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At least 631 records · Page 35Linked to original sources
PubMed2005

Pharmacokinetic-pharmacodynamic modelling of antibacterial activity of cefpodoxime and cefixime in in vitro kinetic models.

The bacterial time-kill curves of cefpodoxime and cefixime against four bacterial strains (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae/penicillin sensitive and S. pneumoniae/penicillin intermediate) were compared in in vitro infection models in which various human pharmacokinetic profiles of unbound antibiotic were simulated. This approach offers more detailed information than the minimum inhibitory concentration (MIC) does about the time course of antibacterial efficacy of an antibiotic. A pharmacokinetic-pharmacodynamic (PK-PD) model based on unbound antibiotic concentrations at the site of infection, and a sigmoid Emax-relationship with EC50 as the antibiotic concentration necessary to produce 50% of the maximum effect, effectively described the antimicrobial efficacy of both cefpodoxime and cefixime. The EC50 values of cefpodoxime and cefixime were consistent with their respective MIC values. Both antibiotics had similar high potency against H. influenzae (EC50: 0.04 mg/L) and M. catarrhalis (EC50: 0.12 mg/L), while the potency of cefpodoxime against S. pneumoniae strains was about 10-fold higher than that of cefixime (EC50s/sensitive strain: 0.02 mg/L versus 0.27 mg/L; EC50s/intermediate strain: 0.09 mg/L versus 0.69 mg/L). Applications of this model and unbound tissue PK profiles obtained from a previous clinical study performed in our group, showed that cefpodoxime has higher bacteriological potency than cefixime against S. pneumoniae. Simulations based on this model allow the comparison of antibacterial efficacy of different antibiotics and dosing regimens.

Anti-Bacterial Agents↗
PubMedDate not supplied

Kinetic modelling as a tool for the design of a vascular bioartificial pancreas: feedback between modelling and experimental validation.

A bioartificial pancreas is a system which contains isolated islets of Langerhans protected against immune rejection by an artificial membrane, permeable to glucose and insulin, but not to lymphocytes and immunoglobulins. However, it is necessary to design a device which performs as a closed-loop insulin delivery system, more specifically which rapidly responds to a change in the recipient's blood glucose concentration by an appropriate change in insulin release. We have designed a system intended to be connected as an arteriovenous shunt of the recipient; islets are placed between two flat ultrafiltration membranes, and blood circulates successively above the upper, and below the lower, membrane, in reverse direction. A complete kinetic model of glucose transfer from blood to the islet compartment, of insulin generation by the islets displaying a biphasic insulin pattern, and of insulin transfer into the bloodstream was described, and parameters were calculated on the basis of experimental data obtained when islets of Langerhans were perfused in vitro with a synthetic buffer. The resulting calculations indicated that both diffusional and convective transfers were involved in glucose and insulin mass transfer across the membrane, the contribution of diffusion being the most important. The geometry of the system was therefore modified in order to decrease the resistance to flow inside the blood channel. This should increase, at a given hydrostatic pressure, the blood flow rate, and thereby improve the diffusional transfer of insulin. This should also decrease the thrombogenicity of the device.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Kinetic modeling of lutein production by heterotrophic Chlorella at various pH and temperatures.

Kinetics of lutein production by heterotrophic Chlorella protothecoides was investigated with respect to pH and temperature. Flask cultures with initial pH 5.0-8.0 were carried out, and it was found that pH 6.0 was optimal for the algal growth. Further tests in fermentors showed that the highest biomass concentration, maximum cellular lutein content and lutein yield were achieved at pH 6. 6. In addition, it was shown that optimal biomass concentration and lutein yield were obtained at 28 degrees C, while application of 35 degrees C resulted in the highest cellular lutein content. A mathematical model was developed for the description of the processes under these cultivation conditions and the kinetic model fitted well to the experimental data. The obtained results may contribute to the commercial production of lutein by C. protothecoides.

Chlorella↗
PubMed2006

Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 cells.

