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The main objective of this article is to propose the closed-form solution of one-compartment pharmacokinetic model with simultaneous first-order and Michaelis-Menten elimination for the case of constant infusion. For the case of bolus administration, we have previously established a closed-form solution of the model through introducing a transcendent X function. In the same vein, we found here a closed-form solution of constant infusion could be realized through introducing another transcendent Y function. For the general case of constant infusion of limited duration, the closed-form solution is then fully expressed using both X and Y functions. As direct results, several important pharmacokinetic surrogates, such as peak concentration [Formula: see text] and total drug exposure AUC[Formula: see text], are found the closed-form expressions and ready to be analyzed. The new pharmacokinetic knowledge we have gained on these parameters, which largely exhibits in a nonlinear feature, is in clear contrast to that of the linear case. Finally, with a pharmacokinetic model adapted from that formerly reported on phenytoin, we numerically analyzed and illustrated the roles of different model parameters and discussed their influence on drug exposure. To conclude, the present findings elucidate the intrinsic quantitative structural properties of such pharmacokinetic model and provide a new avenue for future modelling and rational drug designs.

A nonautonomous mathematical model of chemotherapy cancer treatment with time-dependent infusion concentration of the chemotherapy agent is developed and studied. In particular, a mutual inhibition type model is adopted to describe the interactions between the chemotherapy agent and cells, in which the chemotherapy agent is modeled as the prey being consumed by both cancer and normal cells, thereby reducing the population of both. Properties of solutions and detailed dynamics of the nonautonomous system are investigated, and conditions under which the treatment is successful or unsuccessful are established. It can be shown both theoretically and numerically that with the same amount of chemotherapy agent infused during the same period of time, a treatment with variable infusion may over perform a treatment with constant infusion.

Background: Accurate, precise and straightforward methods for measuring glomerular filtration rate (GFR) and/or renal plasma flow (RPF) are still in demand today. The time-consuming constant infusion technique (CIT) is the gold standard and preferred for research, whereas the simple, but less precise, single injection technique (SIT) is used in clinical settings. This study investigated the use of 99mTc-DTPA and 99mTc-MAG3 by CIT as a measure of renal function. We developed and evaluated a model to balance the primer dose and infusion rate in an attempt to obtain plasma steady state as quickly as possible. Methods: 14 healthy subjects received 99mTc-DTPA and 6 hypertensive patients received 99mTc-MAG3 in a standardized protocol. All participants had an eGFR above 60 ml/min and none had fluid retention. An intravenous primer injection of the relevant tracer was followed by a sustained infusion over 4.5 h with the same radiopharmaceutical. Blood and urine samples were collected at fixed intervals. Results: 99mTc-DTPA clearance reached steady state after 210 min (plasma clearance 78 ± 18 ml/min, urine clearance 110 ± 28 ml/min), whereas 99mTc-MAG3 clearance achieved steady state after 150 min (plasma clearance 212 ± 56 ml/min, urine clearance 233 ± 59 ml/min). Conclusion: Constant infusion technique with fixed primer and infusion rate using 99mTc-MAG3 is feasible for research purposes. The longer time for reaching plasma steady state using 99mTc-DTPA makes CIT with this tracer less optimal. If the primer/sustained balance can be optimized, for example using a priori SIT information, 99mTc-DTPA as tracer for CIT may also be feasible.

