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At least 505 records · Page 28Linked to original sources
PubMed1996

An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs.

An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters: Kue (exit rate constant of unbound drug from the effect compartment), Pue (ratio of the unbound clearances to and from the effect compartment), fue (fraction of drug in effect compartment that is not bound to nonspecific binding sites), Kd (equilibrium dissociation constant of drug-receptor binding), and Rtot (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V1, V2, fu, fu2, CLu10, CLu20, CLu12, CLu21) and the PK/PD model parameters (kue, Pue, fue, Kd, Rtot) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect, ED90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratio V1/fu, CLu10, kue, Pue (at equipotent doses the time course is not affected by Pue), fue, Kd, and Rtot (only if Rtot is high), whereas they are less affected by the ratio V2/fu2, CLu20, CLu12, and CLu21. In general, the model parameters affect the ED90 and the time course of action in the same direction, e.g., an increase of V1 results in an increase of ED90 and an increase of onset time and duration. However, the unbound clearance CLu10, the intercompartmental unbound clearance CLu12 and the receptor affinity Kd have an opposite effect on ED90 and the time course parameters, e.g., an increase of CLu10 results in an increase of ED90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value of keo, which is a function of kue, fue, Kd, Rtot, as well as the unbound drug concentration in the effect compartment Cue. On the other hand, the model proposed by Donati and Meistelman gives correct values of keo (equal to the product fue.kue), but the receptor affinity Kd and the receptor density Rtot obtained by this method are apparent values, which depend on fu, fue, and Pue.

Blood Proteins↗
PubMed1990

An in vivo quantitative angiogenesis model using tumor cells entrapped in alginate.

A new in vivo system of monitoring tumor cell induced blood vessel growth using a sodium alginate entrapment process was developed. The alginate polymer of guluronic and mannuronic acids surrounds and sequesters cells from direct contact with their immediate environment, but permits diffusible angiogenic factors to pass through to induce neovascularization in the host. The alginate beads containing tumor cells were injected subcutaneously into animals and coalesced as a point source. The tumor cells are protected from direct contact with the host's immune system, so that various tumor types may be evaluated for their angiogenic potential across histocompatibility or species barriers. C57BI/6, BALB/c and nude mice as well as squirrel monkeys were used as host animals. This provided tumor cell testing in a syngeneic, allogeneic, or xenogeneic system. We found that alginate-Lewis lung carcinoma cells were potent inducers of blood vessel growth. As few as 100 alginate-Lewis lung carcinoma cells were needed to induce macroscopically visible blood vessels by 3 days. Dose-response experiments with alginate-Lewis lung carcinoma cells showed a greater level of blood vessel induction as cell numbers increased. Neovascularization was monitored qualitatively by macroscopic photography and microscopic histologic evaluation. Also, neovascularization was monitored quantitatively by measuring the level of hemoglobin at the injection site of alginate or by measuring the amount of radioactive red blood cells pooled at the injection site of the alginate beads. Both the measured levels of hemoglobin and radiolabeled red blood cells increased at the alginate site with each log increase of tumor cells delivered, which paralleled our findings at the macroscopic and microscopic level. This in vivo angiogenesis model was relatively simple and the procedures technically easy to perform. Most importantly, this model allowed both a qualitative and quantitative assessment of tumor-induced blood vessel growth.

Alginates↗
PubMedDate not supplied

A quantitative angiogenesis model for efficacy testing of chemopreventive agents.