PURPOSE: The mechanism of intestinal drug transport for hydrophilic cations such as ranitidine is complex, and evidence suggests a role for carrier-mediated apical (AP) uptake and saturable paracellular mechanisms in their overall absorptive transport. The purpose of this study was to develop a model capable of describing the kinetics of cellular accumulation and transport of ranitidine in Caco-2 cells, and to assess the relative contribution of the transcellular and paracellular routes toward overall ranitidine transport. METHODS: Cellular accumulation and absorptive transport of ranitidine were determined in the absence or presence of uptake and efflux inhibitors and as a function of concentration over 60 min in Caco-2 cells. A three-compartment model was developed, and parameter estimates were utilized to assess the expected relative contribution from transcellular and paracellular transport. RESULTS: Under all conditions, ranitidine absorptive transport consisted of significant transcellular and paracellular components. Inhibition of P-glycoprotein decreased the AP efflux rate constant (k21) and increased the relative contribution of the transcellular transport pathway. In the presence of quinidine, both the AP uptake rate constant (k12) and k21 decreased, resulting in a predominantly paracellular contribution to ranitidine transport. Increasing the ranitidine donor concentration decreased k12 and the paracellular rate constant (k13). No significant changes were observed in the relative contribution of the paracellular and transcellular routes as a function of ranitidine concentration. CONCLUSIONS: These results suggest the importance of uptake and efflux transporters as determinants of the relative contribution of transcellular and paracellular transport for ranitidine, and provide evidence supporting a concentration-dependent paracellular transport mechanism. The modeling approach developed here may also be useful in estimating the relative contribution of paracellular and transcellular transport for a wide array of drugs expected to utilize both pathways.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Establishment of a first-order kinetic model of light chain-associated amyloid fibril extension in vitro.

Light chain-associated (AL) amyloidosis is a common and fatal systemic amyloidosis. AL amyloid fibrils (fAL) are composed of intact or fragmental monoclonal light chains (AL proteins). To elucidate the molecular mechanisms of fAL formation from AL proteins, we purified fAL and AL proteins from the amyloid-deposited organs of five AL amyloidosis patients. By electron microscopy and fluorometric thioflavin T method, we observed optimal fibril extension at pH 2.0-3.5 for the fibrils obtained from four patients, while at pH 7.5-8.0 for those obtained from one patient. Fragmental AL proteins were more efficient in the extension reaction than intact AL proteins. The fibrils obtained from all five patients showed clear fibril extension electron microscopically at pH 7.5. The extension of the fibrils obtained from all five patients could be explained by a first-order kinetic model, i.e., fibril extension proceeds via the consecutive association of AL proteins onto the ends of existing fibrils. Fibril extension was accelerated by dermatan sulfate proteoglycan, and inhibited by apolipoprotein E, alpha1-microglobulin, fibronectin, and an antioxidant nordihydroguaiaretic acid. These findings contribute to our understanding of the molecular mechanism underlying the pathogenesis of AL amyloidosis, and will be useful for developing a therapeutic strategy against the disease.

Adult↗
PubMed1991

Kinetics and quality assurance: prescription therapy through kinetic modeling.

With recent startling statistics showing an increase in mortality risk of dialysis patients in the United States compared to other countries, managers and practitioners have been motivated to carefully examine not only the dialysis prescription, but what is actually delivered to the patient. In October 1990, prior to ANNA's Clinical Concerns in Nephrology meetings in Cincinatti and San Antonio, attendants were invited to participate in an education session examining the monitoring and evaluation of prescription therapy for peritoneal and hemodialysis. The title of the session was "The Nurse's Role in Prescription Therapy--What Does it Really Mean?" The sponsor was Fresenius USA, Inc. This educational offering gave the nephrology nurse the opportunity to learn how to manage the delivery of care based on the theory of kinetic modeling for peritoneal and hemodialysis therapy. Quality assurance indicators, data collection tools, and the latest technology were described for the monitoring and evaluation of the adequacy of therapy. The following article is adopted from the original transcripts of the five-member panel of experts who participated in the session. We appreciate the willingness of the speakers to share this timely and important material with the ANNA Journal readers.

Data Collection↗
PubMedDate not supplied

[Kinetic modeling of energy metabolism and generation of active forms of oxygen in hepatocyte mitochondria].

