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  • Springer  (588)
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  • 1995-1999  (588)
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  • Springer  (588)
  • American Institute of Physics (AIP)
  • Cell Press
  • Institute of Electrical and Electronics Engineers (IEEE)
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  • 1
    Electronic Resource
    Electronic Resource
    On the stability of wavelet and Gabor frames (Riesz bases) (1999)
    Springer
    The journal of Fourier analysis and applications 5 (1999), S. 105-125 
    Details
    ISSN: 1531-5851
    Keywords: 26B05 ; 42B10 ; 42C99 ; frame ; Gabor system ; Riesz basis ; stability ; wavelet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract If the sequence of functions ϕj, k is a wavelet frame (Riesz basis) or Gabor frame (Riesz basis), we obtain its perturbation system ψj,k which is still a frame (Riesz basis) under very mild conditions. For example, we do not need to know that the support of ϕ or ψ $$(\hat \phi or\hat \psi )$$ is compact as in [14]. We also discuss the stability of irregular sampling problems. In order to arrive at some of our results, we set up a general multivariate version of Littlewood-Paley type inequality which was originally considered by Lemarié and Meyer [17], then by Chui and Shi [9], and Long [16].
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01274192
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  • 2
    Electronic Resource
    Electronic Resource
    Human Interindividual Variability in Parameters Related to Health Risks (1999)
    Springer
    Risk analysis 19 (1999), S. 711-726 
    Details
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007045922532
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  • 3
    Electronic Resource
    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007017116171
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  • 4
    Electronic Resource
    Electronic Resource
    A stability criterion via fluid limits and its application to a polling system (1999)
    Springer
    Queueing systems 32 (1999), S. 131-168 
    Details
    ISSN: 1572-9443
    Keywords: stability ; positive recurrence ; fluid limit ; polling system ; exhaustive service policy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract We introduce a generalized criterion for the stability of Markovian queueing systems in terms of stochastic fluid limits. We consider an example in which this criterion may be applied: a polling system with two stations and two heterogeneous servers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1019187004209
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  • 5
    Electronic Resource
    Electronic Resource
    Stability of relative equilibria in arbitrary axisymmetric gravitational and magnetic fields (1999)
    Springer
    Celestial mechanics and dynamical astronomy 74 (1999), S. 19-57 
    Details
    ISSN: 1572-9478
    Keywords: stability ; Hamiltonian ; two centers ; oblate planet ; galactic disks ; dipole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Relative equilibria occur in a wide variety of physical applications, including celestial mechanics, particle accelerators, plasma physics, and atomic physics. We derive sufficient conditions for Lyapunov stability of circular orbits in arbitrary axisymmetric gravitational (electrostatic) and magnetic fields, including the effects of local mass (charge) and current density. Particularly simple stability conditions are derived for source‐free regions, where the gravitational field is harmonic (∇2U = 0) or the magnetic field irrotational (∇ × B = 0). In either case the resulting stability conditions can be expressed geometrically (coordinate‐free) in terms of dimensionless stability indices. Stability bounds are calculated for several examples, including the problem of two fixed centers, the J2 planetary model, galactic disks, and a toroidal quadrupole magnetic field.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008388105585
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  • 6
    Electronic Resource
    Electronic Resource
    Unrestricted Planar Problem of a Symmetric Body and a Point Mass. Triangular Libration Points and Their Stability (1999)
    Springer
    Celestial mechanics and dynamical astronomy 75 (1999), S. 251-285 
    Details
    ISSN: 1572-9478
    Keywords: unrestricted problem ; rotational motion ; rigid body dynamics ; libration points ; stability ; resonances
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We present an analysis of the model introduced by Kokoriev and Kirpichnikov (1988) for the study of unrestricted planar motion of a point mass and a symmetric rigid body whose gravity field is approximated by two point masses (a dumb-bell model). To show possible generalization of the model, we give a systematic derivation of equations of motion for a more general unrestricted problem of a point and a rigid body possessing a plane of dynamical symmetry. We give a simple description of bifurcation of triangular libration points, and we perform an analysis of their linear stability. We propose to extend the model of Kokoriev and Kirpichnikov (1988) to a case when the symmetric body is oblate. In the proposed model the gravity field of moving and rotating body is approximated by two complex masses at complex distance (a complex dumb-bell model). An analysis of bifurcation of the triangular libration points in this model is also presented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008337017789
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  • 7
    Electronic Resource
    Electronic Resource
    The Stability of Self-Organized Rule-Following Work Teams (1999)
    Springer
    Computational & mathematical organization theory 5 (1999), S. 5-30 
    Details
    ISSN: 1572-9346
    Keywords: network models ; organization theory ; rule following ; self organized ; stability ; work teams ; work routine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Self-organized rule-following systems are increasingly relevant objects of study in organization theory due to such systems&2018; capacity to maintain control while enabling decentralization of authority. This paper proposes a network model for such systems and examines the stability of the networks&2018; repetitive behavior. The networks examined are Ashby nets, a fundamental class of binary systems: connected aggregates of nodes that individually compute an interaction rule, a binary function of their three inputs. The nodes, which we interpret as workers in a work team, have two network inputs and one self-input. All workers in a given team follow the same interaction rule. We operationalize the notion of stability of the team&2018;s work routine and determine stability under small perturbations for all possible rules these teams can follow. To study the organizational concomitants of stability, we characterize the rules by their memory, fluency, homogeneity, and autonomy. We relate these measures to work routine stability, and find that stability in ten member teams is enhanced by rules that have low memory, high homogeneity, and low autonomy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009689326098
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  • 8
    Electronic Resource
    Electronic Resource
    Stability of a three‐station fluid network (1999)
    Springer
    Queueing systems 33 (1999), S. 293-325 
    Details
    ISSN: 1572-9443
    Keywords: stability ; fluid models ; multiclass queueing networks ; piecewise linear Lyapunov functions ; linear Lyapunov functions ; monotone global stability ; static buffer priority disciplines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract This paper studies the stability of a three‐station fluid network. We show that, unlike the two‐station networks in Dai and Vande Vate [18], the global stability region of our three‐station network is not the intersection of its stability regions under static buffer priority disciplines. Thus, the “worst” or extremal disciplines are not static buffer priority disciplines. We also prove that the global stability region of our three‐station network is not monotone in the service times and so, we may move a service time vector out of the global stability region by reducing the service time for a class. We introduce the monotone global stability region and show that a linear program (LP) related to a piecewise linear Lyapunov function characterizes this largest monotone subset of the global stability region for our three‐station network. We also show that the LP proposed by Bertsimas et al. [1] does not characterize either the global stability region or even the monotone global stability region of our three‐station network. Further, we demonstrate that the LP related to the linear Lyapunov function proposed by Chen and Zhang [11] does not characterize the stability region of our three‐station network under a static buffer priority discipline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1019184331042
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  • 9
    Electronic Resource
    Electronic Resource
    Implicit Multifunction Theorems (1999)
    Springer
    Set-valued analysis 7 (1999), S. 209-238 
    Details
    ISSN: 1572-932X
    Keywords: nonsmooth analysis ; subdifferentials ; coderivatives ; implicit function theorem ; solvability ; stability ; open mapping theorem ; metric regularity ; multidirectional mean value inequality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We prove a general implicit function theorem for multifunctions with a metric estimate on the implicit multifunction and a characterization of its coderivative. Traditional open covering theorems, stability results, and sufficient conditions for a multifunction to be metrically regular or pseudo-Lipschitzian can be deduced from this implicit function theorem. We prove this implicit multifunction theorem by reducing it to an implicit function/solvability theorem for functions. This approach can also be used to prove the Robinson–Ursescu open mapping theorem. As a tool for this alternative proof of the Robinson–Ursescu theorem, we also establish a refined version of the multidirectional mean value inequality which is of independent interest.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008775413250
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  • 10
    Electronic Resource
    Electronic Resource
    Dynamic scheduling in multiclass queueing networks: Stability under discrete-review policies (1999)
    Springer
    Queueing systems 31 (1999), S. 171-206 
    Details
    ISSN: 1572-9443
    Keywords: scheduling ; open multiclass queueing networks ; discrete-review policies ; fluid models ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract This paper describes a family of discrete-review policies for scheduling open multiclass queueing networks. Each of the policies in the family is derived from what we call a dynamic reward function: such a function associates with each queue length vector q and each job class k a positive value r k (q), which is treated as a reward rate for time devoted to processing class k jobs. Assuming that each station has a traffic intensity parameter less than one, all policies in the family considered are shown to be stable. In such a policy, system status is reviewed at discrete points in time, and at each such point the controller formulates a processing plan for the next review period, based on the queue length vector observed. Stability is proved by combining elementary large deviations theory with an analysis of an associated fluid control problem. These results are extended to systems with class dependent setup times as well as systems with alternate routing and admission control capabilities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1019106213778
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  • 11
    Electronic Resource
    Electronic Resource
    Recurrence and transience properties of some neural networks: an approach via fluid limit models (1999)
    Springer
    Queueing systems 32 (1999), S. 99-130 
    Details
    ISSN: 1572-9443
    Keywords: neural network ; inhibition ; stability ; Markov process ; fluid limit ; Harris-recurrence ; transience
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract The subject of the paper is the stability analysis of some neural networks consisting of a finite number of interacting neurons. Following the approach of Dai [5] we use the fluid limit model of the network to derive a sufficient condition for positive Harris-recurrence of the associated Markov process. This improves the main result in Karpelevich et al. [11] and, at the same time, sheds some new light on it. We further derive two different conditions that are sufficient for transience of the state process and illustrate our results by classifying some examples according to positive recurrence or transience.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1019135020138
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  • 12
    Electronic Resource
    Electronic Resource
    Window flow control in FIFO networks with cross traffic (1999)
    Springer
    Queueing systems 32 (1999), S. 195-231 
    Details
    ISSN: 1572-9443
    Keywords: window flow control ; TCP ; stability ; multiclass networks ; stationary ergodic point processes ; (max,+)-linear system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract We focus on window flow control as used in packet-switched communication networks. The approach consists in studying the stability of a system where each node on the path followed by the packets of the controlled connection is modeled by a FIFO (First-In-First-Out) queue of infinite capacity which receives in addition some cross traffic represented by an exogenous flow. Under general stochastic assumptions, namely for stationary and ergodic input processes, we show the existence of a maximum throughput allowed by the flow control. Then we establish bounds on the value of this maximum throughput. These bounds, which do not coincide in general, are reached by time-space scalings of the exogenous flows. Therefore, the performance of the window flow control depends not only on the traffic intensity of the cross flows, but also on fine statistical characteristics such as the burstiness of these flows. These results are illustrated by several examples, including the case of a nonmonotone, nonconvex and fractal stability region.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1019191105117
