant metabolic acidosis post-operatively. Two overlapping phases were observed. The early phase started before incision, characterised by a rising chloride and falling anion gap, unrelated to saline use. The late phase was partly associated with lactate, related to surgery type, and early fluids appeared protective. There was a trend towards longer intensive care unit (+1.3 days) and hospital (+3.2 days) stay with metabolic acidosis. This is the first large study of the evolution of this common finding, demonstrating a pre-incision component. The early phase appears unavoidable or unpredictable, but the late phase might be modified by early fluid administration. It remains unclear whether acidosis of this type should be avoided.

scholarly journals Dopamine does not limit fetal cerebrovascular responses to hypoxia

2007 ◽  
Vol 102 (1) ◽  
pp. 130-134 ◽  
Author(s):  
Dennis E. Mayock ◽  
Rachel Bennett ◽  
Roderick D. Robinson ◽  
Christine A. Gleason
Keyword(s):  
Infusion Rate ◽  
Perfusion Pressure ◽  
High Dose ◽  
Fetal Hypoxia ◽  
Fetal Sheep ◽  
Dopamine Infusion ◽  
Cerebrovascular Resistance ◽  
Arterial Blood ◽  
Cerebral Vasodilatation ◽  
Near Term

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 μg·kg−1·min−1 while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 ± 14.1% and CVR decreased 38.9 ± 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 μg·kg−1·min−1, begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 μg·kg−1·min−1. Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 μg·kg−1·min−1. This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.

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