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  • pharmacokinetics  (133)
  • stability  (87)
  • Zea mays
  • Springer  (283)
  • American Meteorological Society
  • Elsevier
  • National Academy of Sciences
  • Periodicals Archive Online (PAO)
  • 1995-1999  (128)
  • 1990-1994  (155)
  • 1999  (128)
  • 1991  (155)
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  • Springer  (283)
  • American Meteorological Society
  • Elsevier
  • National Academy of Sciences
  • Periodicals Archive Online (PAO)
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  • 1995-1999  (128)
  • 1990-1994  (155)
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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
    Factors influencing dispersal of larval Coleomegilla maculata from the weed Acalypha ostryaefolia to sweet corn (1999)
    Springer
    Entomologia experimentalis et applicata 90 (1999), S. 313-322 
    Details
    ISSN: 1570-7458
    Keywords: Coleoptera ; Coccinellidae ; Coleomegilla maculata ; Euphorbiaceae ; Acalypha ostryaefolia ; Zea mays ; dispersal ; predator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The polyphagous predator, Coleomegilla maculata (DeGeer) (Coleoptera: Coccinellidae), commonly oviposits on the native weed, Acalypha ostryaefolia Riddell (Euphorbiaceae), in and around Kentucky sweet corn fields. Cannibalism of eggs by C. maculata adults and larvae is drastically lower on A. ostryaefolia than on nearby sweet corn plants. We examined ovipositional preference of C. maculata for A. ostryaefolia plants or sweet corn plants, dispersal of larvae from A. ostryaefolia plants, capability for dispersal of larvae across bare soil (e.g., to nearby plants), ability of larvae to climb from ground level up A. ostryaefolia plants or sweet corn plants, and effect of A. ostryaefolia borders adjacent to sweet corn plots on C. maculata population density in sweet corn. The ovipositional preference study revealed that C. maculata laid more eggs on A. ostryaefolia than on corn. First-instar C. maculata that hatched from egg clusters on A. ostryaefolia dispersed predominantly by falling, rather than crawling, to the ground. Glandular trichomes on A. ostryaefolia petioles and stems apparently inhibited intraplant movement of first instars, resulting in those larvae falling directly from leaves to the ground. Some first instars were capable of moving at least 8 m across bare soil in 24 h. From the ground, significantly more first instars climbed sweet corn plants than climbed A. ostryaefolia plants. Significantly more larvae were present in sweet corn plots bordered by A. ostryaefolia plants than in sweet corn plots without an A. ostryaefolia border. These findings show that physical attributes of companion plants can significantly influence natural enemy populations on crop plants by affecting interplant dispersal of natural enemies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026429217088
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  • 5
    Electronic Resource
    Electronic Resource
    Stability properties of proliferatively coupled cell replication models (1991)
    Springer
    Acta biotheoretica 39 (1991), S. 1-14 
    Details
    ISSN: 1572-8358
    Keywords: Hematological diseases ; first order partial differential equations ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract To address the possibility that proliferative disorders may originate from interactions between multiple populations of proliferating and maturing cells, we formulate a model for this process as a set of coupled nonlinear first order partial differential equations. Using recent results for the asymptotic behaviour of the solutions to this model, we demonstrate that there exists a region of coupling coefficients, maturation rates, and proliferation rates that will guarantee the stable coexistence of coupled cellular populations. The analysis shows that increases in the coupling between populations may ultimately lead to a loss of stability. Furthermore, the analysis indicates that increases (decreases) in the maturation and/or proliferation rates above (below) critical levels will lead either to instability in the populations or the destruction of one population and the persistence of the other.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00046404
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  • 6
    Electronic Resource
    Electronic Resource
    Influence of washing and of heat-treatment conditions on the thermal stability of VPI-5 (1991)
    Springer
    Catalysis letters 10 (1991), S. 225-232 
    Details
    ISSN: 1572-879X
    Keywords: VPI-5 ; stability ; molecular sieve ; post-synthesis treatments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Thorough washing of a VPI-5 synthesized with n-dipropylamine as template improves greatly its thermal stability while no major change is observed in the template content. A detailed study of the influence of the pretreatment conditions shows that in order to obtain a high thermal stability (up to at least 960 °C) two parameters are of importance. The removal of both the template and the adsorbed water requires either a low heating rate at atmospheric pressure or a low pressure (less than 3 Torr) when the heating rate is 300 ° per hour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00772075
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  • 7
    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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  • 8
    Electronic Resource
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    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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  • 9
    Electronic Resource
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    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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  • 10
    Electronic Resource
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    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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  • 11
    Electronic Resource
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    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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  • 12
    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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  • 13
    Electronic Resource
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    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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  • 14
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    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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  • 15
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    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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  • 16
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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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  • 17
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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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  • 18
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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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  • 19
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    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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  • 20
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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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  • 21
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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 
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    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.