Target-controlled infusion (TCI) of propofol is used for general anesthesia. However, the only pharmacokinetic parameter commercially used for Japanese patients is weight, and pharmacokinetic models are based on European physical attributes. Drug metabolism also differs in races. This study aimed to identify optimal continuous doses of propofol for Japanese patients and to create a simulated pharmacokinetic (PK) model. Thirty Japanese patients were enrolled. Patients received a constant infusion of 9 mg/kg/h of propofol. Arterial blood samples were collected and the time course of plasma propofol concentrations was modeled using the nonlinear mixed effects model (NONMEM) three-compartmental PK model. We validated the model by intravenously injecting 10 patients with a TCI driver system programmed with the NONMEM model. Our model’s performance was evaluated using the median prediction error (MDPE), median absolute prediction error (MDAPE), and Wobble. We analyzed 320 blood samples for model building and 160 samples for validating our new model. The calculated parameters for the three-compartmental PK model were volume [V1, 3.58; V2, 13.0 + 0.49 × (Age—64); and V3, 186] and elimination clearance [CL1, 0.77 + (WT—54) × 0.04 + (HT—158) × 0.03; CL2, 0.89 + 0.12 × (Age—64); and CL3, 0.98 × exp ((Age—64)/10)]. The new model improved MDPE, MDAPE, and Wobble values (11.5% ± 43.8%, 14.3% ± 33.0%, and 25.0% ± 21.3%, respectively). We created a new pharmacokinetic model for Japanese patients, which is more accurate than the three existing models applied to Japanese populations. Electronic document is a “live” template. The various components of your paper [title, text, heads, etc.] are already defined on the style sheet, as illustrated by the portions given in this document.

Tumor-targeting bacteria elicit anticancer effects by infiltrating hypoxic regions, releasing toxic agents and inducing immune responses. Although current research has largely focused on the influence of chemical and immunological aspects on the mechanisms of bacterial therapy, the impact of physical effects is still elusive. Here, we propose a mathematical model for the anti-tumor activity of bacteria in avascular tumors that takes into account the relevant chemo-mechanical effects. We consider a time-dependent administration of bacteria and analyze the impact of bacterial chemotaxis and killing rate. We show that active bacterial migration towards tumor hypoxic regions provides optimal infiltration and that high killing rates combined with high chemotactic values provide the smallest tumor volumes at the end of the treatment. We highlight the emergence of steady states in which a small population of bacteria is able to constrain tumor growth. Finally, we show that bacteria treatment works best in the case of tumors with high cellular proliferation and low oxygen consumption.

Introduction The brain's energy budget can be non-invasively assessed with different imaging modalities such as functional MRI (fMRI) and PET (fPET), which are sensitive to oxygen and glucose demands, respectively. The introduction of hybrid PET/MRI systems further enables the simultaneous acquisition of these parameters. Although a recently developed method offers the quantification of task-specific changes in glucose metabolism (CMRGlu) in a single measurement, direct comparison of the two imaging modalities is still difficult because of the different temporal resolutions. Thus, we optimized the protocol and systematically assessed shortened task durations of fPET to approach that of fMRI. Methods Twenty healthy subjects (9 male) underwent one measurement on a hybrid PET/MRI scanner. During the scan, tasks were completed in four blocks for fMRI (4 × 30 s blocks) and fPET: participants tapped the fingers of their right hand repeatedly to the thumb while watching videos of landscapes. For fPET, subjects were randomly assigned to groups of n = 5 with varying task durations of 10, 5, 2 and 1 min, where task durations were kept constant within a measurement. The radiolabeled glucose analogue [18F]FDG was administered as 20% bolus plus constant infusion. The bolus increases the signal-to-noise ratio and leaves sufficient activity to detect task-related effects but poses additional challenges due to a discontinuity in the tracer uptake. First, three approaches to remove task effects from the baseline term were evaluated: (1) multimodal, based on the individual fMRI analysis, (2) atlas-based by removing presumably activated regions and (3) model-based by fitting the baseline with exponential functions. Second, we investigated the need to capture the arterial input function peak with automatic blood sampling for the quantification of CMRGlu. We finally compared the task-specific activation obtained from fPET and fMRI qualitatively and statistically. Results CMRGlu quantified only with manual arterial samples showed a strong correlation to that obtained with automatic sampling (r = 0.9996). The multimodal baseline definition was superior to the other tested approaches in terms of residuals (p Conclusion Using a bolus plus constant infusion protocol, the necessary task duration for reliable quantification of task-specific CMRGlu could be reduced to 5 and 2 min, therefore, approaching that of fMRI. Important for valid quantification is a correct baseline definition, which was ideal when task-relevant voxels were determined with fMRI. The absence of a correlation and the different activation pattern between fPET and fMRI suggest that glucose metabolism and oxygen demand capture complementary aspects of energy demands.