One of the approaches in chemoprevention to prevent or delay the progression of precancerous lesions, is to apply chemopreventive agents that can potentially block angiogenesis. A quantitative in vivo angiogenesis inhibition assay was developed to test the efficacy of twelve chemopreventive agents that represent different chemical classes and multiple biological activities, using the chick chorioallantoic membrane (CAM) model and an oncogene-transfected angiogenic cell line (6 Ti ras/SV myc # 4). These tumorigenic cells held by a primary agarose pellet, were placed alone or with a secondary pellet incorporating five concentrations of the test agent, on an exposed CAM of 7-day-old chick embryo for 72 hours in a humidified chamber at 35 degrees C. The cell-induced angiogenic blood vessels, including the microvessels radiating from the cell pellet focal area, were scored using a computerized custom image analysis system. The results show that nonsteroidal antiinflammatory drugs (NSAIDS); aspirin, sulindac, sulindac sulfide and sulindac sulfone, were effective inhibitors of cell-induced angiogenesis (23-66%). Aspirin displayed a dose-dependent response with the highest inhibition at 300 microM and an EC50 (the effective molar concentration that inhibits angiogenesis by 50%) of 26 microM. Sulindac sulfone was more effective than sulindac with an EC50 of 5 microM versus 85 microM. However, sulindac sulfide showed an intermediate response with an EC50 of 41 microM. The retinoids; all-trans-retinoic acid (ATRA), 9-cis-retinoic acid (9-cis-RA), and 13-cis-retinoic acid (13-cis-RA) were also highly effective inhibitors of cell-mediated CAM-angiogenesis. 13-cis-RA with an EC50 of 3.6 nM, has been the most efficacious test agent. > 400-fold more effective than 9-cis-RA (1.5 microM). ATRA exhibited an intermediate response between 9-cis-RA and 13-cis-RA with an EC50 of 0.3 microM, and was 100-fold more efficacious than 9-cis-RA. However, the synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), was not an effective inhibitor of CAM angiogenesis. Thalidomide, a compound with multiple biological activities, exhibited dose-dependent inhibition ranging from 10-1000 microM with an EC50 of 19 microM. Other agents that exhibited dose-dependent inhibition included Bowman-Birk inhibitor (BBI), EC50: 10 microg/ml, tamoxifen, EC50, 0.05 microM and difluoromethyl omithine (DFMO), with an EC50 of 13 microM. These results suggest that tumor-associated angiogenesis can be modulated by non-toxic concentrations of chemopreventive agents representing multiple biological activities and multiple targets.

Angiogenesis Inhibitors↗
PubMed2004

Time course and cellular distribution of hsp27 and hsp72 stress protein expression in a quantitative gerbil model of ischemic injury and tolerance: thresholds for hsp72 induction and hilar lesioning in the context of ischemic preconditioning.

The distribution and time course of expression of the heat shock/stress proteins, hsp27 and hsp72, were evaluated in a highly controlled gerbil model of ischemic injury and tolerance induction, in which the duration of ischemic depolarization in each hippocampus provides a precise quantitative index of insult severity. Gerbils were subjected to brief priming insults (2- to 3.5-minute depolarization) that produce optimal preconditioning, to severe test insults (6- to 8.5-minute depolarization) that produce complete CA1 neuron loss in naive animals, or to combined insults administered 1 week apart, after which almost complete tolerance to CA1 neuron injury is observed. Immunoreactivities of hsp27, hsp72, glial fibrillary acidic protein and microtubule-associated protein 2 (MAP2) were evaluated in animals perfused at defined intervals after the final insult in each treatment group, using a variation of established antigen-retrieval procedures that significantly improves detection of many proteins in vibratome brain sections. Hsp72 was detected in CA1 neurons of some hippocampi 2 to 4 days after preconditioning, but this was only seen after the longest priming depolarizations, whereas shorter insults that still induced optimal tolerance failed to induce hsp72. Hsp72 was induced after test insults in preconditioned hippocampi, but at a higher depolarization threshold than observed for naive animals. An astrocytic localization of hsp27 was observed in regions of neuron injury, as indicated by reduced MAP2 immunoreactivity, and was primarily restricted to dentate hilus after preconditioning insults. These results establish that limited hilar lesions are characteristic of optimal preconditioning, whereas prior neuronal expression of either hsp72 or hsp27 is not required for ischemic tolerance.

Animals↗
PubMedDate not supplied

Optimized block-wise variable combination by particle swarm optimization for partial least squares modeling in quantitative structure-activity relationship studies.

The use of numerous descriptors that are indicative of molecular structure is becoming common in quantitative structure-activity relationship (QSAR) studies. As all of the descriptors might carry more or less molecular information, it seems more advisable to investigate the possible variable combination rather than variable selection. In this paper, an optimized block-wise variable combination (OBVC) by particle swarm optimization based on partial least squares modeling has been proposed for variable combination. An F statistic is also introduced to determine the dimensionality of the PLS model. The performance is assessed using two QSAR data sets. Experimental results have shown the good performance of this technique compared to those obtained by stepwise regression.

Amines↗
PubMedDate not supplied

Characterizing observation volumes and the role of excitation saturation in one-photon fluorescence fluctuation spectroscopy.