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    URL: http://dx.doi.org/10.1007/s004190050203
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    Multivariate exploratory data analysis in chemical industry (1991)
    Springer
    Microchimica acta 104 (1991), S. 467-482 
    Details
    ISSN: 1436-5073
    Keywords: prediction ; stability ; multivariate methods ; graphical analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sizeable data bases are now being routinely generated in a variety of contexts in chemical industry. Statistical investigations of such data bases are aimed both at initially uncovering structure and eventually proposing models, in particular for predicting product quality by the mix or characteristics of the chemical compounds. “Online Multivariate Exploratory Graphical Analysis” (OMEGA) stands for a structured exploratory study of the relationships in a multivariate data set, where, rather than testing for one specific property, as many clues as possible for interesting structures are searched for by different dimension reductions and succeeding interactive graphical analyses. The stability of the projections obtained by the different dimension reduction methods is assessed by simulation producing graphical displays particularly supporting the identification of influential points. The variation of the predictions obtained by the different dimension reduction methods is assessed by cross-validation delivering misclassification rates or cross-validated R2 values. The interpretation of the new coordinates corresponding to dimension reduction is supported by loading simplifications and graphical displays for judging its adequacy. The OMEGA strategy has been found to be an effective tool for routine searching for structure.
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    URL: http://dx.doi.org/10.1007/BF01245532
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    Nonabelian K-theory: The nilpotent class of K 1 and general stability (1991)
    Springer
    K-Theory 4 (1991), S. 363-397 
    Details
    ISSN: 1573-0514
    Keywords: Nonabelian K 1 ; noncommutative homotopy ; general linear group ; superspecial linear groups ; descending central series ; stability ; relative normal subgroups ; nilpotent sandwich classifications ; quasi-finite algebras
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A functorial filtration GL n =S−1L n $$ \supseteq$$ S0L n $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n $$ \supseteq$$ ⋯ $$ \supseteq$$ E n of the general linear group GL n, n ⩾ 3, is defined and it is shown for any algebra A, which is a direct limit of module finite algebras, that S−1 L n (A)/S0L n (A) is abelian, that S0L n (A) $$ \supseteq$$ S1L n (A) $$ \supseteq$$ ⋯ is a descending central series, and that S i L n (A) = E n(A) whenever i ⩾ the Bass-Serre dimension of A. In particular, the K-functors k 1 S i L n =S i L n /E n are nilpotent for all i ⩾ 0 over algebras of finite Bass-Serre dimension. Furthermore, without dimension assumptions, the canonical homomorphism S i L n (A)/S i+1 L n (A)→S i L n+ 1(A)/S i+1 L n + 1 (A) is injective whenever n ⩾ i + 3, so that one has stability results without stability conditions, and if A is commutative then S0L n (A) agrees with the special linear group SL n (A), so that the functor S0L n generalizes the functor SL n to noncommutative rings. Applying the above to subgroups H of GL n (A), which are normalized by E n(A), one obtains that each is contained in a sandwich GL′ n (A, ρ) $$ \supseteq$$ H $$ \supseteq$$ E n(A, ρ) for a unique two-sided ideal ρ of A and there is a descending S0L n (A)-central series GL′ n (A, ρ) $$ \supseteq$$ S0L n (A, ρ) $$ \supseteq$$ S1L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ E n(A, ρ) such that S i L n (A, ρ)=E n(A, ρ) whenever i ⩾ Bass-Serre dimension of A.
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    URL: http://dx.doi.org/10.1007/BF00533991
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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 
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    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.
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    URL: http://dx.doi.org/10.1023/A:1007803207538
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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 
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    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'.