Constant infusion is a method used for measuring protein synthesis rate in living object which uses low concentration of amino acid tracers. Flooding dose method is another technique used to measure the rate of protein synthesis which uses labelled amino acid together with large amount of unlabelled amino acid. The latter method was firstly developed to solve the problem in determination of precursor pool arise from constant infusion method. The objective of this writing is to compare the results from several researches on measuring protein synthesis rate using flooding dose and constant infusion methods and to obtain the criteria or prerequisite on the type of sample and tracer for each method. The measurements of protein synthesis rate using both methods are presented and results from both methods are compared. Both methods are eligible for measuring protein synthesis rate as long as the true precursor can be measured. The uncertainties in determining the precursor in constant infusion method and the effect of flooding on the stimulation of protein are the limitation on using the two methods. Bolus injection which imitates the flooding dose method but using smaller dose of tracer can be a good alternative in measuring protein synthesis rate.

INTRODUCTION: Recent evidence suggests that the conscious brain is characterized by a diverse repertoire of functional connectivity patterns while the anesthetized brain shows stereotyped activity. However, classical time‐averaged methods of connectivity dismiss dynamic and temporal characteristics of functional configurations. Here we demonstrate a new approach which characterizes time‐varying patterns of functional connectivity at the subsecond time scale. METHODS: We introduce phase‐lag entropy (PLE), a measure of the diversity of temporal patterns in the phase relationships between two signals. The proposed measure was applied to multichannel electroencephalogram (EEG), which were recorded from two distinct experimental settings: (1) propofol was administrated at a constant infusion rate for 60 min (n = 96); (2) administration of propofol by a target effect‐site concentration‐controlled infusion with simultaneous assessment of the level of consciousness (n = 10). RESULTS: From the first dataset, two substantial changes of the phase relationship during anesthesia was found: (1) the dynamics of the phase relationship between frontal channels became progressively less diverse and more stereotyped during unconsciousness, quantified as a reduction in PLE; and (2) the reduction in PLE was consistent across subjects. Furthermore, PLE provided better performance in the classification of states of consciousness than did phase‐lag index, a classical time‐averaged connectivity method. From the second dataset, PLE showed the highest agreement with the level of consciousness, compared to existing anesthetic depth indicators. CONCLUSIONS: This study suggests that a scarcity of functional configurations is closely associated with anesthetically induced unconsciousness, and shows promise as a basis for a new consciousness monitoring system during general anesthesia. Hum Brain Mapp 38:4980–4995, 2017. © 2017 Wiley Periodicals, Inc.

PurposeTo evaluate intraocular pressure (IOP) fluctuation during vitrectomy, we directly monitored IOP in vivo using 2 vitrectomy machines with or without constant infusion pressure monitoring and control.MethodsAmong 61 eyes of 61 consecutive patients, 32 were assigned to the Accurus system (group 1) and 29 were assigned to the Constellation system (group 2) in this prospective case series. The IOP fluctuations were evaluated during routine vitrectomy procedures.ResultsThe initial IOP before vitrectomy was 20.3 ± 2.4 mm Hg in group 1 using a conventional vented gas forced infusion system and 20.0 ± 0.0 mm Hg in group 2 using active IOP control at 20 mm Hg (p = 0.532). However, the average IOP change during core vitrectomy was -8.6 ± 4.3 mm Hg in group 1 and -0.8 ± 1.1 in group 2 (pConclusionsThe IOP fluctuated significantly during routine vitrectomy using both systems. Hypotony and partial ocular collapse were more frequently observed during vitrectomy with the Accurus system than with the Constellation system. Both systems were vulnerable to IOP surge during indentation and intravitreal injection.