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  • 13
    Electronic Resource
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    Numerical computation of stability and detection of Hopf bifurcations of steady state solutions of delay differential equations (1999)
    Springer
    Advances in computational mathematics 10 (1999), S. 271-289 
    Details
    ISSN: 1572-9044
    Keywords: delay differential equations ; steady state solutions ; stability ; 34K20 ; 65J10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract The characteristic equation of a system of delay differential equations (DDEs) is a nonlinear equation with infinitely many zeros. The stability of a steady state solution of such a DDE system is determined by the number of zeros of this equation with positive real part. We present a numerical algorithm to compute the rightmost, i.e., stability determining, zeros of the characteristic equation. The algorithm is based on the application of subspace iteration on the time integration operator of the system or its variational equations. The computed zeros provide insight into the system’s behaviour, can be used for robust bifurcation detection and for efficient indirect calculation of bifurcation points.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018986817622
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  • 14
    Electronic Resource
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    A New Approach to Backward Error Analysis of Lu Factorization (1999)
    Springer
    BIT 39 (1999), S. 385-402 
    Details
    ISSN: 1572-9125
    Keywords: Gaussian elimination ; stability ; backward error analysis ; growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A new backward error analysis of LU factorization is presented. It allows to obtain a sharper upper bound for the forward error and a new definition of the growth factor that we compare with the well known Wilkinson growth factor for some classes of matrices. Numerical experiments show that the new growth factor is often of order approximately log2 n whereas Wilkinson's growth factor is of order n or $$\sqrt n$$ .
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022358300517
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  • 15
    Electronic Resource
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    Runge–Kutta–Nyström‐type parallel block predictor–corrector methods (1999)
    Springer
    Advances in computational mathematics 10 (1999), S. 115-133 
    Details
    ISSN: 1572-9044
    Keywords: Runge–Kutta–Nyström methods ; predictor–corrector methods ; stability ; parallelism ; 65M12 ; 65M20
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract This paper describes the construction of block predictor–corrector methods based on Runge–Kutta–Nyström correctors. Our approach is to apply the predictor–corrector method not only with stepsize h, but, in addition (and simultaneously) with stepsizes a i h, i = 1 ...,r. In this way, at each step, a whole block of approximations to the exact solution at off‐step points is computed. In the next step, these approximations are used to obtain a high‐order predictor formula using Lagrange or Hermite interpolation. Since the block approximations at the off‐step points can be computed in parallel, the sequential costs of these block predictor–corrector methods are comparable with those of a conventional predictor–corrector method. Furthermore, by using Runge–Kutta–Nyström corrector methods, the computation of the approximation at each off‐step point is also highly parallel. Numerical comparisons on a shared memory computer show the efficiency of the methods for problems with expensive function evaluations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018930732643
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  • 16
    Electronic Resource
    Electronic Resource
    Exponential Integrators for Quantum-Classical Molecular Dynamics (1999)
    Springer
    BIT 39 (1999), S. 620-645 
    Details
    ISSN: 1572-9125
    Keywords: Numerical integrator ; oscillatory solutions ; Schrödinger equation ; quantum-classical coupling ; error bounds ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We study time integration methods for equations of mixed quantum-classical molecular dynamics in which Newtonian equations of motion and Schrödinger equations are nonlinearly coupled. Such systems exhibit different time scales in the classical and the quantum evolution, and the solutions are typically highly oscillatory. The numerical methods use the exponential of the quantum Hamiltonian whose product with a state vector is approximated using Lanczos' method. This allows time steps that are much larger than the inverse of the highest frequencies. We describe various integration schemes and analyze their error behaviour, without assuming smoothness of the solution. As preparation and as a problem of independent interest, we study also integration methods for Schrödinger equations with time-dependent Hamiltonian.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022335122807
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  • 17
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    Three Dimensional Laser Simulation Code on a Desktop Personal Computer (1999)
    Springer
    Optical review 6 (1999), S. 28-36 
    Details
    ISSN: 1349-9432
    Keywords: optical propagation equation ; stability ; picosecond pulse ; 3-dimensional computation ; Fresnel’s distribution ; fast Fourier transform
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We present a new simulation code able to simulate the entire propagation of laser pulse, from the amplifiers level up to the focusing stage. This algorithm has some new characteristics that we intend to present. It computes the three-dimensional optical propagation equation using no approximation other than its picosecond expression. The stability has been carefully studied so that it can be applied to any geometry. This is a great improvement since, up to now only cylindrical geometry was accessible for accuracy. In this paper we also present a method using Fast Fourier Transform able to evaluate with a high accuracy, Fresnel’s distribution of a focused laser pulse. The advantages provided by our algorithm are its rapidity and its high physical understanding of the focusing phenomena.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s10043-999-0028-1
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  • 18
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    Global dynamical behavior of a three-body system with flexible connection in the gravitational field (1999)
    Springer
    Archive of applied mechanics 69 (1999), S. 47-54 
    Details
    ISSN: 1432-0681
    Keywords: Key words Bifurcation ; stability ; multibody system dynamics ; singularity theory ; Liapunov's direct method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Summary In this paper, the global behavior of relative equilibrium states of a three-body satellite with flexible connection under the action of the gravitational torque is studied. With geometric method, the conditions of existence of nontrivial solutions to the relative equilibrium equations are determined. By using reduction method and singularity theory, the conditions of occurrence of bifurcation from trivial solutions are derived, which agree with the existence conditions of nontrivial solutions, and the bifurcation is proved to be pitchfork-bifurcation. The Liapunov stability of each equilibrium state is considered, and a stability diagram in terms of system parameters is presented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004190050203
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  • 19
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    Sensitivity and Stability of the Classifications of Returns to Scale in Data Envelopment Analysis (1999)
    Springer
    Journal of productivity analysis 12 (1999), S. 55-75 
    Details
    ISSN: 1573-0441
    Keywords: Data envelopment analysis (DEA) ; returns to scale (RTS) ; sensitivity ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Economics
    Notes: Abstract Sensitivity of the returns to scale (RTS) classifications in data envelopment analysis is studied by means of linear programming problems. The stability region for an observation preserving its current RTS classification (constant, increasing or decreasing returns to scale) can be easily investigated by the optimal values to a set of particular DEA-type formulations. Necessary and sufficient conditions are determined for preserving the RTS classifications when input or output data perturbations are non-proportional. It is shown that the sensitivity analysis method under proportional data perturbations can also be used to estimate the RTS classifications and discover the identical RTS regions yielded by the input-based and the output-based DEA methods. Thus, our approach provides information on both the RTS classifications and the stability of the classifications. This sensitivity analysis method can easily be applied via existing DEA codes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007803207538
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  • 20
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    Can the ecosystem mimic hypotheses be applied to farms in African savannahs? (1999)
    Springer
    Agroforestry systems 45 (1999), S. 131-158 
    Details
    ISSN: 1572-9680
    Keywords: competition ; fertility ; microclimate ; risk ; stability ; water
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The first ecosystem mimic hypothesis suggests clear advantages if man-made land use systems do not deviate greatly in their resource use patterns from natural ecosystems typical of a given climatic zone. The second hypothesis claims that additional advantages will accrue if agroecosystems also maintain a substantial part of the diversity of natural systems. We test these hypotheses for the savannah zone of sub-Saharan Africa, with its low soil fertility and variable rainfall. Where annual food crops replace the natural grass understorey of savannah systems, water use will decrease and stream and groundwater flow change, unless tree density increases relative to the natural situation. Increasing tree density, however, will decrease crop yields, unless the trees meet specific criteria. Food crop production in the parkland systems may benefit from lower temperatures under tree canopies, but water use by trees providing this shade will prevent crops from benefiting. In old parkland trees that farmers have traditionally retained when opening fields for crops, water use per unit shade is less than in most fast growing trees introduced for agroforestry trials. Strong competition between plants adapted to years with different rainfall patterns may stabilise total system productivity -- but this will be appreciated by a farmer only if the components are of comparable value. The best precondition for farmers to maintain diversity in their agroecosystem hinges on the availability of a broad basket of choices, without clear winners or 'best bets'.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006245605705
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  • 21
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    Classical Lattice-Gas Models of Quasicrystals (1999)
    Springer
    Journal of statistical physics 95 (1999), S. 835-850 
    Details
    ISSN: 1572-9613
    Keywords: quasicrystals ; nonperiodic tilings ; classical lattice-gas models ; nonperiodic ground states ; nonperiodic Gibbs states ; stability ; frustration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract One of the fundamental problems of quasicrystals is to understand their occurrence in microscopic models of interacting particles. We review here recent attempts to construct stable quasicrystalline phases. In particular, we compare two recently constructed classical lattice-gas models with translation-invariant interactions and without periodic ground-state configurations. The models are based on nonperiodic tilings of the plane by square-like tiles. In the first model, all interactions can be minimized simultaneously. The second model is frustrated; its nonperiodic ground state can arise only by the minimization of the energy of competing interactions. We put forward some hypotheses concerning stabilities of nonperiodic ground states. In particular, we introduce two criteria, the so-called strict boundary conditions, and prove their equivalence to the zero-temperature stability of ground states against small perturbations of potentials of interacting particles. We discuss the relevance of these conditions for the low-temperature stability, i.e., for the existence of thermodynamically stable nonperiodic equilibrium states.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1004542115011
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    Non-Self-Similar Behavior in the LSW Theory of Ostwald Ripening (1999)
    Springer
    Journal of statistical physics 95 (1999), S. 867-902 
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    ISSN: 1572-9613
    Keywords: kinetics of phase transitions ; domain coarsening ; asymptotic behavior ; self-similarity ; stability ; chaos
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The classical Lifshitz–Slyozov–Wagner theory of domain coarsening predicts asymptotically self-similar behavior for the size distribution of a dilute system of particles that evolve by diffusional mass transfer with a common mean field. Here we consider the long-time behavior of measure-valued solutions for systems in which particle size is uniformly bounded, i.e., for initial measures of compact support. We prove that the long-time behavior of the size distribution depends sensitively on the initial distribution of the largest particles in the system. Convergence to the classically predicted smooth similarity solution is impossible if the initial distribution function is comparable to any finite power of distance to the end of the support. We give a necessary criterion for convergence to other self-similar solutions, and conditional stability theorems for some such solutions. For a dense set of initial data, convergence to any self-similar solution is impossible.