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    URL: http://dx.doi.org/10.1023/A:1006245605705
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    Crop yield and tree-leaf production in three planting patterns of temperate-zone alley cropping in Oregon, USA (1999)
    Springer
    Agroforestry systems 46 (1999), S. 273-288 
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    ISSN: 1572-9680
    Keywords: A,nus rubra ; hedgerow intercropping ; Robina pseudoacacia ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The objective of this study was to determine crop and tree productivity in several alley cropping planting patterns. The four- year study was conducted in western Oregon, United States and involved irrigated sweet corn (Zea mays) intercropped between hedgerows of red alder (Alnus rubra) and black locust (Robina pseudoacacia). Three alley cropping planting patterns with variable plant populations and tree-crop proximity were tested with each tree species in a randomized block design. Space available to trees and crops determined yield of both plant components. High crop yield coincided with low pruning yield, and vice versa. Compared to monocropping, yield reductions in traditional alley cropping planting patterns with widely spaced, double tree rows ranged from 5% to 15%. A. rubra and R. pseudoacacia coppiced readily and produced 0.9 to 4.7 tons of dry matter pruning biomass per growing season, depending on planting pattern and year. A. rubra yield continually increased during the trial, while the ability of R. pseudoacacia to produce green manure after frequent coppicing appeared to weaken. After four years, soil organic matter was 4 to 7% higher in the topsoil of an alley cropping system compared to a monocropping system. However, continuous growing of sweet corn resulted in decreased soil organic matter levels in both cropping systems compared to original levels. Crop yield reductions and the need for additional management inputs constrain the implementation of alley cropping in temperate climates. Only if benefits other than minor soil fertility improvements are realized is alley cropping a feasible alternative in temperate climate regions.
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    URL: http://dx.doi.org/10.1023/A:1006204018212
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    Classical Lattice-Gas Models of Quasicrystals (1999)
    Springer
    Journal of statistical physics 95 (1999), S. 835-850 
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    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.
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    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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    Expression of MADS box genes ZMM8 and ZMM14 during inflorescence development of Zea mays discriminates between the upper and the lower floret of each spikelet (1999)
    Springer
    Development genes and evolution 209 (1999), S. 411-420 
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    ISSN: 1432-041X
    Keywords: Key words Flower development ; Floral determinacy ; Spikelet ; MADS box genes ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Most floral meristem and organ identity genes of dicotyledonous plants belong to the MADS box gene family. Since they are generally transcribed in those tissues and organs whose identity they determine, they are excellent markers for developmental processes. Here we report the cDNA cloning of a pair of MADS box genes, ZMM8 and ZMM14, from the monocotyledonous plant maize. Maize inflorescences are composed of spikelets which contain two florets, an upper and a lower one. Although upper and lower florets develop in a very similar way in male inflorescences, ZMM8 and ZMM14 expression was found in all organs of upper florets, but no transcripts were detected in lower florets. In contrast, two other MADS box genes were found to be expressed in lower florets in the same way as in upper florets. Our observations suggest that during spikelet development ZMM8 and ZMM14 work as selector genes which are involved in distinguishing the upper from the lower floret. Alternatively, these genes may be involved in conferring determinacy to the spikelet or upper floret meristem. Our data suggest that in the phylogenetic lineage that led to maize an ancient type of MADS box gene has been recruited during evolution for the establishment of novel positional information not found within the simple inflorescences of dicotyledonous plants such as Arabidopsis.
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    URL: http://dx.doi.org/10.1007/s004270050271
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    Observations on the subcellular distribution of the ammonium ion in maize root tissue using in-vivo 14N-nuclear magnetic resonance spectroscopy (1991)
    Springer
    Planta 183 (1991), S. 359-367 
    Details
    ISSN: 1432-2048
    Keywords: Ammonium compartmentation ; Cytoplasm ; Vacuole ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We show that the pH dependence of the base-catalysed exchange rate of the ammonium ion provides a basis for discriminating between the cytoplasmic and vacuolar pools of ammonium in plant tissues. In vivo, 14N-nuclear magnetic resonance spectra were recorded with and without 1H-decoupling and information on the subcellular distribution of NH 4 + was obtained from a lineshape analysis of the 1H-coupled spectrum. We applied this method to maize (Zea mays L.) root tissues and found that: (i), the cytoplasmic ammonium concentration was low, which was in accord with the large activity of glutamine synthetase present in the roots; and (ii), inhibition of glutamine synthetase with methionine sulphoximine increased the cytoplasmic ammonium concentration, and led to the appearance of ammonium in the xylem sap.