Classical mathematical models for chemotherapy assume a constant infusion rate of the chemotherapy agent. However in reality the infusion rate usually varies with respect to time, due to the natural (temporal or random) fluctuation of environments or clinical needs. In this work we study a non-autonomous chemotherapy model where the injection rate and injection concentration of the chemotherapy agent are time-dependent. In particular, we prove that the non-autonomous dynamical system generated by solutions to the non-autonomous chemotherapy system possesses a pullback attractor. In addition, we investigate the detailed interior structures of the pullback attractor to provide crucial information on the effectiveness of the treatment. The main analytical tool used is the theory of non-autonomous dynamical systems. Numerical experiments are carried out to supplement the analysis and illustrate the effectiveness of different types of infusions.

Introduction We measured the tiagabine-induced enhancement of the GABA A receptor's affinity for benzodiazepine ligands ("GABA shift") using [ 18 F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [ 18 F]FMZ binding were compared to that of [ 18 F]FMZ PET with single bolus injection (SB). Materials and methods Sprague–Dawley rats underwent [ 18 F]FMZ PET scans with B/I, which consisted of baseline and "GABA shift" sessions in a scan, or scans with SB one week apart. Tiagabine (10mg/kg) was intravenously injected after the baseline session. [ 18 F]FMZ binding potentials (BP ND ) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BP ND changes (%) before and after the tiagabine treatment were also calculated. Results In PET studies with B/I ( K bol =20min), [ 18 F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [ 18 F]FMZ BP ND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BP ND change (B/I) and 6–14% BP ND change (SB), respectively. In PET studies with SB, a statistically significant increase of [ 18 F]FMZ BP ND was found only in the striatum, due to the greater inter-individual variance compared to those with B/I. Conclusions Data demonstrated that an [ 18 F]FMZ PET study with B/I ( K bol =20min) is both reliable and sensitive for the assessment of altered GABA A receptor function induced by tiagabine treatment in the rat brain. These results may help to improve the efficiency of the development of new GABA-targeting drugs in the preclinical stage using [ 18 F]FMZ PET.

Functional Positron Emission Tomography (fPET) provides a method to track molecular dynamics in the human brain. With a radioactively labelled glucose-analogue, [18F]-flurodeoxyglucose (FDG-fPET), it is now possible to index the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function, and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware makes it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET.The temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radioactive tracer. In this work we present two alternative continuous infusion protocols and compare them to a traditional bolus approach. We detail a method for acquiring blood samples, time-locking PET, MRI and experimental stimulus, and administrating the non-traditional tracer delivery. By applying a visual stimulus, we demonstrate cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16-seconds.SummaryRadiotracer infusion protocols for positron emission tomography (PET) provide improved temporal resolution over bolus administration. Here, we describe radiotracer administration for two protocols, constant infusion and bolus plus infusion protocol. We compare this to the standard bolus administration protocol. Using [18-F] fluorodeoxyglucose PET (FDG-PET) as an example, we show that temporal resolutions of approximately 16sec are achievable using these protocols.

In some positron emission tomography (PET) studies, a reversibly binding radioligand is administered as a constant infusion to establish true equilibrium for quantification. This approach reduces scanning time and simplifies data analysis, but assumes similar behavior of the radioligand in plasma across the study population to establish true equilibrium in all subjects. Bias in outcome measurements can result if this assumption is not met. This work developed and validated a correction that reduces bias in total distribution volume ( VT) estimates when true equilibrium is not present. This correction, termed tissue clearance correction (TCC), took the form [Formula: see text], where β is the radioligand clearance rate in tissue, γ is a radiotracer-specific constant, and VT(A) is the apparent VT. Simulations characterized the robustness of TCC across imperfect values of γ and β and demonstrated reduction to false positive rates. This approach was validated with human infusion data for three radiotracers: [18F]FPEB, (−)-[18F]flubatine, and [11C]UCB-J. TCC reduced bias in VT estimates for all radiotracers and significantly reduced intersubject variance in VT for [18F]FPEB data in some brain regions. Thus, TCC improves quantification of data acquired from PET infusion studies.

