scholarly journals Bleomycin Concentration in Patients’ Plasma and Tumors after Electrochemotherapy. A Study from InspECT Group

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1324
Author(s):  
Ales Groselj ◽  
Masa Bosnjak ◽  
Mojca Krzan ◽  
Tina Kosjek ◽  
Kriszta Bottyán ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Concentration Profile ◽  
Plasma Clearance ◽  
Tumor Response ◽  
Pharmacokinetic Profile ◽  
Time Interval ◽  
Concentration Data ◽  
Younger Patients ◽  
Electric Pulses ◽  
Distribution Phase

The plasma concentration profile of bleomycin in the distribution phase of patients younger than 65 years is needed to determine the suitable time interval for efficient application of electric pulses during electrochemotherapy. Additionally, bleomycin concentrations in the treated tumors for effective tumor response are not known. In this study, the pharmacokinetic profile of bleomycin in the distribution phase in 12 patients younger than 65 years was determined. In 17 patients, the intratumoral bleomycin concentration was determined before the application of electric pulses. In younger patients, the pharmacokinetics of intravenously injected bleomycin demonstrated a faster plasma clearance rate than that in patients older than 65 years. This outcome might indicate that the lowering of the standard bleomycin dose of 15,000 IU/m2 with intravenous bleomycin injection for electrochemotherapy is not recommended in younger patients. Based on the plasma concentration data gathered, a time interval for electrochemotherapy of 5–15 min after bleomycin injection was determined. The median bleomycin concentration in tumors 8 min after bleomycin injection, at the time of electroporation, was 170 ng/g. Based on collected data, the reduction of the bleomycin dose is not recommended in younger patients; however, a shortened time interval for application of electric pulses in electrochemotherapy to 5–15 min after intravenous bleomycin injection should be considered.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Usman Arshad ◽  
Max Taubert ◽  
Tamina Seeger-Nukpezah ◽  
Sami Ullah ◽  
Kirsten C. Spindeldreier ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Large Cohort ◽  
Therapeutic Drug ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Concentration Data ◽  
Dose Methotrexate

Abstract Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

Comparison of the Effect-site keOs of Propofol for Blood Pressure and EEG Bispectral Index in Elderly and Younger Patients

1999 ◽  
Vol 90 (6) ◽  
pp. 1517-1527. ◽  
Author(s):  
Tomiei Kazama ◽  
Kazuyuki Ikeda ◽  
Koji Morita ◽  
Mutsuhito Kikura ◽  
Matsuyuki Doi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Concentration ◽  
Bispectral Index ◽  
Time Course ◽  
Drug Infusion ◽  
Time Data ◽  
Aged Patients ◽  
Younger Patients ◽  
Spectral Edge Frequency ◽  
Effect Site

Background Drug effect lags behind the blood concentration. The goal of this investigation was to determine the time course of plasma concentration and the effects of propofol demonstrated by electroencephalogram or blood pressure changes and to compare them between elderly and young or middle-aged patients. Methods A target-controlled infusion was used to rapidly attain and maintain four sequentially increasing, randomly selected plasma propofol concentrations from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and systolic blood pressure (SBP) were used as measures of propofol effect. Because the time courses of these measures following the started drug infusion showed an exponential pattern, the first-order rate constant for equilibration of the effect site with the plasma concentration (k(eO)) was estimated by fitting a monoexponential model to the effect versus time data resulting from the pseudo-steady-state propofol plasma concentration profile. Results The half-times for the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11 each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the respective age groups. All were significantly longer than for BIS (P < 0.05). The propofol concentration at half of the maximal decrease of SBP was significantly greater (P < 0.05) in the elderly than in the younger patients. Conclusions The effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age, SBP decreases to a greater degree but more slowly.

scholarly journals The Influence of Sampling Site upon the Distribution Phase Kinetics of Thiopentone