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    Mitochondrial gene expression in developing male gametophytes of male-fertile and S male-sterile maize (1999)
    Springer
    Sexual plant reproduction 11 (1999), S. 323-330 
    Details
    ISSN: 1432-2145
    Keywords: Key words Cytoplasmic male sterility ; Pollen development ; Zea mays ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Mitochondria play a critical role in the normal development of the plant male gametophyte and in the disruption of normal gametophyte development associated with cytoplasmically inherited male sterility (CMS). To investigate the role of mitochondria in these processes, the accumulation of mitochondrial gene transcripts and the accumulation of nuclear gene transcripts encoding mitochondrial proteins were investigated through male gametophyte development in normal maize and through the course of pollen abortion in CMS-S maize. Male gametophytes differing in developmental stage were isolated from male-fertile or male-sterile plants by sucrose density gradient centrifugation. Mature pollen was collected from dehiscent anthers of male-fertile plants. Aborted pollen, which collapsed during starch accumulation, was isolated from emergent tassels of CMS-S male-sterile plants. Microspores, developing pollen and mature pollen exhibited striking differences in mitochondrial transcript accumulation. Mature pollen lacked detectable mitochondrial transcripts. Aborted pollen of CMS-S plants contained abundant, intact transcripts of all mitochondrial genes studied, but prematurely degraded transcripts of several nuclear genes. Transcripts of the CMS-S associated mitochondrial open reading frames (orf355 and orf77) were detected from the early stages of microspore development through the aborted pollen stage. The implications of these findings are discussed in terms of the mitochondrial requirements for pollen function and the mechanism of pollen abortion in CMS-S maize.
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    URL: http://dx.doi.org/10.1007/s004970050159
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    In vitro fertilization of single, isolated gametes of maize mediated by electrofusion (1991)
    Springer
    Sexual plant reproduction 4 (1991), S. 12-16 
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    ISSN: 1432-2145
    Keywords: In vitro fertilization ; Egg cell ; Sperm cell ; Electrofusion ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Electrofusion-mediated in vitro fertilization of maize using single sperm and egg cells was performed. Sperm cells were released from pollen grains after rupture of the latter by osmotic shock in the fusion medium (0.55 M mannitol). Egg cells were isolated by enzyme treatment (pectinase, pectolyase, hemicellulase, and cellulase) followed by mechanical isolation. The conditions generally used for the electrical fusion of protoplasts of somatic cells were also applied to the protoplasts of gametic cells of maize. Electrofusion was performed with single pairs of gametes under microscopic observation. The mean fusion frequency was 79%. Isolated egg cells of maize showed protoplasmic streaming during 22 days of culture, but they did not divide. However, after fusion of the sperm with the egg cells, these fused cells did develop, with a mean division frequency of 83%, and grew to multicellular structures. Egg cells and fusion products were cultivated with a maize feeder-cell system.
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    Extracellular matrix surface network of embryogenic units of friable maize callus contains arabinogalactan-proteins recognized by monoclonal antibody JIM4 (1999)
    Springer
    Plant cell reports 18 (1999), S. 369-374 
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    ISSN: 1432-203X
    Keywords: Key words Arabinogalactan-proteins ; Somatic embryogenesis ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Embryogenic units of friable maize callus are formed as globular or oblong packets of tightly associated meristematic cells. These units are surrounded by conspicuous cell walls visible in light microscopy after staining with basic fuchsin. Transmission electron microscopy revealed that embryogenic cells are rich in endoplasmic reticulum, polysomes and small protein bodies, and that the outermost layer of their cell walls is composed of fibrillar material. Electron microscopy has also shown that this material covers the surface of embryogenic cells as a distinct layer which we denote as extracellular matrix surface network (ECMSN). Employing histochemical staining with β-glucosyl Yariv phenylglycoside, we localized arabinogalactan-proteins (AGPs) to the outer cell walls of embryogenic units including ECMSN. The most prominent staining was found in cell-cell junction domains. Large non-embryogenic callus cells were not stained with this AGP-specific dye. Immunofluorescence and silver-enhanced immunogold labelling using monoclonal antibody JIM4 has shown that the ECMSN of embryogenic cells is equipped with JIM4 epitope, while non-embryogenic callus cells are devoid of this epitope. We propose that some specific AGPs of the ECMSN might be relevant for cell-cell adhesion and recognition of embryogenic cells during early embryogenic stages, and that the JIM4 antibody can serve as an early marker of embryogenic competence in maize callus culture.
