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PubMed2002

Pharmacodynamics of moxifloxacin against Streptococcus pyogenes in an in vitro kinetic model.

The aim of the present study was to investigate the pharmacodynamics of moxifloxacin against strains of Streptococcus pyogenes with different susceptibilities to erythromycin by using an in vitro kinetic model simulating human pharmacokinetics of moxifloxacin at oral doses of 400 and 200 mg, respectively. When the different strains of S. pyogenes were exposed to the higher dose, the number of bacteria was reduced below the detection limit after 12 h and no regrowth was noted during the following 12 h. At the lower dose there was regrowth of the strains with constitutive and inducible erythromycin resistance of the MLS(B) phenotype. Replication assays of the regrowing bacteria indicated that the failure of moxifloxacin to kill the MLS(B) strains at the lower dose was likely caused by the emergence of preexisting resistant subpopulations. Thus, the present study indicates that the presently used 400-mg dose seems to have an advantage over the lower dose in that the risk for selection of resistant subpopulations is minimized.

Anti-Infective Agents↗
PubMed1989

Acyl group transfer by proteases forming an acylenzyme intermediate: kinetic model analysis (including hydrolysis of acylenzyme- nucleophile complex).

The quantitative analysis of peptide synthesis via transfer of the acyl moiety from the activated donor (S) to the nucleophile (N), catalysed by proteases forming an acylenzyme intermediate, has been continued. The new kinetic model takes into account the hydrolysis of an acylenzyme-nucleophile complex (EAN). The intensity of the hydrolysis is characterized by parameter gamma equal to the ratio of the rate constant of EAN hydrolysis and the rate constant of peptide formation. The ability of the EAN complex to hydrolyse leads to a decrease in the apparent nucleophile reactivity (beta) of the aminocomponent. As a result, the maximal fractional conversions of S and N to the peptide decrease, and the apparent nucleophile reactivity becomes dependent on the nucleophile concentration. The pattern of parameter gamma influence on maximal fractional conversions depends on which component is in an excess. It is with the donor excess that hydrolysis of the EAN complex affects the peptide yield dramatically. Analytical expressions for the estimation of maximal product concentration were obtained and their accuracy evaluated.

Acylation↗
PubMed2004

A minimal kinetic model for a viral DNA packaging machine.

Terminase enzymes are common to both eukaryotic and prokaryotic double-stranded DNA viruses. These enzymes possess ATPase and nuclease activities that work in concert to "package" a viral genome into an empty procapsid, and it is likely that terminase enzymes from disparate viruses utilize a common packaging mechanism. Bacteriophage lambda terminase possesses a site-specific nuclease activity, a so-called helicase activity, a DNA translocase activity, and multiple ATPase catalytic sites that function to package viral DNA. Allosteric interactions between the multiple catalytic sites have been reported. This study probes these catalytic interactions using enzyme kinetic, photoaffinity labeling, and vanadate inhibition studies. The ensemble of data forms the basis for a minimal kinetic model for lambda terminase. The model incorporates an ADP-driven conformational reorganization of the terminase subunits assembled on viral DNA, which is central to the activation of a catalytically competent packaging machine. The proposed model provides a unifying mechanism for allosteric interaction between the multiple catalytic sites of the holoenzyme and explains much of the kinetic data in the literature. Given that similar packaging mechanisms have been proposed for viruses as dissimilar as lambda and the herpes viruses, the model may find general utility in our global understanding of the enzymology of virus assembly.

Adenosine↗
PubMed1989

A kinetic model for plasmid curing.

A simple mathematical model of drug-induced plasmid elimination (curing) considering density-dependent growth rates and plasmid transfers is presented. It describes nonlinear population dynamics of conjugative plasmids during in vitro curing experiments in batch culture. The model was tested on kinetics of acridine orange curing of F'lac plasmid. Effects of density dependence, plasmid elimination, selection for plasmidless segregants, conjugation, initial and maximal population density, and postsegregational killing on curing kinetics are simulated and discussed.

Acridine Orange↗
PubMed2005

A competitive kinetic model of nucleic acid surface hybridization in the presence of point mutants.

Microarray analysis has become increasingly complex due to the growing size of arrays and the inherent cross-binding of targets. In this work, we explore the effects of matched and mismatched target species concentrations, temperature, and the time of hybridization on sensing specificity in two-component systems. A finite element software is used to simulate the diffusion of DNA through a microfluidic chamber to the sensing surface where hybridization of DNA is modeled using the corresponding kinetic equation. Comparison between a single-component system, where only one target is allowed to bind to a specific zone, and a two-component system, where more than one target can hybridize in a sensing zone, uncovers significant kinetic disparities during the transitory state; however, at thermodynamic equilibrium a modified Langmuir isotherm governs the bound amount of both species. The results presented suggest that it may be more appropriate to consider collective rather than quasi-independent interaction of targets in multicomponent systems.