Direct nonenzymatic oxidation of semiquinone by oxygen is one of the main sources of superoxide radicals (O2.-) in mitochondria. By using all the known data on hepatocyte mitochondria, we have revealed the correlation between the rate of superoxide generation by the bc1 complex and the transmembrane potential (delta psi). If the main electrogenic stage of the Q cycle is suggested to be the electron transfer between the cytochrome b hemes, then the rate of superoxide generation sharply increases when delta psi grows from 150 mV to 180 mV. However, this interrelation is ambiguous. Indeed, the increase of the generation rate with the growth of the potential can occur faster when succinate dehydrogenase is inhibited by malonate than when external ADP is exhausted. When the potential is changed by adding phosphate or potassium (K+), the rate of O2.- production remains constant, although the comparison of the rate values at the same delta psi reveals the effect of phosphate or potassium. It turned out that the rate of O2.- generation is a function of delta mu H rather than any of its components. Phosphate and K+ have practically no influence on delta mu H, since the change in delta psi is compensated by delta pH. The rate of superoxide generation by the bc1 complex is a multiple function of the electron-transfer activity of enzymes, the processes determining the membrane potential (e.g., loading), and of the oxygen concentration. The kinetic model proposed in this work may serve a tool to understand how the superoxide production is regulated.

Adenosine Diphosphate↗
PubMed2006

Kinetic model for reactivity in quaternary water-in-oil microemulsions.

A study was carried out on the nitrosation of piperazine (PIP) and N-methylbenzylamine (MeBzAm) by N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in quaternary microemulsions of tetradecyltrimethylammonium bromide (TTABr)/isooctane/alcohol/water, varying the nature and the concentration of the following alcohols: 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol and 1-decanol keeping the [1-alcohol]/[TTABr] = 4 relationship constant. In addition a study was carried out on the influence of the alcohol concentration, working with molar relationships [1-hexanol]/[TTABr]=3, 4 and 5. On the basis of the molar volumes of the alcohol and surfactant and the concentration of alcohol at the interface it was possible to calculate the change in its volume with as varying compositions of the microemulsion. In order to interpret the experimental results a kinetic model was devised which takes into account the distribution of the reactants between the different pseudophases and the change in the volume of the interface. The rate constants at the interface of the microemulsion are lower than in pure water and are independent of the nature of the alcohol used as a cosurfactant and the molar relationship [alcohol]/[TTABr]. This independence indicates that the main role of the cosurfactant is to increase the volume of the interface with the consequent dilution of the reactants.

Journal Article↗
PubMed1991

L-6-[18F]fluoro-dopa metabolism in monkeys and humans: biochemical parameters for the formulation of tracer kinetic models with positron emission tomography.

Characterization of peripheral and cerebral L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) metabolism in humans and monkeys has shown FDOPA to be an analogue of L-DOPA for the study of the dopaminergic system with positron emission tomography (PET). In human studies with carbidopa pretreatment, L-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) was the only FDOPA metabolite detected in plasma. FDOPA administration in monkeys resulted in selective accumulation of FDOPA metabolites in central dopaminergic regions, whereas 3-OMFD of peripheral origin was uniformly distributed among putamen, caudate, frontal cortex, and cerebellum. At 60 min, 3-OMFD and 6-[18F]fluorodopamine (FDA) each represented approximately 35% of the total activity, the remainder being FDOPA and FDA metabolites. These data on monkey and human FDOPA metabolism provide the basis for the configuration of an FDOPA tracer kinetic model with PET.

Adult↗
PubMed1987

Analysis of BP response and Ca2+ metabolism using the saturation kinetics model.