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    URL: http://dx.doi.org/10.1023/A:1004546215920
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    Stable Neuro-Adaptive Control for Robots with the Upper Bound Estimation on the Neural Approximation Errors (1999)
    Springer
    Journal of intelligent and robotic systems 26 (1999), S. 91-100 
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    ISSN: 1573-0409
    Keywords: robots ; neural networks ; adaptiveness ; stability ; approximation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract An indirect adaptive control approach is developed in this paper for robots with unknown nonlinear dynamics using neural networks (NNs). A key property of the proposed approach is that the actual joint angle values in the control law are replaced by the desired joint angles, angle velocities and accelerators, and the bound on the NN reconstruction errors is assumed to be unknown. Main theoretical results for designing such a neuro-controller are given, and the control performance of the proposed controller is verified with simulation studies.
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    URL: http://dx.doi.org/10.1023/A:1008195720685
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    Emergence of symmetric, modular, and reciprocal connections in recurrent networks with Hebbian learning (1999)
    Springer
    Biological cybernetics 81 (1999), S. 211-225 
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    ISSN: 1432-0770
    Keywords: Key words: Hebbian learning rule ; attractor dynamics ; symmetric connections ; multiplicative normalization ; self-organization ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract. While learning and development are well characterized in feedforward networks, these features are more difficult to analyze in recurrent networks due to the increased complexity of dual dynamics – the rapid dynamics arising from activation states and the slow dynamics arising from learning or developmental plasticity. We present analytical and numerical results that consider dual dynamics in a recurrent network undergoing Hebbian learning with either constant weight decay or weight normalization. Starting from initially random connections, the recurrent network develops symmetric or near-symmetric connections through Hebbian learning. Reciprocity and modularity arise naturally through correlations in the activation states. Additionally, weight normalization may be better than constant weight decay for the development of multiple attractor states that allow a diverse representation of the inputs. These results suggest a natural mechanism by which synaptic plasticity in recurrent networks such as cortical and brainstem premotor circuits could enhance neural computation and the generation of motor programs.
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    URL: http://dx.doi.org/10.1007/s004220050557
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    Shear band spacing in gradient-dependent thermoviscoplastic materials (1999)
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    Computational mechanics 23 (1999), S. 8-19 
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    ISSN: 1432-0924
    Keywords: Keywords: Material characteristic length ; strain-rate gradient ; dominant growth rate ; viscoplastic material ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract We study thermomechanical deformations of a viscoplastic body deformed in simple shear. The strain gradients are taken as independent kinematic variables and the corresponding higher order stresses are included in the balance laws, and the equation for the yield surface. Three different functional relationships, the power law, and those proposed by Wright and Batra, and Johnson and Cook are used to relate the effective strain rate to the effective stress and temperature. Effects of strain hardening of the material and elastic deformations are neglected. The homogeneous solution of the problem is perturbed and the stability of the problem linear in the perturbation variables is studied. Following Wright and Ockendon's postulate that the wavelength whose initial growth rate is maximum determines the minimum spacing between adjacent shear bands, the shear band spacing is computed. It is found that the minimum shear band spacing is very sensitive to the thermal softening coefficient/exponent, the material characteristic length and the nominal strain-rate. Approximate analytical expressions for the critical wave length for heat conducting nonpolar materials and locally adiabatic deformations of gradient dependent materials are also derived.
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    URL: http://dx.doi.org/10.1007/s004660050381
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    Thermal Analysis, Microcalorimetry and Combined Techniques for the Study of Pharmaceuticals (1999)
    Springer
    Journal of thermal analysis and calorimetry 56 (1999), S. 1285-1304 
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    ISSN: 1572-8943
    Keywords: amorphous state ; combined techniques ; drug design ; drug product development ; drug substance ; drug technology ; DSC ; excipients ; failure investigations ; hydrates ; MDSC ; microcalorimetry ; pharmaceuticals ; polymorphism ; polymers ; preformulation ; process optimization ; purity ; quality control ; solvates ; stability ; sub-ambient DSC ; TG ; temperature resolved X-ray diffraction ; water interactions ; thermal microscopy ; water sorption-desorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful in all steps of development of new drug products as well as methods for quality control in production. The characterization of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper development of new drug products with very small amount of material in a very short time. Information on stability, purity is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques.
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    URL: http://dx.doi.org/10.1023/A:1010194020563
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    Ignitability of Polymers Related to Polymer Properties and Different Steady States of Combustion Theoretical Approach (1999)
    Springer
    Journal of thermal analysis and calorimetry 55 (1999), S. 727-739 
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    ISSN: 1572-8943
    Keywords: ignition ; polymer combustion modelling ; stability ; steady state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A mathematical model of ignition and burning of organic polymers was used for evaluation and quantification of the tendency of polymers to ignition. The model permits investigation of the influence of one parameter of the polymer on the others. It was found that the model could be used for the verification of the ignitability method developed by Miller et al. [1]. Different steady states of combustion were found when using the model proposed. There is a characteristic steady state for normal flaming combustion, another for non-flaming combustion, and there are also unstable steady states that have no real physical meaning.
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    URL: http://dx.doi.org/10.1023/A:1010157011275
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    Thermodynamics of a 24-Mer Triple Helix Formation and Stability (1999)
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    Journal of thermal analysis and calorimetry 56 (1999), S. 1177-1184 
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    ISSN: 1572-8943
    Keywords: differential scanning calorimetry ; DNA triple helix ; oligonucleotides ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this work we report a thermodynamic characterization of stability and melting behaviour of two 24-mer DNA triplexes. The third strand, that binds the Watson-Crick double helix with Hoogsteen hydrogen bonds, contains 3′-3′ phosphodiester junction that determines the polarity inversion. The target double helix is composed of adjacent and alternate fragments of oligopurine-oligopyrimidine tracts. The two helices differ from the substitution of the cytosine, involved in the junction, with the thymine. Calorimetric data reported here provide a quantitative measure of the influence of pH and base modification on the stability of a DNA triplex.
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    Markov Control Processes with the Expected Total Cost Criterion: Optimality, Stability, and Transient Models (1999)
    Springer
    Acta applicandae mathematicae 59 (1999), S. 229-269 
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    ISSN: 1572-9036
    Keywords: (discrete-time) Markov control processes ; expected total cost ; value iteration ; policy iteration ; stability ; transient control models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract This paper studies the expected total cost (ETC) criterion for discrete-time Markov control processes on Borel spaces, and possibly unbounded cost-per-stage functions. It presents optimality results which include conditions for a control policy to be ETC-optimal and for the ETC-value function to be a solution of the dynamic programming equation. Conditions are also given for the ETC-value function to be the limit of the α-discounted cost value function as α ↑ 1, and for the Markov control process to be `stable" in the sense of Lagrange and almost surely. In addition, transient control models are fully analized. The paper thus provides a fairly complete, up-dated, survey-like presentation of the ETC criterion for Markov control processes on Borel spaces.