Binding, Competitive↗
PubMed1999

A kinetic model for Ascaridia galli populations in chickens treated with mixed salts of copper and zinc.

The action of mixed salts of copper and zinc (basic and neutral) on Hisex chickens experimentally infected with Ascaridia galli has been studied. The data show that the lowest host mortality and decrease in body weight gain and the highest reduction in nematode loading occurs in infected chickens treated with basic salts (in comparison with infected chickens, untreated or treated with neutral salts). A mathematical model has been proposed to provide a quantitative interpretation of the observed results. The model solutions of the kinetics of parasite numbers and of the gain in body weight are in a good agreement with the experimental data. One of the kinetic parameters in the model is defined as a phenomenological constant of the host immune response. Its value is determined in the case of infected and untreated chickens.

Animals↗
PubMed2001

Experimental and clinical evaluation of iterative reconstruction (OSEM) in dynamic PET: quantitative characteristics and effects on kinetic modeling.

UNLABELLED: The purpose of this study was to investigate the quantitative properties and effects of ordered-subset expectation maximization (OSEM) on kinetic modeling compared with filtered backprojection (FBP) in dynamic PET studies. Both phantom and patient studies were performed. METHODS: For phantom studies dynamic two-dimensional emission scans with 10-min frames and 20-min scan intervals were acquired over a 14-h period using an HR+ PET scanner. Various phantoms were scanned: 2-, 5-, 10-, and 20-cm-diameter phantoms filled with an 18F solution (300 kBq/mL) and a NEMA phantom filled with an 18F background (40 kBq/mL) and a cold or 11C insert (450 kBq/mL). Transmission (Tx) scans of 5-60 min were acquired. Data were reconstructed using FBP Hanning 0.5 and OSEM with 2-12 iterations and 12 or 24 subsets. Quantitative accuracy and noise characteristics were assessed. For patient studies, five cardiac, three oncologic, and three brain dynamic 18F-FDG scans were used. Five reconstructions were performed: FBP Hanning 0.5, and OSEM 2 x 12 and OSEM 4 x 16 with and without 5-mm full width at half maximum smoothing. Time-activity curves were calculated using volumes of interest. The input function was derived from arterial sampling. Metabolic rate of glucose (MRglu) was calculated with a standard two-tissue compartment model and Patlak analysis. RESULTS: Contribution of Tx noise to the reconstructed image was smaller for OSEM than for FBP. Differences in signal-to-noise ratio between FBP and OSEM depended on number of iterations and phantom size. Bias with OSEM was observed for regions enclosed within a 5- to 10-fold hotter background. For cardiac studies OSEM 2 x 12 and OSEM 4 x 16 resulted in 13% and 21% higher pixel values and 9% and 15% higher MRglu values compared with FBP. Smoothing decreased all these values to 2%. Similar results were found for most tumor studies. For brain studies MRglu of FBP and OSEM 4 x 16 agreed within 2%. Use of OSEM image-derived input functions for cardiac PET studies resulted in a decrease in calculated MRglu of about 15%. CONCLUSION: For most PET studies OSEM has equal quantitative accuracy as FBP. The higher pixel and MRglu values are explained by the better resolution of OSEM. However, OSEM does not provide accurate image-derived input functions for FDG cardiac PET studies because of bias in regions located within a hotter background.

Algorithms↗
PubMed1996

Kinetic modelling of the proton translocating CF0CF1-ATP synthase from spinach.

The rate of both ATP synthase and hydrolysis catalysed by the thiol-modulated and activated ATP synthase from spinach is measured as a function of all substrates including the protons inside the thylakoid lumen. The most important findings are: (1) sigmoid kinetics with respect to H+in, (2) hyperbolic kinetics with respect to ADP, ATP and phosphate, with Km for phosphate and ADP decreasing upon increasing H+in, (3) binding of ADP and phosphate in random order and competitive to ATP. Simulation of the complete set of experimental data is obtained by a kinetic model featuring Boyer's binding-chain mechanism.

Adenosine Diphosphate↗
PubMed1958

Immunoreactions involving platelets. I. A steric and kinetic model for formation of a complex from a human antibody, quinidine as a haptene, and platelets; and for fixation of complement by the complex.