Fluorescence correlation spectroscopy (FCS) and related distribution analysis techniques have become extremely important and widely used research tools for analyzing the dynamics, kinetics, interactions, and mobility of biomolecules. However, it is not widely recognized that photophysical dynamics can dramatically influence the calibration of fluctuation spectroscopy instrumentation. While the basic theories for fluctuation spectroscopy methods are well established, there have not been quantitative models to characterize the photophysical-induced variations observed in measured fluctuation spectroscopy data under varied excitation conditions. We introduce quantitative models to characterize how the fluorescence observation volumes in one-photon confocal microscopy are modified by excitation saturation as well as corresponding models for the effect of the volume changes in FCS. We introduce a simple curve fitting procedure to model the role of saturation in FCS measurements and demonstrate its accuracy in fitting measured correlation curves over a wide range of excitation conditions.

Algorithms↗
PubMed2005

Toward predictive models of mammalian cells.

Progress in experimental and theoretical biology is likely to provide us with the opportunity to assemble detailed predictive models of mammalian cells. Using a functional format to describe the organization of mammalian cells, we describe current approaches for developing qualitative and quantitative models using data from a variety of experimental sources. Recent developments and applications of graph theory to biological networks are reviewed. The use of these qualitative models to identify the topology of regulatory motifs and functional modules is discussed. Cellular homeostasis and plasticity are interpreted within the framework of balance between regulatory motifs and interactions between modules. From this analysis we identify the need for detailed quantitative models on the basis of the representation of the chemistry underlying the cellular process. The use of deterministic, stochastic, and hybrid models to represent cellular processes is reviewed, and an initial integrated approach for the development of large-scale predictive models of a mammalian cell is presented.

Amino Acid Motifs↗
PubMed2000

Combination of molecular modeling and quantitative structure-activity relationship analysis in the study of antimycobacterial activity of pyridine derivatives.

A set of 4-benzylsulfanyl derivatives of pyridine-2-carbonitriles and pyridine-2-carbothioamides, previously tested for their antimycobacterial activity, were analysed by quantitative structure-activity relationship (QSAR) techniques, using some physicochemical and quantum-chemical parameters. The resulting QSAR revealed that the activity increases with electron withdrawing substituents in the benzyl moiety of studied compounds. HOMO orbitals can play an important role in the description of the mechanism of interactions at the molecular level. Additionally, the results of multiple linear regression indicate the differences between Mycobacterium tuberculosis and M. avium. The hydrophobicity of studied compounds is important for activity against M. avium.

Anti-Infective Agents↗
PubMed1996

A quantitative population model of whisker barrels: re-examining the Wilson-Cowan equations.

Beginning from a biologically based integrate and fire model of a rat whisker barrel, we employ semirigorous techniques to reduce the system to a simple set of equations, similar to the Wilson-Cowan equations, while retaining the ability for both qualitative and quantitative comparisons with the biological system. This is made possible through the clarification of three distinct measures of population activity: voltage, firing rate, and a new term called synaptic drive. The model is activated by prerecorded neural activity obtained from thalamic "barreloid" neurons in response to whisker stimuli. Output is produced in the form of population PSTHs, one each corresponding to activity of spiny (excitatory) and smooth (inhibitory) barrel neurons, which is quantitatively comparable to PSTHs from electrophysiologically studied regular-spike and fast-spike neurons. Through further analysis, the model yields novel physiological predictions not readily apparent from the full model or from experimental studies.

Animals↗
PubMed1993

Comparison of models for quantitative left ventricular wall motion analysis from two-dimensional echocardiograms during acute myocardial infarction.

To develop quantitative analysis of regional left ventricular wall motion in the absence of a gold standard, an objective statistical measure to compare models of wall motion is described. This measure can be derived from wall motion analysis of subgroups of patients with different patterns of wall motion. A priori knowledge of the exact localization of wall motion abnormalities is not needed. Two-dimensional echocardiograms were analyzed from 79 patients with myocardial infarction. The following 4 models were compared: Model I was based on the descent of the base toward the stable apex during systole. Models II and III measured area reduction with fixed- and floating-reference systems, respectively. Model IV was the centerline model. Classification by the electrocardiogram of the myocardial infarction as anterior (n = 37), posterior (n = 17) and inferior (n = 25) provided the a priori probability for classification of myocardial infarction. The a posteriori probability for classification of myocardial infarction was derived from the detection of wall motion abnormalities by echocardiographic analysis. The mean difference between a posteriori and a priori probability is a measure for the diagnostic value of the model, and was measured for 200 regions/patient. Use of the described measure revealed model I to be the most informative model and model III the least informative. Thus, the described statistical measure contributes to the development of regional wall motion analysis.

Adult↗
PubMed1988

Transfollicular percutaneous absorption. Skin model for quantitative studies.