The provision of supplemental dietary calcium (dCa) lowers blood pressure (BP) in the spontaneously hypertensive rat (SHR). Whether calcium's antihypertensive effects can be expressed in the presence of potentially hypertensinogenic nutrients is not known. Furthermore, the amount of dCa required to attenuate hypertension in the SHR remains undetermined. Along with establishing the effects of dCa on BP under conditions of a high Na+ intake, we sought to define the lowest dose of dCa associated with the greatest attenuation in arterial pressure in the young SHR. Thirty-five 6-wk-old SHR were fed one of five diets containing either 0.1, 0.25, 0.5, 1.0, or 2.0% dCa. All diets contained 1.0% Na+. The rates of change (delta) in body weight, BP, and serum ionized calcium were determined between 6 and 20 wk of age. Bone density (BD) was measured only at 20 wk of age. The data were analyzed using the saturation kinetics model. Results indicate that the half-maximal dose (K50) of dCa needed to lower pressure is 0.67 +/- 0.18%, which is higher than the K50 for weight (0.23 +/- 0.18) and BD (0.36 +/- 0.22). It is concluded that supplemental dCa lowers BP despite a high Na+ intake. Furthermore, a dose of approximately 1.5 dCa is sufficient to attenuate the rate of hypertension in the young growing SHR.

Age Factors↗
PubMed1990

Existence of a flip-flop kinetic model for zidovudine (AZT) after oral administration.

Using a three-way crossover experimental design, the effects of food and propantheline bromide on the pharmacokinetics of orally administered zidovudine (AZT; 3'-azido-3'-deoxythymidine) were assessed in six adult male Sprague-Dawley rats by the urinary excretion rate method. Accordingly, a single-10 mg/kg oral dose of AZT was administered as an aqueous solution to either fasting (F) rats, nonfasting (NF) rats or fasting rats pretreated with a 5 mg/kg oral dose of propantheline bromide (P; an inhibitor of GI motility). Quantitative urine collections were made at predetermined intervals for 24-32 hr after AZT administration, and each urine specimen was assayed for unmetabolized AZT by a sensitive and specific high-performance liquid chromatographic method. The mean extent of AZT absorption, as reflected by mean total urinary excretion values expressed as % of AZT dose, ranged from 72.9% to 75.2% and was unaffected by study condition. Kinetic interpretation of the terminal linear phase of the urinary excretion rate vs. time data yielded mean (+/- SD) half-lives of 4.35 +/- 2.1 hr for NF and 3.42 +/- 0.86 hr for P, which were significantly greater than the mean 1.58 +/- 0.63 hr half-life observed for F. The reported mean biological half-life of AZT after a 10 mg/kg intravenous dose to the same strain of rats is 0.76 +/- 0.35 hr (n = 6). After intravenous AZT administration, the terminal half-life reflects drug elimination. However, after oral AZT administration, the observed terminal half-lives reflect drug absorption rather than drug elimination (i.e., a flip-flop kinetic model is operable). There is some evidence to suggest that the disappearance of AZT from the blood of orally dosed AIDS patients may also be controlled by drug absorption.

Absorption↗
PubMed2002

Mutational analyses of the p35-caspase interaction. A bowstring kinetic model of caspase inhibition by p35.

Apoptosis is a highly regulated multistep process for programmed cellular destruction. It is centered on the activation of a group of intracellular cysteine proteases known as caspases. The baculoviral p35 protein effectively blocks apoptosis through its broad spectrum caspase inhibition. It harbors a caspase recognition sequence within a highly protruding reactive site loop (RSL), which gets cleaved by a target caspase before the formation of a tight complex. The crystal structure of the post-cleavage complex between p35 and caspase-8 shows that p35 forms a thioester bond with the active site cysteine of the caspase. The covalent bond is prevented from hydrolysis by the N terminus of p35, which repositions into the active site of the caspase to eliminate solvent accessibility of the catalytic residues. Here, we report mutational analyses of the pre-cleavage and post-cleavage p35/caspase interactions using surface plasmon resonance biosensor measurements, pull-down assays and kinetic inhibition experiments. The experiments identify important structural elements for caspase inhibition by p35, including the strict requirement for a Cys at the N terminus of p35 and the rigidity of the RSL. A bowstring kinetic model for p35 function is derived in which the tension generated in the bowstring system during the pre-cleavage interaction is crucial for the fast post-cleavage conformational changes required for inhibition.

Apoptosis↗
PubMed2005

Energetic mapping of Ni catalysts by detailed kinetic modeling.

