DIRECT VERSUS TRACER MEASUREMENT OF TRANSFER RATES IN A HYDRODYNAMIC SYSTEM CONTAINING A COMPARTMENT WHOSE CONTENTS DO NOT INTERMIX RAPIDLY

1955 ◽  
Vol 33 (6) ◽  
pp. 940-947 ◽  
Author(s):  
Harry Schachter
Keyword(s):  
Model Experiment ◽  
Dynamic Equilibrium ◽  
Preceding Paper ◽  
Central Compartment ◽  
Water Transfer ◽  
Peripheral Compartment ◽  
Transfer Rates ◽  
Stop Watch ◽  
Crystal Violet Dye ◽  
Tracer Dilution

The working basis for the measurement of transfer rates between compartments developed in a preceding paper by Wrenshall is demonstrated for a closed hydrodynamic mammillary system in dynamic equilibrium. Rapid uniform intermixing of the water in one of the peripheral compartments was prevented by the presence there of glass tubelets. Rates of water transfer were measured directly with a graduate cylinder and stop watch, and calculated by means of equation [9] of the preceding paper, using crystal violet dye as tracer. It is clearly demonstrated that to measure transfer rates between the central compartment and the non-uniformly mixing peripheral compartment, it is necessary to extrapolate all tracer measurements to lime of tracer addition to the central compartment. The amount of water contained in the central compartment was measured in the same experiment both directly and by tracer dilution. The procedures and problems involved in performing the above model experiment are compared with those encountered in the tracer measurement of transfer rates and compartmental contents in living mammillary systems.

DIRECT VERSUS TRACER MEASUREMENT OF TRANSFER RATES IN A HYDRODYNAMIC SYSTEM CONTAINING A COMPARTMENT WHOSE CONTENTS DO NOT INTERMIX RAPIDLY

1955 ◽  
Vol 33 (1) ◽  
pp. 940-947 ◽  
Author(s):  
Harry Schachter
Keyword(s):  
Model Experiment ◽  
Dynamic Equilibrium ◽  
Preceding Paper ◽  
Central Compartment ◽  
Water Transfer ◽  
Peripheral Compartment ◽  
Transfer Rates ◽  
Stop Watch ◽  
Crystal Violet Dye ◽  
Tracer Dilution

The working basis for the measurement of transfer rates between compartments developed in a preceding paper by Wrenshall is demonstrated for a closed hydrodynamic mammillary system in dynamic equilibrium. Rapid uniform intermixing of the water in one of the peripheral compartments was prevented by the presence there of glass tubelets. Rates of water transfer were measured directly with a graduate cylinder and stop watch, and calculated by means of equation [9] of the preceding paper, using crystal violet dye as tracer. It is clearly demonstrated that to measure transfer rates between the central compartment and the non-uniformly mixing peripheral compartment, it is necessary to extrapolate all tracer measurements to lime of tracer addition to the central compartment. The amount of water contained in the central compartment was measured in the same experiment both directly and by tracer dilution. The procedures and problems involved in performing the above model experiment are compared with those encountered in the tracer measurement of transfer rates and compartmental contents in living mammillary systems.

WORKING BASIS FOR THE TRACER MEASUREMENT OF TRANSFER RATES OF A METABOLIC FACTOR IN BIOLOGICAL SYSTEMS CONTAINING COMPARTMENTS WHOSE CONTENTS DO NOT INTERMIX RAPIDLY

1955 ◽  
Vol 33 (6) ◽  
pp. 909-925 ◽  
Author(s):  
Gerald A. Wrenshall
Keyword(s):  
Chemical Element ◽  
Dynamic Equilibrium ◽  
Biological Systems ◽  
Central Compartment ◽  
Constrained Systems ◽  
Sources Of Information ◽  
Transfer Rates ◽  
Molecular Substances ◽  
Living Organisms

A working basis is developed for the simultaneous measurement, by means of an isotopic or other label, of all transfer rates of a given chemical element in systems where its transfer between spatially separate compartments of the system must occur by way of a central compartment (mammillary systems). In addition to the measurement of all rates of transfer, the amount of the element within each compartment of a mammillary system can be determined from the same experimental data. The method is applicable in open as well as closed mammillary systems which may or may not be in a state of dynamic equilibrium, and in which rapid uniform intermixing of the element does not occur in peripheral compartments. A basis for the determination of the total rates of appearance and disappearance of multiatomic as well as monatomic substances in any compartment of a system of compartments is presented, without exchanges being restricted to mammillary or other constrained systems. However, only in compartments where chemical transformation of such molecular substances does not occur can the calculated rates of appearance and disappearance of the metabolite be interpreted as rates of transfer into and out of the compartment. Specific problems relating to the tracer measurement of transfer rates in the mammillary systems of living organisms are considered, and a check list is presented for evaluating published experimental results involving tracers as potential sources of information on transfer rates in biological systems determined by means of the above bases for calculation.