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    URL: http://dx.doi.org/10.1023/A:1006368714127
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    Bicelle-based liquid crystals for NMR-measurement of dipolar couplings at acidic and basic pH values (1999)
    Springer
    Journal of biomolecular NMR 13 (1999), S. 187-191 
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    ISSN: 1573-5001
    Keywords: alignment ; bicelle ; dipolar coupling ; liquid crystal ; pH ; stability ; ubiquitin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract It is demonstrated that mixtures of ditetradecyl- phosphatidylcholine or didodecyl-phoshatidylcholine and dihexyl- phosphatidylcholine in water form lyotropic liquid crystalline phases under similar conditions as previously reported for bicelles consisting of dimyristoyl-phosphatidylcholine (DMPC) and dihexanoyl- phosphatidylcholine (DHPC). The carboxy-ester bonds present in DMPC and DHPC are replaced by ether linkages in their alkyl analogs, which prevents acid- or base-catalyzed hydrolysis of these compounds. 15N-1H dipolar couplings measured for ubiquitin over the 2.3–10.4pH range indicate that this protein retains a backbone conformation which is very similar to its structure at pH 6.5 over this entire range.
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    Reproductive biology ofCaesalpinia calycina andC. pluviosa (Leguminosae) of the caatinga of north-eastern Brazil (1999)
    Springer
    Plant systematics and evolution 217 (1999), S. 43-53 
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    ISSN: 1615-6110
    Keywords: Leguminosae ; Caesalpinia ; Angiosperms ; bee-pollination ; andromonoecy ; late-acting self-incompatibility ; fruiting success
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The pollination biology, breeding system and fruiting success ofCaesalpinia calycina andC. pluviosa var.sanfranciscana were studied in caatinga vegetation in Bahia, NE Brazil. The principal pollinators for both species were carpenter bees.Caesalpinia calycina is andromonoecious but inC. pluviosa all flowers are hermaphrodite. InC. calycina all selfed flowers were abscised within 72 h despite rapid self-pollen tube growth to the ovary and ovule penetration. Prevention of selfing therefore seems to be controlled by a post-zygotic mechanism. Both species had very low fruit-set and it is suggested that this is at least in part due to geitonogamous pollinations with ovule penetration by self pollen tubes.
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    The role of competition in invertebrate community development in a recently formed stream in Glacier Bay National Park, Alaska (1999)
    Springer
    Aquatic ecology 33 (1999), S. 175-184 
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    ISSN: 1573-5125
    Keywords: Chironomidae ; interspecific competition ; streams ; stability ; succession
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract New streams formed following ice recession in Glacier Bay National Park, southeastern Alaska allow insights into the role of abiotic and biotic interactions in the assemblage of benthic communities. Reductions in abundance of a pioneer chironomid colonizer, Diamesa alpina/lupus, in one new stream, Wolf Point Creek, is considered to be a result of competitive interactions with subsequent colonizers, as opposed to intolerance of warmer water temperature as previously suggested. Reduced densities of potential competitors (25–50 larvae per 500 cm2) in a cobble transplant experiment between streams, allowed persistence of D. alpina/lupus at low densities. In addition, significantly more D. alpina/lupus larvae emigrated from artificial stream channels containing other chironomid taxa than channels without potential competitors while there was no significant correlation of emigration with water temperature. A small number of D. alpina/lupus transplanted from a cold stream (4–6 °C) survived at water temperatures of 10–15 °C for 1 week. These results infer that interference competition is the causal mechanism in the decline of D. alpina/lupus. Complete exclusion of D. alpina/lupus from the stream has not occurred and water temperature may play a role in partitioning D. alpina/lupus from other taxa on a temporal or a spatial basis.
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    A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug (1999)
    Springer
    Investigational new drugs 17 (1999), S. 49-56 
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    ISSN: 1573-0646
    Keywords: pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
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    A Sensitive Docetaxel Assay in Plasma by Solid-Phase Extraction and High Performance Liquid Chromatography – UV Detection: Validation and Suitability in Phase I Clinical Trial Pharmacokinetics (1999)
    Springer
    Investigational new drugs 17 (1999), S. 325-333 
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    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
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    Stability of a class of neural network models with delay (1999)
    Springer
    Applied mathematics and mechanics 20 (1999), S. 912-916 
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    ISSN: 1573-2754
    Keywords: delay ; neural network ; stability ; TN911.23 ; O332
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract In this paper, by using Liapunov functional, some sufficient conditions are obtained for the stability of the equilibrium of a neural network model with delay of the type $$u'_i \left( t \right) = - b_i u_i \left( t \right) + \sum\limits_{j = 1}^n {T_{ij} f_j } \left( {\mu _j u_j \left( {t - \tau _j } \right)} \right) + c_i ,\tau _j \geqslant 0,i = 1,2 \cdots ,n.$$
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    A method for following the unstable path between two saddle-node bifurcation points in nonlinear dynamic system (1999)
    Springer
    Applied mathematics and mechanics 20 (1999), S. 1384-1388 
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    ISSN: 1573-2754
    Keywords: nonlinear dynamic system ; bifurcation ; stability ; TB123 ; O322
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract A computation algorithm based on the Poincaré Mapping in combination with Pseudo-Arc Length Continuation Method is presented for calculating the unstable response with saddle-node bifurcation, and the singularity, which occurs using the general continuation method combined with Poincaré Mapping to follow the path, is also proved. A normalization equation can be introduced to avoid the singularity in the process of iteration, and a new iteration algorithm will be presented too. There will be two directions in which the path can be continued at each point, but only one can be used. The method of determining the direction will be presented in the paper. It can be concluded that is method is effective in analysis of nonlinear dynamic system with saddle-node bifurcations.
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    Some dynamical properties of a viscoelastic cylindrical shell (1999)
    Springer
    Applied mathematics and mechanics 20 (1999), S. 233-240 
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    ISSN: 1573-2754
    Keywords: viscoelasticity ; cylindrical shell ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract In this paper, the dynamic stability of a viscoelastic circular cylindrical shell subject to an axial compressive force and a uniformly distributed radial compressive load is discussed. By using the Laplace transformation, stability conditions of viscoelastic shell under constant loads are yielded. By using synthetically the classical dynamic methods, the various dynamical properties for the dynamical system defined by the viscoelastic shell and the effect of parameters on the stability of structure are obtained.
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    Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 301-323 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
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    Assuming Peripheral Elimination: Its Impact on the Estimation of Pharmacokinetic Parameters of Muscle Relaxants (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
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    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
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    Convergence of Delayed Dynamical Systems (1999)
    Springer
    Neural processing letters 10 (1999), S. 267-271 
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    ISSN: 1573-773X
    Keywords: recurrent neural networks ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract In this paper, we point out that the conditions given in [1] are sufficient but unnecessary for the global asymptotically stable equilibrium of a class of delay differential equations. Instead, we prove that under weaker conditions, it is still global asymptotically stable.
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    Stable and Real-Time Scheduling of a Class of Hybrid Dynamic Systems (1999)
    Springer
    Discrete event dynamic systems 9 (1999), S. 45-64 
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    ISSN: 1573-7594
    Keywords: hybrid dynamic systems ; event feedback ; real-time scheduling ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Based on some practical engineering problems arising from process control and space-structure control, this paper studies a class of hybrid dynamic systems in which N plants are controlled by a central controller in sharing time manner, where the plants are described by differential equations and the controller works according to the mechanism of discrete events. An event feedback strategy is suggested to be a scheduling policy such that one and only one plant among N plants is chosen to be controlled at any time. Some conditions of asymptotical and exponential stability are then given and an exponential upper bound of states norm is also estimated for the event feedback scheduling strategy. An algorithm based on event feedback strategy is presented to determine the control laws of the plants to meet the given performance. An example follows to illustrate the application and effect of the results.
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    Explicit second-order accurate schemes for the nonlinear Schrödinger equations (1999)
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    Lithuanian mathematical journal 39 (1999), S. 20-32 
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    ISSN: 1573-8825
    Keywords: Schrödinger equation ; explicit finite-difference schemes ; stability ; energy conservation ; convergence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We consider three-level explicit schemes for solving the nonlinear variable coefficient Schrödinger-type equation. Using spectral and energy methods we establish the stability and convergence of these schemes. The existence of discrete conservation laws is investigated. General results are applied for the DuFort-Frankel and leap-frog diffenrence schemes.
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    URL: http://dx.doi.org/10.1007/BF02465532
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    Rapid Attainment of Steady-State Plasma Drug Concentrations Within Precise Limits in Multicompartment Mammillary Systems (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
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    URL: http://dx.doi.org/10.1023/A:1020951230947
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    Population Pharmacokinetics and Pharmacodynamics of the Anti-CD11a Antibody hu1124 in Human Subjects with Psoriasis (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 397-420 
    Details
    ISSN: 1573-8744
    Keywords: psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
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    URL: http://dx.doi.org/10.1023/A:1020917122093
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    Drug–Drug Pharmacodynamic Interaction Detection by a Nonparametric Population Approach. Influence of Design and of Interindividual Variability (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 531-554 
    Details
    ISSN: 1573-8744
    Keywords: drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
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    URL: http://dx.doi.org/10.1023/A:1023290530853
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    Role of the Minimal State Variable Criterion in Rational Expectations Models (1999)
    Springer
    International tax and public finance 6 (1999), S. 621-639 
    Details
    ISSN: 1573-6970
    Keywords: expectations ; bubbles ; uniqueness ; stability ; state variables ; multiplicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Economics
    Notes: Abstract This paper concerns the minimal-state-variable (MSV) criterion for selection among solutions in rational expectationsmodels that feature a multiplicity of paths that satisfy all of the model's conditions. It compares the MSVcriterion with others, including the widely used saddle-path (dynamic stability) criterion. It is emphasized that theMSV criterion can be viewed as a scientifically useful classification scheme that delineates the unique solutionthat is free of bubble components. In the process of demonstrating uniqueness for a broad class of linear models,the paper exposits a convenient computational procedure. Applications to current issues are outlined.