1984 ◽  
Vol 12 (1) ◽  
pp. 5-8 ◽  
Author(s):  
Robin Barrett ◽  
G. G. Graham ◽  
T. A. Torda
Keyword(s):  
Plasma Concentration ◽  
Intravenous Administration ◽  
Femoral Artery ◽  
Time Course ◽  
Sampling Site ◽  
Acute Tolerance ◽  
Hplc Assay ◽  
Distribution Phase ◽  
Kinetics Of

In six sheep anaesthetised with ketamine blood was sampled from the jugular and femoral veins and the femoral artery at frequent intervals for 12 minutes following the intravenous administration of 5 or 10 mg/kg sodium thiopentone. Samples were also taken from cubital veins and radial arteries of five patients who received 5 mg/kg thiopentone. The plasma concentration of thiopentone was determined by an HPLC assay. The time course of plasma concentration of thiopentone showed considerable variation according to sampling site as well as variation between individuals. Such sampling site-dependent variation may result in the appearance of acute tolerance.

Transvascular albumin and IgG flux in skin after a continuous 3-h bradykinin infusion

1992 ◽  
Vol 263 (4) ◽  
pp. H1064-H1070
Author(s):  
J. R. Wallace ◽  
D. R. Bell
Keyword(s):  
Plasma Concentration ◽  
Femoral Artery ◽  
Plasma Clearance ◽  
Initial Response ◽  
Sustained Response ◽  
Distribution Space ◽  
Endothelial Gaps ◽  
Ig G ◽  
Endogenous Albumin ◽  
Sustained Increase

Bradykinin (1 microgram/min) was infused into the femoral artery of one hindleg of anesthetized rabbits for 3 h. Measurements of the initial extravascular uptake for labeled albumin and immunoglobulin (Ig) G were compared with measurements of the lymph protein flux for endogenous albumin and IgG. With bradykinin, the initial extravascular uptake for both albumin and IgG, calculated as the 1-h extravascular distribution space at plasma concentration divided by time and expressed as a plasma clearance, was 12 times the control values. For both proteins, the lymph fluxes were not significantly greater than the values for extravascular uptake, indicating that the sustained increase in lymph protein flux was not due to washout of interstitial protein. The extravascular uptake for IgG was approximately 80% of that for albumin in both control and bradykinin animals, suggesting that the sustained response did not change the selectivity between the two proteins. Changes in the extravascular masses of endogenous albumin and IgG suggest that the initial response to bradykinin was a transient formation of endothelial gaps that did not restrict transvascular IgG transport more than albumin.

Radiochemical method for measuring plasma clearance and urinary excretion of pteroylglutamic acid.

1979 ◽  
Vol 25 (10) ◽  
pp. 1783-1786
Author(s):  
M da Costa ◽  
S P Rothenberg ◽  
Z Rosenberg
Keyword(s):  
Urinary Excretion ◽  
Plasma Clearance ◽  
Normal Subjects ◽  
Serum Folate ◽  
Metabolic Clearance ◽  
Folate Binding Protein ◽  
Radiochemical Method ◽  
Baseline Serum ◽  
Distribution Phase

Abstract A radiochemical procedure is described for specific determination of pteroylglutamate in serum and urine. This method depends on denaturation of methyltetrahydrofolate with peroxide and measurement of the residual folate by a ligand-binding radioassay. The binding determinant for the radioassay is a folate-binding protein, partially purified from chronic myelogenous lekemia cells, that has low affinity for the reduced folates and thus will preferentially measure residual pteroylglutamate rather than any nondenatured residual methyltetrahydrofolate. We used this assay to measure the clearance from plasma and the urinary excretion of pteroylglutamate and a small fraction of serum folate that is stable to this oxidation procedure. The plasma clearance after intravenous injection is characterized by an initial rapid distribution phase followed by a second, slower metabolic phase; after about 2 h all of the administered pteroylglutamate has been cleared from the blood. The peak concentration of total folate in serum 1--2 min after administration of pteroylglutamate exceeded the sum of the endogenous stable and baseline serum folate, indicating that a reduced labile folate was released from the liver and perhaps from other tissues. This reduced folate had a slower metabolic clearance rate and was excreted to some extent in urine. Only 2.3 and 7.9% of the pteroylglutamate administered to two normal subjects was excreted as stable folate.