Although the consumption of dairy protein results in a robust increase in muscle protein synthesis (MPS), the magnitude of the increase is dependent upon the dose of protein ingested and the age of the individual. The minimum dose of dairy protein that can stimulate MPS in middle age (50.1 ± 4.5 years), a period of life during which muscle mass is typically lost, is not known. Sixteen middle-aged men (45–60 years) were randomly assigned to consume beverages containing either 10 g of milk protein (MP10) or 6 g of MP plus 20 g of carbohydrate (MP6 + CHO). A primed constant infusion of 13 C 6 phenylalanine was maintained and muscle biopsy samples were collected to calculate MPS. MP10 increased MPS above fasting levels for 90 min after ingestion, whereas MP6 + CHO did not increase MPS. This study demonstrates that between 6 and 10 g of MP is required to stimulate MPS in middle-aged men.

Transcutaneous measurement of the glomerular filtration rate ( t GFR) is now frequently used in animal studies. t GFR allows consecutive measurements on the same animal, including multiple measurements on a daily basis, because no blood sampling is required. Here we derive and validate a novel kinetic model for the description of transcutaneously measured FITC-Sinistrin excretion kinetics. In contrast to standard 1- to 3-compartment models, our model covers the complete kinetic, including injection and distribution of the tracer in the plasma compartment. Because the model describes the complete progression of the measurement, it allows further refinement by correcting for baseline shifts observed occasionally during measurement. Possible reasons for shifts in the background signal include photo bleaching of the skin, autofluorescence, changes of physiological state of the animals during the measurements, or effects arising from the attachment of the measurement device. Using the new 3-compartment kinetic model with modulated baseline ( t GFR 3cp.b.m ), t GFR measurements in rats can reach comparable precision as those from GFR measurements assessed using a gold standard technique based on constant infusion of a tracer. Moreover, the variability of simultaneous (parallel) measurements, as well as repeated t GFR measurements in the same animals, showed higher precision when t GFR 3cp.b.m was compared with the 1-compartment t GFR 1cp model.

Parametric kinetic models such as lp-ntPET are used to estimate spatiotemporal patterns of endogenous neurotransmitter release, such as smoking-induced dopamine (DA) release. Applicability of such models is often limited by noise in the voxel-level time activity curves (TAC). Previous work has demonstrated the usefulness of HYPR-based spatial post-processing to increase neurotransmitter release detection sensitivity. Here we extend on this work by developing more realistic noise modelling and including additional denoising approaches. Using simulations and data acquired in non-human primates (NHP), we demonstrate that HYPR-based denoised reconstructions coupled with HYPR post-processing enables a ∼ 7 fold reduction in the detectable size of the region with neurotransmitter release, less biased parameters of interest, and favours bolus vs. bolus + constant infusion protocols.

Objectives: Constant infusion lumbar infusion test (LIT) is an important way to find which patients, of those with signs and symptoms corresponding to normal pressure hydrocephalus (NPH) who will improve from shunt operation. LIT is a stress test on the ability for cerebrospinal fluid re-absorbtion. The aim of this study is to show how the information from LIT can be improved by quantitative analysis and avoidance of methodological pitfalls. Material and methods: The potential pitfalls, and the analysis method, are described in detail. The analysis was applied on pre-operative constant infusion LIT from 31 patients operated for NPH, with known outcome. The pre- and post-operative walking speed was used to grade pathology progression or improvement. Results: The maximal, plateau, intra-spinal pressure at constant infusion LIT is an ambivalent indicator for NPH: while low maximal pressure indicates no cerebrospinal fluid (CSF) absorbtion pathology, too high pressure (≥47 mmHg) may mean no diagnosis, because of stenosis of the Sylvian aqueduct. When subjects with too high intra-spinal pressure were excluded, the new analysis gave a couple of diagnostic volume parameters, of which one appears to be an optimal LIT parameter for identifying NPH patients with 14% better accuracy than plateau pressure. Conclusion: By avoiding methodological pitfalls, and optimal analysis of the results from lumbar infusion test, the number of NPH patients who do not have a successful outcome after shunt operation may be further decreased. (Less)

To determine the accuracy and precision of constant infusion transpulmonary thermodilution cardiac output (CITT-Q) assessment during exercise in humans, using indocyanine green (ICG) dilution and b ...