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    URL: http://dx.doi.org/10.1023/A:1008746610773
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    Numerical modeling of nonlinear deformation and buckling of composite plate-shell structures under pulsed loading (1999)
    Springer
    Mechanics of composite materials 35 (1999), S. 495-506 
    Details
    ISSN: 1573-8922
    Keywords: layered structure ; shells ; frames ; stringers ; nonlinearity ; stability ; pulsed loading ; numerical methods
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Nonlinear three-dimensional problems of dynamic deformation, buckling, and posteritical behavior of composite shell structures under pulsed loads are analyzed. The structure is assumed to be made of rigidly joined plates and shells of revolution along the lines coinciding with the coordinate directions of the joined elements. Individual structural elements can be made of both composite and conventional isotropic materials. The kinematic model of deformation of the structural elements is based on Timoshenko-type hypotheses. This approach is oriented to the calculation of nonstationary deformation processes in composite structures under small deformations but large displacements and rotation angles, and is implemented in the context of a simplified version of the geometrically nonlinear theory of shells. The physical relations in the composite structural elements are based on the theory of effective moduli for individual layers or for the package as a whole, whereas in the metallic elements this is done in the framework of the theory of plastic flow. The equations of motion of a composite shell structure are derived based on the principle of virtual displacements with some additional conditions allowing for the joint operation of structural elements. To solve the initial boundary-value problem formulated, an efficient numerical method is developed based on the finite-difference discretization of variational equations of motion in space variables and an explicit second-order time-integration scheme. The permissible time-integration step is determined using Neumann's spectral criterion. The above method is especially efficient in calculating thin-walled shells, as well as in the case of local loads acting on the structural element, when the discretization grid has to be condensed in the zones of rapidly changing solutions in space variables. The results of analyzing the nonstationary deformation processes and critical loads are presented for composite and isotropic cylindrical shells reinforced with a set of discrete ribs in the case of pulsed axial compression and external pressure.
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    URL: http://dx.doi.org/10.1007/BF02259471
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    A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
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    ISSN: 1573-8744
    Keywords: propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
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    URL: http://dx.doi.org/10.1023/A:1020903315017
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    Indirect-Response Modeling of Desmopressin at Different Levels of Hydration (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    Details
    ISSN: 1573-8744
    Keywords: desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
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    URL: http://dx.doi.org/10.1023/A:1023238514015
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    Constructing a Prediction Interval for Time to Reach a Threshold Concentration Based on a Population Pharmacokinetic Analysis: An Application to Basiliximab in Renal Transplantation (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 213-230 
    Details
    ISSN: 1573-8744
    Keywords: prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
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    URL: http://dx.doi.org/10.1023/A:1020658023774
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    Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    Details
    ISSN: 1573-8744
    Keywords: T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
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    On Invariant Manifolds in Singularly Perturbed Systems (1999)
    Springer
    Journal of dynamical and control systems 5 (1999), S. 501-507 
    Details
    ISSN: 1573-8698
    Keywords: Singular perturbation ; invariant manifold ; overflowing manifold ; stability ; characteristic numbers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract A singularly perturbed system with a small parameter ε at the velocity of the slow variable y and with the fast variable x is considered. The main hypothesis is that for all y from some bounded domain D, the fast subsystem has a stable invariant or overflowing manifold M 0(y) and that the motions in this system going in the directions transversal to M 0(y) are more fast than the mutual approaching of trajectories on M 0(y) (a precise statement is given in terms of appropriate Lyapunov-type characteristic numbers). It is proved that for a sufficiently small ε, the whole system has an invariant manifold close to $$\bigcup\limits_{y \in D} {M_0 (y) \times \{ y\}}$$ the degree of its smoothness is specifed.
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    Preparation and Characterization of Carmustine Loaded Polyanhydride Wafers for Treating Brain Tumors (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 762-765 
    Details
    ISSN: 1573-904X
    Keywords: polymer implant ; brain cancer ; carmustine ; polyanhydride ; stability ; controlled release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011995728760
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    Formulation and Lyoprotection of Poly(Lactic Acid-Co-Ethylene Oxide) Nanoparticles: Influence on Physical Stability and In Vitro Cell Uptake (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 859-866 
    Details
    ISSN: 1573-904X
    Keywords: nanoparticles ; poly(lactic acid) ; poly(lactic acid-co-ethylene oxide) ; freeze-drying ; stability ; flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the feasibility of producing freeze-dried poly-(ethylene oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid the mononuclear phagocytic system (MPS), as a function of the PEO chain length and surface density. Methods. The nanoparticles were produced by the salting-out method using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid-co-ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross-flow filtration and freeze-dried as such or with variable amounts of trehalose as a lyoprotectant. The redispersibility of the particles was determined immediately after freeze-drying and after 12 months of storage at −25° C. The uptake of the nanoparticles by human monocytes was studied in vitro by flow cytometry. Results. PLA-PEO nanoparticles could be produced from all the polymeric blends used. Particle aggregation after freeze-drying was shown to be directly related to the presence of PEO. Whereas this problem could be circumvented by use of trehalose, subsequent aggregation was shown to occur during storage. These phenomena were possibly related to the specific thermal behaviours of PEO and trehalose. In cell studies, a clear relationship between the PEO content and the decrease of uptake was demonstrated. Conclusions. The rational design of freeze-dried PEO-surface modified nanoparticles with potential MPS avoidance ability is feasible by using the polymer blends approach combined with appropriate lyoprotection and optimal storage conditions.
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    URL: http://dx.doi.org/10.1023/A:1018826103261
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    Relationship Between Etomidate Plasma Concentration and EEG Effect in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 924-929 
    Details
    ISSN: 1573-904X
    Keywords: etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
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    URL: http://dx.doi.org/10.1023/A:1018894523734
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    Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 944-948 
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    ISSN: 1573-904X
    Keywords: bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
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    A Physiological Pharmacokinetic Model for Solute Disposition in Tissues Below a Topical Application Site (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1392-1398 
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    ISSN: 1573-904X
    Keywords: topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
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    Isolation, Characterization, and Stability of Positional Isomers of Mono-PEGylated Salmon Calcitonins (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 813-818 
    Details
    ISSN: 1573-904X
    Keywords: calcitonin ; polyethylene glycol ; PEGylation ; peptide ; tryptic digestion ; stability ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To separate and characterize the different positional isomers of mono-PEGylated salmon calcitonins (mono-PEG-sCTs) and to evaluate the effects of the PEGylation site on the stability of different mono-PEG-sCTs in rat kidney homogenate. Methods. Mono-PEG-sCTs were prepared using succinimidyl carbonate monomethoxy polyethylene glycol (5,000 Da) and separated by gel-filtration HPLC followed by reversed-phase HPLC. To characterize PEGylated sCTs, matrix-assisted laser desorption ionization time of flight mass spectrometry (M ALDI-TOF MS) and reversed-phase HPLC of the trypsin digested samples were performed. Mono-PEG-sCTs and sCT in rat kidney homogenates were measured by column-switching reversed-phase HPLC with on-line detection of the radioiodinated samples using a flow-through radioisotope detector. Results. Three different mono-PEGylated sCTs were separated by reversed-phase gradient HPLC. From the MALDI-TOF MS analysis, the average molecular weight of mono-PEG-sCTs was confirmed as around 8650 Da. The presence of PEG moiety in the mono-PEG-sCTs was also manifested by the fact that the distance between two adjacent mass spectum lines was 44 Da which corresponds to PEG monomer unit. Tryptic digestion analysis demonstrated that these mono-PEG-sCTs are 3 positional isomers of N-terminus, Lys18- and Lys11-residue modified mono-PEGylated sCTs. The degradation half-life of these 3 positional isomers in rat kidney homogenates significantly increased in order of the N-terminus (125.5 min), Lys11- (157.3 min), and Lysl8-residue modified mono-PEGylated sCT (281.5 min) over the native sCT (4.8 min). Conclusions. Three positional isomers of mono-PEGylated sCTs were purified and characterized. Of these, the resistance to proteolytic degradation was highest for the Lysl8-residue modified mono-PEG-sCT. These studies demonstrate that the in vivo stability of PEGylated sCTs is highly dependent on the site of PEG molecule attachment.