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    Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 369-374 
    Details
    ISSN: 1432-1041
    Keywords: Alpidem ; Anxiolytics ; pharmacokinetics ; tolerance ; metabolites ; sedation ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, placebo-controlled, crossover experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0–54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1–4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng · ml−1, respectively. In 50% of the subjects cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng · ml−1 · h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18,1 and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related. Thus the kinetics of alpidem and its three major metabolites were linear after doses of 25 to 200 mg. The drug was well tolerated by most of the subjects. Sedation and dizziness occurred mainly after the 100 and 200 mg doses.
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    Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 449-452 
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    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; Caffeine ; pharmacokinetics ; P-450 mono-oxygenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diabetes may alter the pharmacokinetics of aminopyrine and antipyrine, which are used to assess liver function. Caffeine has recently been used to test liver function, but the effect of diabetes on caffeine kinetics is not known. The kinetics of caffeine has been examined in patients with decompensated Type I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the apparent caffeine clearance, half-life, and apparent volume of distribution were similar to controls. It is concluded that decompensated diabetes does not influence the cytochrome P-448 mono-oxygenase system responsible for caffeine metabolism.
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    Dopamine pharmacokinetics in critically ill newborn infants (1991)
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    European journal of clinical pharmacology 40 (1991), S. 593-597 
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    ISSN: 1432-1041
    Keywords: Dopamine ; Newborns ; critically ill patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 μg · kg−1 · min−1, for presumed or proven sepsis and hypotensive shock. Steady-state concentrations of dopamine ranged from 0.013–0.3 μg/ml. Total body clearance averaged 115 ml · kg−1 · min−1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg−1 and 6.9 min, respectively. No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate. Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.
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    The concentration-dependent disposition and kinetics of inulin (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 619-624 
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    ISSN: 1432-1041
    Keywords: Inulin ; pharmacokinetics ; half life ; distribution ; concentration-dependent clearance ; healthy subjects ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml·min−1) following intravenous infusion of 70 mg·kg−1 over 5 min. Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg·l−1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%. The concentration-dependent renal clearance of inulin was confirmed in “step-up” and “step-down” constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg·l−1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time. Under these conditions the mean plasma half life, volume of distribution (Vss) and total body clearance of inulin in the healthy males, healthy females and patients with chronic renal failure were 73.2, 65.5 and 172.4 min, 10.5, 9.6 and 8.81·70 kg−1 and 113.3, 111.5 and 43.3 ml·min−1·70 kg−1 respectively. There were no sex differences in any of the kinetic variables. The mechanism of the concentration-dependent clearance of inulin is unknown but the findings are consistent with saturable renal tubular reabsorption. Care is required with the use of inulin for measurement of the glomerular filtration rate by the single injection technique.
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    Effect of ampicillin on mefloquine pharmacokinetics in thai males (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 631-633 
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    ISSN: 1432-1041
    Keywords: Mefloquine ; ampicillin ; Thai subjects ; pharmacokinetics ; enterohepatic recycling ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day). These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.
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    Lack of effect of multiple dose sucralfate on the pharmacokinetics of roxatidine acetate (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 637-638 
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    ISSN: 1432-1041
    Keywords: Roxatidine acetate ; sucraflate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00279987
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    Pharmacokinetics of halofantrine and n-desbutylhalofantrine in patients with falciparum malaria following a multiple dose regimen of halofantrine (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 161-164 
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    ISSN: 1432-1041
    Keywords: Halofantrine ; Malaria falciparum ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax)=896 and 491 ng·ml−1; time to reach the Cmax (tmax)=15 and 56 h; elimination half-life (t1/2)=91 and 79 h and the mean residence time (MRT)=71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.
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    Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 165-169 
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    ISSN: 1432-1041
    Keywords: Fosinopril ; fosinoprilat ; CAPD ; ACE-inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml−1, 4.8 h, and 3.19 μg·h·ml−1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng·ml−1, tmax of 9 h, and AUC of 18.1 μg·h·ml−1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min−1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.
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    Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 171-174 
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    ISSN: 1432-1041
    Keywords: Bisoprolol ; pharmacokinetics ; obesity ; blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single i. v. dose of dlbisoprolol 0.16 mg·kg−1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight). Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (Vz) (182 vs 135 1) and a decrease in Vz per kg body weight (2 vs 2.7 l·kg−1). There was a negative correlation between Vz l·kg−1 and the percentage of ideal body weight (r=−0.672). Total body clearance was increased, but t1/2 and renal clearance was unchanged. It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.