Theoretically percutaneous absorption comprises two components: the transepidermal route and the transappendageal route, so-called 'shunt' diffusion. The relative importance of 'shunt' diffusion was investigated with a model of appendage-free skin. After treatment with 60 degrees C water for exactly 1 min, hairless dorsal rat skin regrows as a continuous epidermis. We present preliminary results of hydrocortisone diffusion in vitro, in appendage-free skin relative to normal skin. With intact skin under our experimental conditions, the steady-state flux and the total diffusion in 24 h were 50-fold larger.

Administration, Cutaneous↗
PubMed1998

Mixed quantitative/qualitative modeling and simulation of the cardiovascular system.

The cardiovascular system is composed of the hemodynamical system and the central nervous system (CNS) control. Whereas the structure and functioning of the hemodynamical system are well known and a number of quantitative models have already been developed that capture the behavior of the hemodynamical system fairly accurately, the CNS control is, at present, still not completely understood and no good deductive models exist that are able to describe the CNS control from physical and physiological principles. The use of qualitative methodologies may offer an interesting alternative to quantitative modeling approaches for inductively capturing the behavior of the CNS control. In this paper, a qualitative model of the CNS control of the cardiovascular system is developed by means of the fuzzy inductive reasoning (FIR) methodology. FIR is a fairly new modeling technique that is based on the general system problem solving (GSPS) methodology developed by G.J. Klir (Architecture of Systems Problem Solving, Plenum Press, New York, 1985). Previous investigations have demonstrated the applicability of this approach to modeling and simulating systems, the structure of which is partially or totally unknown. In this paper, five separate controller models for different control actuations are described that have been identified independently using the FIR methodology. Then the loop between the hemodynamical system, modeled by means of differential equations, and the CNS control, modeled in terms of five FIR models, is closed, in order to study the behavior of the cardiovascular system as a whole. The model described in this paper has been validated for a single patient only.

Central Nervous System↗
PubMedDate not supplied

[Quantitative kinetic model of ATP hydrolysis-synthesis by membrane H+-ATPase].

A mathematical model of fermentative reactions of synthesis-hydrolysis of ATP by H+-ATPase, coupled to the charge transport across the membrane has been constructed. Quantitative calculations of the rate of hydrolysis--synthesis of ATP were performed. The nature of the membrane electrochemical gradient delta mu H+ is discussed.

Adenosine Triphosphate↗
PubMed2006

A Thurstonian model for quantitative genetic analysis of ranks: a Bayesian approach.

A fully Bayesian method for quantitative genetic analysis of data consisting of ranks of, e.g., genotypes, scored at a series of events or experiments is presented. The model postulates a latent structure, with an underlying variable realized for each genotype or individual involved in the event. The rank observed is assumed to reflect the order of the values of the unobserved variables, i.e., the classical Thurstonian model of psychometrics. Parameters driving the Bayesian hierarchical model include effects of covariates, additive genetic effects, permanent environmental deviations, and components of variance. A Markov chain Monte Carlo implementation based on the Gibbs sampler is described, and procedures for inferring the probability of yet to be observed future rankings are outlined. Part of the model is rendered nonparametric by introducing a Dirichlet process prior for the distribution of permanent environmental effects. This can lead to potential identification of clusters of such effects, which, in some competitions such as horse races, may reflect forms of undeclared preferential treatment.

Bayes Theorem↗
PubMed1998

A general kinetic model for quantitative perfusion imaging with arterial spin labeling.

Recently, several implementations of arterial spin labeling (ASL) techniques have been developed for producing MRI images sensitive to local tissue perfusion. For quantitation of perfusion, both pulsed and continuous labeling methods potentially suffer from a number of systematic errors. In this study, a general kinetic model for the ASL signal is described that can be used to assess these errors. With appropriate assumptions, the general model reduces to models that have been used previously to analyze ASL data, but the general model also provides a way to analyze the errors that result if these assumptions are not accurate. The model was used for an initial assessment of systematic errors due to the effects of variable transit delays from the tagging band to the imaging voxel, the effects of capillary/tissue exchange of water on the relaxation of the tag, and the effects of incomplete water extraction. In preliminary experiments with a human subject, the model provided a good description of pulsed ASL data during a simple sensorimotor activation task.

Arousal↗
PubMed2000

A method to prevent excessive numbers of Markov states in Markov models for quantitative safety and reliability assessment.

This paper presents a method that will drastically reduce the calculation effort required to obtain quantitative safety and reliability assessments to determine safety integrity levels for applications in the process industry. The method described combines all benefits of Markov modeling with the practical benefits of reliability block diagrams.

Computer Simulation↗