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    Venous Irritation, Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 930-938 
    Details
    ISSN: 1573-904X
    Keywords: submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
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    Distribution and Binding Kinetics of Ciprofloxacin and Ofloxacin in the Hindlimb of the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 587-591 
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    ISSN: 1573-904X
    Keywords: quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011939616948
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    Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1219-1225 
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    ISSN: 1573-904X
    Keywords: C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
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    Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1226-1232 
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    ISSN: 1573-904X
    Keywords: HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
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    Pharmacokinetic Features and Metabolism of Calphostin C, A Naturally Occurring Perylenequinone with Antileukemic Activity (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1003-1009 
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    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
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    Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1093-1097 
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    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
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    Magnoliid reproductive organs from the Cenomanian-Turonian of north-western Kazakhstan:Magnoliaceae andIlliciaceae (1999)
    Springer
    Plant systematics and evolution 216 (1999), S. 265-288 
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    ISSN: 1615-6110
    Keywords: Illiciaceae ; Illiciospermum ; Liriodendroidea ; Magnoliaceae ; Angiosperms ; Cretaceous ; fossil seeds ; Kazakhstan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Cenomanian-Turonian sediments from the Sarbay locality in north-western Kazakhstan have yielded a rich assemblage of plant fossils including well preserved flowers, fruits, and seeds of angiosperms. This work describes fossil seeds assigned to theMagnoliaceae and theIlliciaceae. Three new species of the extinct magnoliaceous genusLiriodendroidea, L. asiatica, L. costata, andL. tenuitesta, are established and new information on the previously described species,L. alata, is provided. TheLiriodendroidea seeds are closely similar to seeds of extantLiriodendron, but are distinguished in being much smaller and winged. A new genus and species,Illiciospermum pusillum, is established based on seeds with close similarity to those of the extant genusIllicium. The seeds are small, anatropous and exotestal with outer epidermis of testa forming a palisade layer. The facets of the palisade cells have deeply undulate anticlinal walls. The micropyle area is seen on the outer integument as a transverse slit placed on a raised strophiole-like structure close to the hilum. TheIlliciospermum seeds represent the first unequivocal record of theIlliciaceae in the Cretaceous. Another seed of possible illiciaceous affinity is described as aff.Illiciospermum sp.
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    Therps16 intron and the phylogeny of theRubioideae (Rubiaceae) (1999)
    Springer
    Plant systematics and evolution 214 (1999), S. 161-186 
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    ISSN: 1615-6110
    Keywords: Rubiaceae ; Rubioideae ; Angiosperms ; cladistics ; DNA sequences ; phylogeny ; rps16 intron ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The phylogeny of the subfamilyRubioideae (Rubiaceae) was estimated from sequence variation in therps16 intron (cpDNA) in 143 ingroup and 5 outgroup taxa. The analysis largely confirms a recent one based onrbcL sequences, but branch support is often much stronger. Three of the traditional subfamilies are supported,Rubioideae, Cinchonoideae s. str., andIxoroideae s. l. while there is no support forAntirheoideae. TheRubioideae are the sister group of all otherRubiaceae and comprise the tribesAnthospermeae, Coccocypseleae, Cruckshanksieae, Coussareeae, Gaertnereae, Hedyotideae, Knoxieae, Morindeae, Ophiorrhizeae, Paederieae, Pauridiantheae, Perameae, Psychotrieae, Rubieae, Spermacoceae, Theligoneae, andUrophylleae. TheHamelieae andHillieae belong to theCinchonoideae. Rachicallis andSiemensia should be transferred from theHedyotideae to theCinchonoideae. ThePauridiantheae, Urophylleae, Ophiorrhizeae, andRaritebe form the basalmost subclade of theRubioideae. The second basalmost clade consists of the generaLasianthus andPerama. The third basalmost clade consists of the tribesCoussareeae, Coccocypseleae andCruckshanksieae, and the generaDeclieuxia andHindsia. The tribesKnoxieae, Anthospermeae, Argostemmateae, Paederieae, Theligoneae, Rubieae, Hedyotideae, andSpermacoceae are members of one clade. TheKnoxieae are monophyletic ifOtiophora, Otomeria, andPentas are included. The tribeAnthospermeae is supported as monophyletic, but its subtribes are not. ThePaederieae, together withTheligonum, form a paraphyletic grade basal to theRubieae. TheHedyotideae, includingSchismatoclada, form a grade at the base of theSpermacoceae. TheGaertnereae are monophyletic and distinct from thePsychotrieae. TheMorindeae are monophyletic and includeDamnacanthus andMitchella. Schradera is the sister group of theMorindeae. ThePsychotrieae are monophyletic when theGaertnereae, Lasianthus, andDeclieuxia are excluded. The recognition of a subtribeHydnophytineae leaves the rest of thePsychotrieae paraphyletic.Psychotria is paraphyletic with respect to all other genera of the tribe. Approximately 50 genera are here classified for the first time based on molecular data.
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    Genome characterization and relationships between two species of the genusLobelia (Campanulaceae) determined by repeated DNA sequences (1999)
    Springer
    Plant systematics and evolution 214 (1999), S. 211-218 
    Details
    ISSN: 1615-6110
    Keywords: Campanulaceae ; Lobelia ; Angiosperms ; in situ hybridization ; karyotype evolution ; rDNA ; telomere
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Three repeated DNA sequences (rDNA 5S, 18S-5.8S-26S and telomeric repeats) were localised in the genomes ofLobelia brasiliensis andL. imperialis var.kanitzii (subg.Tupa), both with 2n = 28, by fluorescence in situ hybridization (FISH). The results were used to analyse the genomic relationship between the species. With probe pTa71, the karyotypes of these species showed only one NOR site. Probe pTa794, which contains 5S rDNA, demonstrated differences between the species. Telomeric sequences, studied with probe pLT11, were not detected in ectopic sites, but different telomeres showed signals of varying intensity. Based on the results obtained, considerations are made on karyotype evolution inLobelia.
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    On the Stability of a Laminar Wall Jet with Heat Transfer (1999)
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    Flow, turbulence and combustion 62 (1999), S. 137-162 
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    ISSN: 1573-1987
    Keywords: laminar wall jet ; heat transfer ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract The hydrodynamic stability of a low speed, plane, non-isothermal laminar wall jet at a constant temperature boundary condition was investigated theoretically and experimentally. The mean velocity and temperature profiles used in the stability analysis were obtained by implementing the Illingworth–Stewartson transformation that allows one to extend the classical Glauert solution to a thermally non-uniform flow. The stability calculations showed that the two unstable eigenmodes coexisting at moderate Reynolds numbers are significantly affected by the heat transfer. Heating is destabilizing the flow while cooling is stabilizing it. However, the large-scale instabilities associated with the inflection point of the velocity profile still amplify in spite of the high level of the stabilizing temperature difference. The calculated stability characteristics of the wall jet with heat transfer were compared with experimental data. The comparison showed excellent agreement for small amplitudes of the imposed perturbations. The agreement is less good for the phase velocities of the sub-harmonic wave and this is attributed to experimental difficulties and to nonlinear effects.
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    Orbital Migration Of Giant Planets: Using Numerical Integration To Investigate Consequences For Other Bodies (1999)
    Springer
    Earth, moon and planets 87 (1999), S. 103-115 
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    ISSN: 1573-0794
    Keywords: Accretion ; exoplanetary system ; extrasolar planets ; numerical integration ; orbital migration ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Abstract A number of extrasolar planets have been detected in close orbits around nearby stars. It is probable that these planets did not form in these orbits but migrated from their formation locations beyond the ice line. Orbital migration mechanisms involving angular momentum transfer through tidal interactions between the planets and circumstellar gas-dust disks or by gravitational interaction with a residual planetesimal disk together with several means of halting inward migration have been identified. These offer plausible schemes to explain the orbits of observed extrasolar giant planets and giant planets within the Solar System. Recent advances in numerical integration methods and in the power of computer workstations have allowed these techniques to be applied to modelling directly the mechanisms and consequences of orbital migration in the Solar System. There is now potential for these techniques also to be applied to modelling the consequences of the orbital migration of planets in the observed exoplanetary systems. In particular the detailed investigation of the stability of terrestrial planets in the habitable zone of these systems and the formation of terrestrial planets after the dissipation of the gas disk is now possible. The stability of terrestrial planets in the habitable zone of selected exoplanetary systems has been established and the possibility of the accretion of terrestrial planets in these systems is being investigated by the author in collaboration with Barrie W. Jones (Open University), and with John Chambers (NASA-Ames) and Mark Bailey of Armagh Observatory, using numerical integration. The direct simulation of orbital migration by planetesimal scattering must probably await faster hardware and/or more efficient algorithms.
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    Robust Stability of Multivariate Polynomials. Part 1: Small Coefficient Perturbations (1999)
    Springer
    Multidimensional systems and signal processing 10 (1999), S. 7-20 
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    ISSN: 1573-0824
    Keywords: multivariate polynomials ; stability ; robust stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract This paper presents a detailed analysis of some classes of stable multivariate polynomials. The main aim of the analysis is to give conditions under which polynomials preserve stability when they are subjected to small coefficient variations. The maximal class of such polynomials is introduced. Some basic properties of polynomials from this class are obtained.