Temperature-programmed desorption (TPD) of CO has been performed on supported and unsupported nickel catalysts. The unsupported Ni catalyst consists of a Ni(14 13 13) single crystal which has been studied under ultrahigh vacuum conditions. The desorption energy for CO at low CO surface coverage was found to be 119 kJ/mol, and the binding energy of C to the Ni(111) surface of the crystal was 703 kJ/mol. The supported catalysts consist of nickel supported on hydrotalcite-like compounds with three different Mg2+/Al3+ ratios. The experimental results show that for the supported Ni catalysts TPD of CO leads to desorption of both CO and CO2, with the latter being dominant. Dissociation of CO takes place, and considerable amounts of residue C are left on the surface. The residue C is removed by temperature-programmed oxidation (TPO). The results show that a low Mg2+/Al3+ ratio in the hydrotalcite precursor seems to result in more steplike sites, kinks, and defects for carbon monoxide dissociation. A detailed kinetic modeling of the TPO results based on elementary reaction steps has been conducted to give an energetic map of supported Ni catalysts. Experimental results from the ideal Ni surface fit nicely with literature values, providing useful information for identifying active sites on supported Ni catalysts.

Journal Article↗
PubMed2002

Thermodynamic and kinetic models for the extraction of essential oil from savory and polycyclic aromatic hydrocarbons from soil with hot (subcritical) water and supercritical CO2.

Mechanisms that control the extraction rates of essential oil from savory (Satureja hortensis) and polycyclic aromatic hydrocarbons (PAHs) from historically-contaminated soil with hot water and supercritical carbon dioxide were studied. The extraction curves at different solvent flow-rates were used to determine whether the extractions were limited primarily by the near equilibrium partitioning of the analyte between the matrix and solvent (i.e. partitioning thermodynamics, or the "elution" step) or by the rate of analyte desorption from the matrix (i.e. kinetics, or the "initial desorption" step). Two simple models were applied to describe the extraction profiles obtained with hot water and with supercritical CO2: (1) a model based solely on the thermodynamic distribution coefficient KD, which assumes that analyte desorption from the matrix is rapid compared to elution. and (2) a two-site kinetic model which assumes that the extraction rate is limited by the analyte desorption rate from the matrix, and is not limited by the thermodynamic (KD) partitioning that occurs during elution. For hot water extraction, the thermodynamic elution of analytes from the matrix was the prevailing mechanism as evidenced by the fact that extraction rates increased proportionally with the hot water flow-rate. This was also confirmed by the fact that simple removal calculations based on a single KD (for each essential oil compound) gave good fits to experimental data for flow-rates from 0.25 to 4 ml/min. In contrast, supercritical CO2 extraction showed only minimal dependence on flow-rate, and the simple KD model could only describe the initial 20-50% of the extraction. However, a simple two-site kinetic model gave a good fit for all CO2 flow-rates tested. The results of these investigations demonstrated that very simple models can be used to determine and describe extractions which are limited primarily by partitioning thermodynamics, or primarily by desorption kinetics. Furthermore, these results show that the time required for the recovery of essential oil from savory with hot water can be minimized by increasing flow-rate, with little change in the total volume of water required. In contrast, raising the flow-rate of supercritical CO2 has little effect on the mass of essential oils recovered per unit of time, indicating that optimal recovery of these compounds with supercritical CO2 (amount recovered for the lowest amount of CO2) requires longer extraction times rather than faster flow-rates.

Carbon Dioxide↗
PubMed2000

Insulin receptor binding kinetics: modeling and simulation studies.