A steric and kinetic model for the sequence and mechanism of reactions leading to formation of a complex from an antibody, a haptene (quinidine), and a cell membrane (platelets), and to fixation of complement by the complex was deduced from the effects of varying the initial concentration of each component of the complex on the amount of complement fixed, from kinetic aspects of the sequential reactions, and from other chemical and physical properties of the various components involved. Theoretical results calculated using equations based on the model, which were derived by Dr. Terrell L. Hill, were similar in all respects to experimental results. Results of this study were consistent with the possibilities that the protein moiety of a haptenic antigen involved in development of an antibody which attaches to a cell is not necessarily a component of the cell, and that the cell reacts with the antibody by virtue of having a surface favorable for non-specific adsorption of certain haptene-antibody complexes.

Antibodies↗
PubMed2006

Kinetic modeling of tumor growth and dissemination in the craniospinal axis: implications for craniospinal irradiation.

BACKGROUND: Medulloblastoma and other types of tumors that gain access to the cerebrospinal fluid can spread throughout the craniospinal axis. The purpose of this study was to devise a simple multi-compartment kinetic model using established tumor cell growth and treatment sensitivity parameters to model the complications of this spread as well as the impact of treatment with craniospinal radiotherapy. METHODS: A two-compartment mathematical model was constructed. Rate constants were derived from previously published work and the model used to predict outcomes for various clinical scenarios. RESULTS: The model is simple and with the use of known and estimated clinical parameters is consistent with known clinical outcomes. Treatment outcomes are critically dependent upon the duration of the treatment break and the radiosensitivity of the tumor. Cross-plot analyses serve as an estimate of likelihood of cure as a function of these and other factors. CONCLUSION: The model accurately describes known clinical outcomes for patients with medulloblastoma. It can help guide treatment decisions for radiation oncologists treating patients with this disease. Incorporation of other treatment modalities, such as chemotherapy, that enhance radiation sensitivity and/or reduce tumor burden, are predicted to significantly increase the probability of cure.

Algorithms↗
PubMed1982

Modification of the saturation kinetics model to produce a more versatile protein quality assay.

The saturation kinetics (SK) model relates response to nutrient (protein) intake in higher organisms by the equations: r = (bK1 + Rmax In)(K1 + In); where r is response and I is intake. Experimental data are fitted to this equation by interactive computer programs in which the intercept, b; a nutrition constant K1; an asymptotic response value Rmax; and an apparent kinetic order, n, are calculated. This model, unlike linear methods (PER, NPU) closely fits experimental data and predicts protein quality over a wide range of intake values. However, the SK model fails to converge to realistic values of Rmax and K1 unless protein of a sufficient quality or concentration or both, to produce a distinct plateau is fed. Also, the model may fail to distinguish statistically between the qualities of proteins which are easily differentiated by linear methods. These problems are ameliorated by assigning predetermined values to b and Rmax. When b was fixed as the mean response (body nitrogen) of rats fed protein-free diet, and Rmax was assigned a value related to the maximum response of rats fed an excess of high quality protein (casein), reasonable and statistically different values of K1 and n were predicted for casein, peanut protein and wheat gluten.

Animals↗
PubMed1991

A kinetic model of the circulatory regulation of tissue plasminogen activator.

A computer simulation was developed to study the regulation of active tissue plasminogen activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA, PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The model indicates that as the active PAI-1 concentration increases, the percent of t-PA in the active form decreases exponentially. Further, the reaction between t-PA and PAI-1 substantially reduces the half-lives of both active factors. By adjusting the t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion and not to variations in the t-PA secretion rate. In conclusion, the model predicts that PAI-1 is an important regulator of the concentration, half-life and circadian variation of active t-PA.

Adult↗
PubMed1999

A kinetic model incorporating energy spilling for substrate removal in substrate-sufficient batch culture of activated sludge.

Batch assays are currently used to study the kinetic behavior of microbial growth. However, it has been shown that the outcome of batch experiments is greatly influenced by the initial ratio of substrate concentration (S(o)) to biomass concentration (Xo). Substrate-sufficient batch culture is known to have mechanisms of spilling energy that lead to significant nongrowth-associated substrate consumption, and the Monod equation is no longer appropriate. By incorporating substrate consumption associated with energy spilling into the balance of the substrate oxidation reaction, a kinetic model for the observed specific substrate consumption rate was developed for substrate-sufficient batch culture of activated sludge, and was further verified by experimental data. It was demonstrated that the specific substrate consumption rate increased with the increase of the S(o)/Xo ratio, and the majority of substrate was consumed through energy spilling at high S(o)/Xo ratios. It appears that the S(o)/Xo ratio is a key parameter in regulating metabolic pathways of microorganisms.

Bacteria, Aerobic↗
PubMed2003

Kinetic modelling of blood glucose variation in a bioartificial pancreas.