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    Stability and resilience in benthic macroinvertebrate assemblages (1999)
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    Hydrobiologia 403 (1999), S. 123-133 
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    ISSN: 1573-5117
    Keywords: disturbance ; stability ; resilience ; Trichoptera ; Ephemeroptera ; Psychomyia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Benthic macroinvertebrate assemblages of Bushkill Creek, Northampton County, PA were studied at the same site during the 1970s (11 dates) and 1990s (8 dates) to evaluate stability and resilience. In the 1970s, a Surber sampler was used, and in the 1990s, a Hess sampler. Assemblages appeared stable over a wide range of environmental stresses with the exception of 1994–1995 when total numbers and total Trichoptera decreased. Taxa richness and EPT indices varied little in 1994–1995 from other sampled years. By July 1996, all metrics (Trichoptera numbers, total numbers, taxa richness, EPT index, Bray-Curtis Index) resembled the 1970s exception for lower wet weight. Bray-Curtis indices and taxa composition were similar in July 1972 and July 1996, suggesting assemblage stability over 25 years. The Trichoptera, Psychomyia (Psychomiidae) and Leucotrichia (Hydroptilidae), decreased during the 1990s and never rebounded to 1970s numbers. During winter 1994, the coldest temperatures and greatest cumulative snowfall occurred in the region. These conditions probably stressed the assemblage with low temperatures, anchor/frazil ice and ice break-up. The assemblage was then exposed to four bankful floods in winter/spring 1994 and five bankful floods in winter/spring 1996. Recovery time following these multiple disturbances was 27 months. Previous recovery times from winter and flood disturbances were considerably shorter (2–5 months). The 1990s recovery time (5–9 times previusly recorded) for this assemblage was apparently extended by multiple physical disturbances, outside the predicted range. The assemblages had not been previously exposed to such severe conditions and, therefore, recovery time was extended. Despite severe weather conditions, the assemblage recovered and exhibited both stability and resilience in its return to an assemblage similar to the 1970s.
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    Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 309-323 
    Details
    ISSN: 1573-6830
    Keywords: cytochrome P450 ; enzyme inhibition ; enzyme induction ; pharmacokinetics ; drug interaction ; in vitro assessment ; clinical assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man. 2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes. 3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data. 4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.
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    Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know? (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 355-372 
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    ISSN: 1573-6830
    Keywords: enantiomers ; racemic ; chiral ; stereoselective ; pharmacokinetics ; cytochrome P450 ; geometric isomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.
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    Metabolism and Pharmacokinetics of Selective Serotonin Reuptake Inhibitors (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 443-466 
    Details
    ISSN: 1573-6830
    Keywords: selective serotonin reuptake inhibitors ; metabolism ; pharmacokinetics ; fluoxetine ; fluvoxamine ; paroxetine ; sertraline ; citalopram ; cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.
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    Metabolism of Tricyclic Antidepressants (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 373-409 
    Details
    ISSN: 1573-6830
    Keywords: antidepressants ; tricyclic ; metabolism ; hydroxy metabolites ; pharmacokinetics ; pharmacogenetics ; drug–drug interactions ; toxicity ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.
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    URL: http://dx.doi.org/10.1023/A:1006949816036
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    Procedures for the characterisation of bioaerosol particles. Part I: aerosolisation and recovery agent effects (1999)
    Springer
    Aerobiologia 15 (1999), S. 267-280 
    Details
    ISSN: 1573-3025
    Keywords: aerosolisation effects ; bioaerosol ; bioaerosol sampling ; effects of recovery agents ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The sampling and assay of bioaerosols are important ina number of industrial and health-care applications. Airborne microorganisms are notoriously difficult toenumerate accurately under such conditions and nosingle procedure is suitable for all applications. Problems are compounded by the differences in assaymethod or sampler type selected, making theinterpretation of results difficult.Understanding the airborne behaviour of microorganismsover a range of environmental conditions is vital ifprocedures are to be defined and recommended for theassessment of bioaerosols. Microorganisms that arerobust over a wide range of conditions are ideal astracer particles. Unfortunately, the large majorityof non-fungal bioaerosols are susceptible to damage. A predictable assessment procedure is required whichwill not affect the viability of the collectedsample. This paper examines how aerosolisation may affect the characteristics of two speciesof microorganism (Pseudomonas fluorescens andMS2 coliphage). It forms part of a larger programmeto develop standards for the assessment of biologicalparticles. The aim of the work was to develop procedures toexamine the effects of aerosolisation onmicroorganisms, with particular reference topre-aerosolisation protocol (spray suspension age) andpost-sampling handling protocol (aerosol age incollection solution). These procedures were then usedto examine the effect of recovery agents, addedto the spray suspension prior to aerosolisation, onthe culturability of E.coli. Aerosolisation reduces the culturability of P. fluorescensand the viability of viability of MS2coliphage. Pre-sampling and post-collection handlingand storage of these aerosolised microorganisms werealso found to have an effect. This and earlierstudies have shown that the culturable fraction ofmicroorganisms can be affected by the same factorsdescribed above. Of five microorganisms tested so farin the main programme, only Penicillium expansumspores were shown to be robust and stable with aconstant culturable fraction. Therefore, recommendinga particular microorganism (apart from P. expansum) as an airborne biological standard foraerosol studies is not advised. It is recommendedthat a microorganism, representative of the envisagedapplication, be characterised it in terms of theaerosolisation parameters, storage time and conditionsin the manner reported in this study. This can beachieved using the experimental equipment described.The addition of 0.1 mM concentrations of the sugarsinositol, trehalose and raffinose to spray suspensionsof Escherichia coli, prior to aerosolisation,made no significant difference to the culturablefraction of the aerosol.
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    URL: http://dx.doi.org/10.1023/A:1007638711384
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    Equilibrium stability of generalized Birkhoff's autonomous system (1999)
    Springer
    Applied mathematics and mechanics 20 (1999), S. 564-567 
    Details
    ISSN: 1573-2754
    Keywords: generalized Birkhoff's system ; equilibrium state ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract In this paper, equilibrium stability of generalized Birkhoff's autonomous system is discussed. First, equilibrium equations of generalized Birkhoff's autonomous system are set up, and then the linear approximate method and direct method of stability in equilibrium state are studied. Some results on equilibrium of generalized Birkhoff's autonomous system are obtained on the basis of Lyapunov's thorem. Last, the application of the results is illustrated with an example.
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    URL: http://dx.doi.org/10.1007/BF02463754
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    Portfolio optimization via stochastic programming: Methods of output analysis (1999)
    Springer
    Mathematical methods of operations research 50 (1999), S. 245-270 
    Details
    ISSN: 1432-5217
    Keywords: Key words: Portfolio optimization ; stochastic programming ; stability ; postoptimality ; worst-case analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Notes: Abstract. Solutions of portfolio optimization problems are often influenced by errors or misspecifications due to approximation, estimation and incomplete information. Selected methods for analysis of results obtained by solving stochastic programs are presented and their scope illustrated on generic examples – the Markowitz model, a multiperiod bond portfolio management problem and a general strategic investment problem. The approaches are based on asymptotic and robust statistics, on the moment problem and on results of parametric optimization.
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    URL: http://dx.doi.org/10.1007/s001860050097
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    The effect of Li and La on NiO/Al2O3 catalyst for CH4/O2 to syngas reaction (1999)
    Springer
    Reaction kinetics and catalysis letters 68 (1999), S. 243-247 
    Details
    ISSN: 1588-2837
    Keywords: Methane partial oxidation ; nickel-based catalysts ; stability ; sintering and loss of nickel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The thermal stability and an 80 h life test over nickel-based catalysts for CH4/O2 to syngas reaction were investigated by flow-reactor, XPS, XRD and AAS analysis. The results indicate that the introduction of Li and La not only stabilized the support γ-Al2O3 phase, but also suppressed the sintering and loss of nickel, and in addition, enhanced the ability to suppress the carbon-deposition over NiO/Al2O3 during the high-temperature reaction.
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    URL: http://dx.doi.org/10.1007/BF02475508
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    Distribution of a 20-Mer Phosphorothioate Oligonucleotide, CGP69846A (ISIS 5132), into Airway Leukocytes and Epithelial Cells Following Intratracheal Delivery to Brown-Norway Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1542-1549 
    Details
    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
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    URL: http://dx.doi.org/10.1023/A:1015048419558
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    Analyzing Rich Data Using Different Methods Provided by NONMEM: Pharmacokinetics of Telmisartan Following Intravenous Infusion to Healthy Volunteers (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 772-776 
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    ISSN: 1573-904X
    Keywords: nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011997229669
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    Pharmacokinetics and Tissue Disposition in Monkeys of an Antisense Oligonucleotide Inhibitor of Ha-Ras Encapsulated in Stealth Liposomes (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1309-1315 
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    ISSN: 1573-904X
    Keywords: antisense phosphorothioate oligonucleotide ; stealth liposome ; pharmacokinetics ; monkey ; capillary gel electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
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    URL: http://dx.doi.org/10.1023/A:1014822219133
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    Pharmacokinetics of Aminolevulinic Acid After Intravesical Administration to Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 288-295 
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    ISSN: 1573-904X
    Keywords: aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
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    URL: http://dx.doi.org/10.1023/A:1018840827910
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    Characterization of Ocular Pharmacokinetics of Beta-Blockers Using a Diffusion Model After Instillation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1596-1601 
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    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
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    URL: http://dx.doi.org/10.1023/A:1018964823193
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    A Pharmacokinetic Model for Tenidap in Normal Volunteers and Rheumatoid Arthritis Patients (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1608-1615 
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    ISSN: 1573-904X
    Keywords: tenidap ; pharmacokinetics ; EM algorithm ; nonlinear mixed-effects modelling ; covariates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. Methods. Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. Results. Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. Conclusions. The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
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    URL: http://dx.doi.org/10.1023/A:1018969024101
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    Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1694-1701 
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    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
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    Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 176-185 
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    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; pharmacology ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
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    URL: http://dx.doi.org/10.1023/A:1011907920641
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    Influence of Crystal Habit on Trimethoprim Suspension Formulation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 261-265 
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    ISSN: 1573-904X
    Keywords: crystal habit ; trimethoprim suspension ; physical stability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.