Biological actions of insulin regulate glucose metabolism and other essential physiological functions. Binding of insulin to its cell surface receptor initiates signal transduction pathways that mediate cellular responses. Thus, it is of great interest to understand the mechanisms underlying insulin receptor binding kinetics. Interestingly, negative cooperative interactions are observed at high insulin concentrations while positive cooperativity may be present at low insulin concentrations. Clearly, insulin receptor binding kinetics cannot be simply explained by a classical bimolecular reaction. Mature insulin receptors have a dimeric structure capable of binding two molecules of insulin. The binding affinity of the receptor for the second insulin molecule is significantly lower than for the first bound insulin molecule. In addition, insulin receptor aggregation occurs in response to ligand binding and aggregation may also influence binding kinetics. In this study, we develop a mathematical model for insulin receptor binding kinetics that explicitly represents the divalent nature of the insulin receptor and incorporates receptor aggregation into the kinetic model. Model parameters are based upon published data where available. Computer simulations with our model are capable of reproducing both negative and positive cooperativity at the appropriate insulin concentrations. This model may be a useful tool for helping to understand the mechanisms underlying insulin receptor binding and the coupling of receptor binding to downstream signaling events.

Computer Simulation↗
PubMed2006

Methyaluminoxane (MAO) polymerization mechanism and kinetic model from ab initio molecular dynamics and electronic structure calculations.

MAO is the co-catalyst in metallocene catalytic systems, which are widely used in single-site olefin polymerization due to their high stereoselectivity. To date, the structures of the catalytically active compound or compounds in MAO have eluded researchers. Although many structural models have been proposed, none are generally accepted. In this study, aspects of the formation mechanism of MAO are addressed. Molecular dynamics simulations at the MP2 level of theory were carried out for presumed elementary steps in MAO formation via hydrolysis of trimethylaluminum (TMA). Methane production was observed, in agreement with experiment, as well as intermediate species that are consistent with the known structural features of MAO and similar to isolated and structurally characterized aluminoxanes. A (CH3)3Al-OH2 species, which we denote as TMA-OH2, containing a stable Al-O single bond emerged as the building block molecule. From this species, a hexameric cage was formed and activation barriers for the various reactions were calculated. Three distinct channels were identified for growth beyond the hexameric cage. It was concluded that MAO formation is a step polymerization through a bifunctional monomer, with [(CH3)Al-O] as the structural unit and a kinetic model was proposed. The structures that emerged were in agreement with the crystallographic evidence for aluminoxanes and support the experimental data regarding the MAO chemical composition.

Journal Article↗
PubMed1975

Errors and uncertainties in external radiation therapy. A system analysis with a cell kinetic model.

The relative importance of accurate knowledge and control of various biologic and physical factors in external radiation therapy was estimated with a simple cell kinetic treatment response model for a simulated tumour therapy situation. A set of parameter values was chosen for a reference case so that the calculated probability of zero surviving tumour cells was about 0.5. The parameters were varied, one at a time, over a range that was considered representative with respect to uncertainty in dose calculation, dose delivery and the description of the pertinent patient data. Also parameters in the cell kinetic model were varied. The calculations demonstrated a strong influence on the number of surviving cells from even moderate changes in the parameters which affect the tumour dose. Predictions with regard to curability are heavily dependent on the reliability of the biologic parameters in the model.

Cell Survival↗
PubMed1999

[Kinetic modeling of LDL oxidation using software (NELOP program) and validation in a population at vascular risk].

Oxidized LDL (low density lipoprotein) are considered to be the major initiating event in atherogenesis. In vitro models have been studied but no mathematic modeling can assess quantitatively the oxidability of LDL and antioxidant effects. We have developed a mathematic modeling allowing quantification of different kinetic parameters to LDL oxidation. This model has been validated by means of a software (software NELOP) in normal population (HV) and in a cardiovascular risk population, hemodialysis (HD). LDL are collected and purified by sequential ultracentrifugations from 12 healthy volunteers and hemodialysis patients. LDL oxidability (0.1 microM) is initiated by 5 microM copper and monitored continuously by conjugated diene production. All parameters are evaluated and correlated to those obtained by NELOP. Significant correlations between measured and calculated parameters (Vmax: r2 = 0.99, p < 0.05) allow to validate NELOP in both populations. Our results show that hemodialysis LDL present an enhanced susceptibility to copper induced oxidation (lag time: 96.6 +/- 48.6 mn in HV versus 54.5 +/- 22.2 mn in HD). NELOP seems to be a useful tool to evaluate LDL oxidation in cardiovascular risk populations.

Aged↗