The investigation of cerebral metabolic rate of glucose (CMRGlu) at baseline and during specific tasks previously required separate scans with the drawback of high intrasubject variability. We aimed to validate a novel approach to assessing baseline glucose metabolism and task-specific changes in a single measurement with a constant infusion of 18F-FDG. Methods: Fifteen healthy subjects underwent two PET measurements with arterial blood sampling. As a reference, baseline CMRGlu was quantified from a 60-min scan after 18F-FDG bolus application using the Patlak plot (eyes closed). For the other scan, a constant radioligand infusion was applied for 95 min, during which the subjects opened their eyes at 10–20 min and 60–70 min and tapped their right thumb to their fingers at 35–45 min and 85–95 min. The constant-infusion scan was quantified in two steps. First, the general linear model was used to fit regional time–activity curves with regressors for baseline metabolism, task-specific changes for the eyes-open and finger-tapping conditions, and movement parameters. Second, the Patlak plot was used for quantification of CMRGlu. Multiplication of the baseline regressor by β-values from the general linear model yielded regionally specific time–activity curves for baseline metabolism. Further, task-specific changes in metabolism are directly proportional to changes in the slope of the time–activity curve and hence to changes in CMRGlu. Results: Baseline CMRGlu from the constant-infusion scan matched that from the bolus application (test–retest variability, 1.1% ± 24.7%), which was not the case for a previously suggested approach (variability, −39.9% ± 25.2%, P 0.99). Conclusion: Baseline glucose metabolism and task-specific changes can be quantified in a single measurement with constant infusion of 18F-FDG and venous blood sampling. The high sensitivity and regional specificity of the approach offer novel possibilities for functional and multimodal brain imaging.

International audience; We consider a system of two coupled integro-differential equations modelling populations of healthy and cancer cells under therapy. Both populations are structured by a phenotypic variable, representing their level of resistance to the treatment. We analyse the asymptotic behaviour of the model under constant infusion of drugs. By designing an appropriate Lyapunov function, we prove that both densities converge to Dirac masses. We then define an optimal control problem, by considering all possible infusion protocols and minimising the number of cancer cells over a prescribed time frame. We provide a quasi-optimal strategy and prove that it solves this problem for large final times. For this modelling framework, we illustrate our results with numerical simulations, and compare our optimal strategy with periodic treatment schedules.

Dynamic positron emission tomography (PET) combined with the constant infusion of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) as a tracer permits real-time monitoring of systemic transient metabolic changes resulting from photodynamic therapy (PDT) in tumour bearing animals. The effect of PDT on tumour FDG uptake rates was evaluated using four different sulfonated phthalocyanine analogs as photosensitizers (PS) in combination with either continuous or fractionated illumination protocols. Mice bearing two EMT-6 tumours were infused with FDG to start PDT 30 min later. Dynamic images were acquired to produce FDG uptake over time for the treated and reference tumours. Practically all PDT protocols induced a reduction in the FDG uptake rates in the treated tumour during PDT, except for the zinc tetrasulfophthalocyanine, when using fractionated light, reflecting the low photodynamic efficacy of this PS. In general, the response to PDT was characterized by a rebound in the FDG uptake rate after illumination. A strong drop in FDG tumour uptake rates during PDT, followed by a strong rebound, together with short delay-to-response times, corresponded to optimal long-term tumour response outcomes. This dynamic FDG-PET protocol provides real-time observations to predict long-term PDT efficacy, while using fewer animals than conventional methods, thus making possible the rapid optimization of treatment parameters.