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    URL: http://dx.doi.org/10.1023/A:1018832526093
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    Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 309-313 
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    ISSN: 1573-904X
    Keywords: hyperlipidemia ; hypercholesterolemia ; nifedipine ; pharmacokinetics ; protein binding ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg−1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82−2.02 to 5.27−11.05 mmol L−1 48 h post P407 administration (Ig kg−1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC0−∞, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0−∞ was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.
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    Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 117-122 
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    ISSN: 1573-904X
    Keywords: WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharma-codynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
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    A Multiple-Shooting Technique for Optimal Control (1999)
    Springer
    Journal of optimization theory and applications 102 (1999), S. 299-313 
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    ISSN: 1573-2878
    Keywords: Comparison of methods ; optimal control ; sensitivity ; shooting methods ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A new method for solving optimal control problems, here called multiple NOC shooting, is presented. It is developed from NOC shooting. It has some advantages over its parent and over multiple shooting, which are both successful, high-accuracy methods for optimal control. A comparison of the three methods is given, incorporating two examples.
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    New Linear Program Performance Bounds for Queueing Networks (1999)
    Springer
    Journal of optimization theory and applications 100 (1999), S. 575-597 
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    ISSN: 1573-2878
    Keywords: Queueing networks ; scheduling ; stability ; performance evaluation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We obtain new linear programs for bounding the performance and proving the stability of queueing networks. They exploit the key facts that the transition probabilities of queueing networks are shift invariant on the relative interiors of faces and the cost functions of interest are linear in the state. A systematic procedure for choosing different quadratic functions on the relative interiors of faces to serve as surrogates of the differential costs in an inequality relaxation of the average cost function leads to linear program bounds. These bounds are probably better than earlier known bounds. It is also shown how to incorporate additional features, such as the presence of virtual multi-server stations to further improve the bounds. The approach also extends to provide functional bounds valid for all arrival rates.
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    URL: http://dx.doi.org/10.1023/A:1022638523391
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    Binding and Ionophoric Properties of Polythioamide Compounds. Ag(I) and Hg(II) Selectivities (1999)
    Springer
    Journal of inclusion phenomena and macrocyclic chemistry 34 (1999), S. 277-289 
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    ISSN: 1573-1111
    Keywords: complexes ; stability ; extraction ; transport ; tetrathiolactams
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The synthesis of tetrathiolactams and related di- and tetrathioamide compounds is described. The formation constants of their heavy-metal complexes are determined by using the strong UV absorption of the thioamide chromophore. Extraction and transport abilities of tetrathioamide ionophores show selectivities for Ag(I) and Hg(II) cations over alkali, alkaline-earth or other heavy metal cations including transition metals such as Co(II).
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    Polarographic Studies on Anion Coordination Chemistry. Host–Guest Interactions of Hexacyclen and Pentacyclen with Pyrophosphate, Selenite, Selenate, Molybdate and Tungstate Anions (1999)
    Springer
    Journal of inclusion phenomena and macrocyclic chemistry 34 (1999), S. 455-464 
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    ISSN: 1573-1111
    Keywords: hexacyclen ; pentacyclen ; anion complexes ; stoichiometry ; stability ; polarography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The complexation of protonated hexacyclen and pentacyclen with pyrophosphate, selenite, selenate, molybdate and tungstate anions was studied by differential pulse polarography at 25 °C. The stoichiometry and stability of the resulting anion complexes were evaluated from the pH and concentration-dependence of the peak potentials, respectively. The results established 1 : 1 anion receptor complexation in all cases. In the case of all anions studied, hexacyclen was found to form more stable anion complexes than pentacyclen. The fact that the anion-receptor complexation depends on the structural features of both the anions and the macrocycles used is indicative of a steric controlled interaction.
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    Closed-Loop Stability Monitoring of Axial Flow Compression Systems (1999)
    Springer
    Nonlinear dynamics 20 (1999), S. 181-196 
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    ISSN: 1573-269X
    Keywords: monitoring ; stability ; compressors ; axial flow compressors ; stall ; surge ; bifurcation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Monitoring systems are proposed for the detection of incipient instability in axial flow compression systems. The work employs generic features associated with the response to noise inputs of systems bordering on instability. Based on these generic features, a closed-loop monitoring system is proposed. Numerical simulation is used to illustrate the operation of the proposed closed-loop monitoring system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1004596213600
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  • 96
    Electronic Resource
    Electronic Resource
    On the Reconstitution Problem in the Multiple Time-Scale Method (1999)
    Springer
    Nonlinear dynamics 19 (1999), S. 135-158 
    Details
    ISSN: 1573-269X
    Keywords: perturbation methods ; higher-order approximations ; dynamical systems ; codimension ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Higher-order multiple-scale methods for general multiparameter mechanical systems are studied. The role played by the control and imperfection parameters in deriving the perturbative equations is highlighted. The definition of the codimension of the problem, borrowed from the bifurcation theory, is extended to general systems, excited either externally or parametrically. The concept of a reduced dynamical system is then invoked. Different approaches followed in the literature to deal with reconstituted amplitude equations are discussed, both in the search for steady-state solutions and in the analysis of stability. Four classes of methods are considered, based on the consistency or inconsistency of the approach, and on the completeness or incompleteness of the terms retained in the analysis. The four methods are critically compared and general conclusions drawn. Finally, three examples are illustrated to corroborate the findings and to show the quantitative differences between the various approaches.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008330423238
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  • 97
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    Electronic Resource
    Articulated Pipes Conveying Fluid Pulsating with High Frequency (1999)
    Springer
    Nonlinear dynamics 19 (1999), S. 173-193 
    Details
    ISSN: 1573-269X
    Keywords: fluid conveying pipes ; high-frequency pulsating fluid ; separation of slow and fast motion ; stability ; nonlinear dynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Stability and nonlinear dynamics of two articulated pipes conveying fluid with a high-frequency pulsating component is investigated. The non-autonomous model equations are converted into autonomous equations by approximating the fast excitation terms with slowly varying terms. The downward hanging pipe position will lose stability if the mean flow speed exceeds a certain critical value. Adding a pulsating component to the fluid flow is shown to stabilize the hanging position for high values of the ratio between fluid and pipe-mass, and to marginally destabilize this position for low ratios. An approximate nonlinear solution for small-amplitude flutter oscillations is obtained using a fifth-order multiple scales perturbation method, and large-amplitude oscillations are examined by numerical integration of the autonomous model equations, using a path-following algorithm. The pulsating fluid component is shown to affect the nonlinear behavior of the system, e.g. bifurcation types can change from supercritical to subcritical, creating several coexisting stable solutions and also anti-symmetrical flutter may appear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008326812760
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  • 98
    Electronic Resource
    Electronic Resource
    Double Hopf Bifurcations and Chaos of a Nonlinear Vibration System (1999)
    Springer
    Nonlinear dynamics 19 (1999), S. 313-332 
    Details
    ISSN: 1573-269X
    Keywords: double pendulum system ; double Hopf bifurcation ; stability ; chaos
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A double pendulum system is studied for analyzing the dynamic behaviour near a critical point characterized by nonsemisimple 1:1 resonance. Based on normal form theory, it is shown that two phase-locked periodic solutions may bifurcate from an initial equilibrium, one of them is unstable and the other may be stable for certain values of parameters. A secondary bifurcation from the stable periodic solution yields a family of quasi-periodic solutions lying on a two-dimensional torus. Further cascading bifurcations from the quasi-periodic motions lead to two chaoses via a period-doubling route. It is shown that all the solutions and chaotic motions are obtained under positive damping.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008347523779
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  • 99
    Electronic Resource
    Electronic Resource
    Preventing buoyancy-driven flows of two Bingham fluids in a closed pipe – Fluid rheology design for oilfield plug cementing (1999)
    Springer
    Journal of engineering mathematics 36 (1999), S. 327-348 
    Details
    ISSN: 1573-2703
    Keywords: Bingham fluids ; multi-layer flow ; no-flow/yield criteria ; stability ; variational methods.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Technology
    Notes: Abstract The mechanically unstable situation of a heavy Bingham fluid resting on top of a light Bingham fluid in an inclined closed-ended pipe can be stabilised if the fluids have sufficiently large yield stresses. This paper focuses on determining the yield stresses that are sufficient to keep the fluids statically stable for a given fluid density difference, pipe diameter and pipe inclination. The results are applicable to a broad class of practically observable flows. This situation provides an idealised model for the oilfield process of plug cementing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1004511113745
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  • 100
    Electronic Resource
    Electronic Resource
    A Multibody Motion Stability Analysis (1999)
    Springer
    Multibody system dynamics 3 (1999), S. 287-299 
    Details
    ISSN: 1573-272X
    Keywords: multibody dynamics ; symbol manipulation ; linearization ; stability ; Floquet theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract It is shown that use of AUTOLEV, a symbol manipulation computer program for mechanics analyses, can greatly facilitate the stability analysis of motions of multibody systems.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009882505218
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