scholarly journals The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

1987 ◽  
Vol 15 (1) ◽  
pp. 7-14 ◽  
Author(s):  
D. R. Stanski
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Metabolic Clearance ◽  
Drug Infusion ◽  
Fixed Rate ◽  
Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

Plasmatic diatrizoate-I131 disappearance and glomerular filtration in the dog

1963 ◽  
Vol 204 (4) ◽  
pp. 536-540 ◽  
Author(s):  
M. Donald Blaufox ◽  
David R. Sanderson ◽  
W. Newlon Tauxe ◽  
Khalil G. Wakim ◽  
Alan L. Orvis ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Urinary Excretion ◽  
Creatinine Clearance ◽  
Glomerular Filtration ◽  
Biliary Excretion ◽  
Plasma Clearance ◽  
Compartment System ◽  
Intravenous Injections

A study was made of the disappearance of sodium diatrizoate-I131 from the plasma of ten dogs after single intravenous injections. The plasma disappearance curves suggested a two-compartment system. The renal plasma clearance of diatrizoate-I131 calculated from these curves and the conventional renal plasma clearance of creatinine were not statistically different. Clearances calculated from the urinary excretion and midperiod plasma concentration of radioactivity in four experiments yielded values averaging 10% less than the creatinine clearance. Chromatographic studies of commercially available diatrizoate-I131 revealed the presence of about 5% free iodide and of about 5% of unidentified impurities. These impurities seem to account, partly at least, for the differences found between diatrizoate clearance and creatinine clearance. Biliary excretion and erythrocytic uptake of diatrizoate were minimal and did not appear to influence the analysis.

scholarly journals L-Dopa Pharmacokinetic Profile with Effervescent Melevodopa/Carbidopa versus Standard-Release Levodopa/Carbidopa Tablets in Parkinson’s Disease: A Randomised Study

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Fabrizio Stocchi ◽  
Laura Vacca ◽  
Paola Grassini ◽  
Stephen Pawsey ◽  
Holly Whale ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Concentration ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Randomised Study ◽  
Effervescent Tablet

Objectives.To characterize the pharmacokinetic profile of levodopa (L-dopa) and carbidopa after repeated doses of the effervescent tablet of melevodopa/carbidopa (V1512; Sirio) compared with standard-release L-dopa/carbidopa in patients with fluctuating Parkinson’s disease. Few studies assessed the pharmacokinetics of carbidopa to date.Methods.This was a single-centre, randomized, double-blind, double-dummy, two-period crossover study. Patients received V1512 (melevodopa 100 mg/carbidopa 25 mg) or L-dopa 100 mg/carbidopa 25 mg, 7 doses over 24 hours (Cohort 1), 4 doses over 12 hours (Cohort 2), or 2 doses over 12 hours in combination with entacapone 200 mg (Cohort 3). Pharmacokinetic parameters included area under the plasma-concentration time curve (AUC), maximum plasma concentration (Cmax), and time toCmax(tmax).Results.Twenty-five patients received at least one dose of study medication. L-dopa absorption tended to be quicker and pharmacokinetic parameters less variable after V1512 versus L-dopa/carbidopa, both over time and between patients. Accumulation of L-dopa in plasma was less noticeable with V1512. Carbidopa exposure and interpatient variability was lower when V1512 or L-dopa/carbidopa was given in combination with entacapone. Both treatments were well tolerated.Conclusions.V1512 provides a more reliable L-dopa pharmacokinetic profile versus standard-release L-dopa/carbidopa, with less drug accumulation and less variability. This trial is registered with ClinicalTrials.govNCT00491998.

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