Methods are presented for assessing the performance of biomaterials for a bioartificial pancreas using a kinetic model of blood glucose variation. The model is composed of simultaneous differential equations that simulate variation of blood glucose concentration of rats outside the biomaterial and decrease of islet number inside the biomaterial. The resulting calculations agree well with the in vivo experimental data and indicate that the characteristics of bioartificial pancreas can be expressed as the actually working number of islets from the viewpoint of rats, regardless of the functioning of the bioartificial pancreas. The contributions of the capability of a biomaterial permeable to insulin and against immune rejection, and other factors that may induce cell death were involved in the actually working number of islets, i.e., the model used a lumped-parameter expression for assessment of the performance of biomaterials for a bioartificial pancreas. This model would be useful as a research tool for analysis of clinical investigation of bioartificial pancreas and physiological significance of blood glucose variation dynamics.

Animals↗
PubMed1992

[A kinetic model for heparin dosing in patients on chronic hemodialysis].

The quality of anticoagulation was evaluated in 5 patients receiving heparin during chronic hemodialysis. 50 kinetic studies were performed using 2 monitoring tests, TTPK and TCK. Basal and intradialysis measurements were used to estimate sensitivity and the elimination constant according to formulae described by Milthorpe. Mean basal TTPK time was 27.3 sec and TCK time was 211 sec. Mean initial intradialysis TTPK time was 107.5 sec and after correction applying the kinetic model it was 62 sec. Intradialysis TCK time varied from 806 to 683 sec after correction. At the end of the study, mean intradialysis TTPK time was 61 sec not significantly different from the target time of 55 sec. TCK time, however, was significantly greater than target (684 vs 434 sec).

Adult↗
PubMed2002

Kinetic model for nitrogen-limited wine fermentations.

A physical and mathematical model for wine fermentation kinetics has been developed to predict sugar utilization curves based on experimental data from wine fermentations with various initial nitrogen and sugar concentrations in the juice. The model is based on: (1) yeast cell growth limited by nitrogen; (2) sugar utilization rates and ethanol production rates proportional solely to the number of viable cells; and (3) a death rate for cells proportional to alcohol content. All but one parameter in the model can be estimated from existing data. However, experiments to find this final parameter, a constant describing cell death, indicate that cell death may not be the critical factor in determining fermentation kinetics as cell viability remains significant until sugar utilization has ceased. The model, nevertheless, predicts a transition from normal to sluggish to stuck fermentations as initial nitrogen levels decrease. It also predicts that fermentations with high initial Brix levels may go to completion when supplemented with nitrogen in the form of ammonia. Therefore, we hypothesize that the model is valid but that ethanol causes the yeast cells to become inactive while remaining viable. Experimental verification of the model has been performed using flask-scale experiments. The model has also been used to evaluate the possibility of using nitrogen or viable cell additions to avoid or correct problem (i.e., sluggish or stuck) fermentations.

Carbohydrate Metabolism↗
PubMed1977

A kinetic model for microtubule polymerization during oral regeneration in Stentor coeruleus.

The regeneration of oral cilia in the protozoan cell, Stentor coeruleus, has been investigated in the presence of agents which do not favor the polymerization of microtubules. These agents, low temperature and the tubulin binding drugs, podophyllotoxin and beta-peltatin, slow the rate of regeneration. A kinetic model is proposed to test the hypothesis that microtubule polymerization is the rate limiting step in oral regeneration. The results suggest that the tubulin concentration of normal regenerating cells is slightly in excess of an amount which would kinetically limit the regeneration rate.

Animals↗
PubMed1997

Kinetic modeling of folate metabolism through use of chronic administration of deuterium-labeled folic acid in men.

This study was conducted as an initial investigation of in vivo folate kinetics in healthy men (n = 4) and made use of a chronic-administration protocol with stable-isotope labeling. Subjects were given 0.453 mumol (200 micrograms) total folic acid in aqueous solution daily throughout the 18-wk study while they consumed self-selected folate-adequate diets. After a 2-wk pretrial period with unlabeled folic acid, subjects were given 0.227 mumol (100 micrograms) pteroyl-L-[2H4]glutamic acid/d ([2H4]folic acid) combined with 0.227 mumol nonlabeled folic acid or [2H2]pteroylhexaglutamic acid/d for the next 8 wk; then for the next 8 wk the [2H4]folic acid was withdrawn and the subjects received only nonlabeled folic acid. Little unmetabolized folic acid was excreted in urine. Isotopic enrichment of urinary folate during [2H4]folic acid administration and withdrawal was consistent with a kinetic model having a rapid turnover pool and a slow turnover pool. In contrast with previous two-pool models, provisions were made for folate turnover by urinary folate excretion (as measured here) and by fecal excretion and catabolic processes. The precision of modeling will be improved in future studies by measurement of enrichment of additional pools. However, this study shows clearly the slow turnover of the whole-body folate pool (< or = 1% per day) and the feasibility of further long-term kinetic analysis.

Adult↗