WORKING BASIS FOR THE TRACER MEASUREMENT OF TRANSFER RATES OF A METABOLIC FACTOR IN BIOLOGICAL SYSTEMS CONTAINING COMPARTMENTS WHOSE CONTENTS DO NOT INTERMIX RAPIDLY

1955 ◽  
Vol 33 (1) ◽  
pp. 909-925 ◽  
Author(s):  
Gerald A. Wrenshall
Keyword(s):  
Chemical Element ◽  
Dynamic Equilibrium ◽  
Biological Systems ◽  
Central Compartment ◽  
Constrained Systems ◽  
Sources Of Information ◽  
Transfer Rates ◽  
Molecular Substances ◽  
Living Organisms

A working basis is developed for the simultaneous measurement, by means of an isotopic or other label, of all transfer rates of a given chemical element in systems where its transfer between spatially separate compartments of the system must occur by way of a central compartment (mammillary systems). In addition to the measurement of all rates of transfer, the amount of the element within each compartment of a mammillary system can be determined from the same experimental data. The method is applicable in open as well as closed mammillary systems which may or may not be in a state of dynamic equilibrium, and in which rapid uniform intermixing of the element does not occur in peripheral compartments. A basis for the determination of the total rates of appearance and disappearance of multiatomic as well as monatomic substances in any compartment of a system of compartments is presented, without exchanges being restricted to mammillary or other constrained systems. However, only in compartments where chemical transformation of such molecular substances does not occur can the calculated rates of appearance and disappearance of the metabolite be interpreted as rates of transfer into and out of the compartment. Specific problems relating to the tracer measurement of transfer rates in the mammillary systems of living organisms are considered, and a check list is presented for evaluating published experimental results involving tracers as potential sources of information on transfer rates in biological systems determined by means of the above bases for calculation.

scholarly journals Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Sarah Whalley ◽  
Freddie Mukasa Kibengo ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rate Constant ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
First Order ◽  
Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

scholarly journals Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 380 ◽  
Author(s):  
Quentin Allard ◽  
Zoubir Djerada ◽  
Claire Pouplard ◽  
Yohann Repessé ◽  
Dominique Desprez ◽  
...  
Keyword(s):  
Half Life ◽  
Random Effect ◽  
Real Life ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Severe Haemophilia ◽  
Fviii Activity ◽  
Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

scholarly journals A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

2014 ◽  
Vol 58 (11) ◽  
pp. 6735-6741 ◽  
Author(s):  
Michael Neely ◽  
Edward L. Kaplan ◽  
Jeffrey L. Blumer ◽  
Dennis J. Faix ◽  
Michael P. Broderick
Keyword(s):  
Young Adults ◽  
Central Compartment ◽  
Penicillin G ◽  
Simulated Patients ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Benzathine Penicillin ◽  
Final Population ◽  
Benzathine Penicillin G

ABSTRACTSerum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group AStreptococcus pyogenes(GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

scholarly journals Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Critical Illness ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Peripheral Compartment ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Intercompartmental Clearance

ABSTRACT The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h−1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h−1. A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

The Reactivating and Therapeutic Efficacy of Oximes to Counteract Russian VX Poisonings

2006 ◽  
Vol 25 (5) ◽  
pp. 397-401 ◽  
Author(s):  
Jiri Kassa ◽  
Daniel Jun ◽  
Kamil Kuca
Keyword(s):  
Therapeutic Efficacy ◽  
Central Compartment ◽  
Toxic Effects ◽  
Peripheral Compartment ◽  
Structural Analogue ◽  
Hi 6 ◽  
Alkyl Groups ◽  
Brain Acetylcholinesterase ◽  
Acute Toxic

Russian VX ( O-isobutyl- S-(2-diethylaminoethyl)methylphosphonothioate) is the structural analogue of VX agent. It differs from VX agent ( O-ethyl- S-(2-diisopropylaminoethyl) methylphosphonothioate) by two alkyl groups. The potency of currently available oximes (pralidoxime, obidoxime, HI-6) to reactivate Russian VX–inhibited acetylcholinesterase and to eliminate Russian VX–induced acute toxic effects was evaluated using in vivo methods. In vivo determined percentage of reactivation of Russian VX–inhibited blood and brain acetylcholinesterase in poisoned rats shows that HI-6 seems to be the most efficacious reactivator of Russian VX–inhibited acetylcholinesterase among currently used oximes in the peripheral compartment, whereas no difference between reactivating efficacy of all tested oximes was observed in the central compartment. The oxime HI-6 was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in Russian VX–poisoned mice among all studied oximes. Thus, the oxime HI-6 seems to be the most suitable oxime for the antidotal treatment of acute poisonings with Russian VX as in the case of VX, sarin, cyclosarin, and soman poisonings.

Seasonal patterns in body mass, body composition, and water transfer rates of free-ranging and captive black-tailed deer (Odocoileus hemionus sitkensis) in Alaska

1993 ◽  
Vol 71 (7) ◽  
pp. 1397-1404 ◽  
Author(s):  
Katherine L. Parker ◽  
Michael P. Gillingham ◽  
Thomas A. Hanley ◽  
Charles T. Robbins
Keyword(s):  
Body Composition ◽  
Body Mass ◽  
Body Fat ◽  
Energy Content ◽  
Odocoileus Hemionus ◽  
Water Transfer ◽  
Transfer Rates ◽  
In Captivity ◽  
Odocoileus Hemionus Sitkensis ◽  
Free Ranging

Body mass, body composition, and water transfer rates were determined over a continuous 2-year period in nine free-ranging Sitka black-tailed deer (Odocoileus hemionus sitkensis). Body masses showed a cyclical pattern, declined 14 – 31% between October and March, and were best described by a five-parameter, biologically based regression model. The amount of mass lost by black-tailed deer over winter depended on the peak body mass attained during fall. During winter, animals used 70 – 82% of their body fat and 10 – 15% of their protein reserves. Body fat was preferentially mobilized at rates 2.3 – 11.6 times higher than protein. Because of the higher energy content of fat, fat accounted for 83 – 92% of the catabolized energy. Water transfer rates varied seasonally with average summer values approximately four times those of winter; lactating deer had significantly higher rates of water transfer than nonlactating animals. Seasonal changes in all of the above parameters for wild deer were greater than those for eight deer of the same age in captivity.

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