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    Steady state pharmacokinetics of hydrolysed bopindolol in young and elderly men (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 175-178 
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    ISSN: 1432-1041
    Keywords: Bopindolol ; pharmacokinetics ; beta-adrenoceptor blocker ; age ; hydrolysed bopindolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Steady-state pharmacokinetic parameters of the new, long-acting beta-adrenoceptor blocker bopindolol have been measured in 17 young and 20 elderly healthy men. The t1/2β and the AUC(0→24 h) of hydrolysed bopindolol (the active metabolite) were both increased (40% and 26%, respectively) in the elderly subjects but tmax, Cmax and CL/f were not altered. However, after adjusting the parameters to allow for the different average body weights of the two groups, Cmax and CL/f became significantly different (+29% and −30%, respectively). AUC(0→24 h) was increased by 41%. The changes of up to 41% in pharmacokinetic parameters were smaller than the alterations of 50–100% usually seen when titrating doses of antihypertensive drugs. The clinical relevance of the effects was not examined, but similar changes have been reported for other beta-blockers which did not appear to be clinically relevant and did not affect the dosage required to treat hypertension.
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    Dose-dependent absorption and elimination of cefadroxil in man (1991)
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    European journal of clinical pharmacology 41 (1991), S. 179-183 
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    ISSN: 1432-1041
    Keywords: Cefadroxil ; saturable absorption ; saturable renal tubular reabsorption ; cephalexin ; competitive inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg−1. As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg−1, the peak plasma concentrations, normalized to 5 mg · kg−1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l−1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l−1. When the same subjects were given 5 mg·kg−1 of cefadroxil together with 45 mg·kg−1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil. Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil. The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg−1 was significantly increased by the simultaneous administration of high-dose cephalexin. The renal clearance of cefadroxil ranged from 98 ml·min·l−1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l−1 to 156 mg·l−1 at concentrations greater than 40 mg·l−1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.
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    Interaction of ORG 10172, a low molecular weight heparinoid, and digoxin in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 245-250 
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    ISSN: 1432-1041
    Keywords: Org 10172 ; Digoxin ; heparinoid ; pharmacokinetics ; pharmacodynamics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potential pharmacokinetic and pharmacodynamic interactions between a new low molecular weight heparinoid Org 10172 (bolus injection of 3250 anti-Xa units) and digoxin (0.25 mg once daily for 8 days) were studied in 6 healthy male volunteers using an open, randomised three-way cross-over design. Digoxin produced a slight increase in clearance of anti-Xa activity from 4.3 to 4.8 ml·min−1, while plasma anti-thrombin and thrombin generation inhibiting (TGI) activity remained unchanged. Digoxin did not affect the actions of Org 10172 on the clotting tests. In the presence of Org 10172 there was a reduction in the AUC of digoxin during one dosing interval after the seventh digoxin tablet from 20 to 17 ng·ml−1·h, and a significant reduction in the average serum digoxin conentration. Since renal digoxin clearance was not significantly changed this probably might be due to a change in the non-renal clearance of digoxin. Atrio-ventricular node conduction, as measured by PR-time intervals, remained unchanged during all three treatments. In conclusion, although the pharmacokinetics of Org 10172 and digoxin were slightly changed by the combination, it is probably safe to administer Org 10172 and digoxin simultaneously. The clinical relevance of the slight decrease in plasma anti-Xa activity levels cannot yet be defined.
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    Pharmacokinetics of tiaprofenic acid in children after a single oral dose (1991)
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    European journal of clinical pharmacology 41 (1991), S. 251-253 
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    ISSN: 1432-1041
    Keywords: Tiaprofenic acid ; children ; pharmacokinetics ; NSAID
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg · kg−1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC. No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age; tmax=2.12h, Cmax=8.78mg · l−1, AUC(0→8 h) 33.9mg · h · l−1, AUC=39.3 mg · h · l−1, t1/2=2.35 h, Vz=0.319 l · kg−1, CL=0.094 l · h−1 · kg−1. Renal clearance was 14 ml · h−1. kg−1. 33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates. The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg · kg−1 TA. Volume of distribution and t1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3–11 year-old children from that in adults.
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    Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 355-357 
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    ISSN: 1432-1041
    Keywords: Midazolam ; pharmacokinetics ; intranasal ; intravenous ; children ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg−1 either by the intravenous (IV) or intranasal (IN) routes. After IN administration the rapid onset of absorption was observed (tmax 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration. The results are consistent with an estimated mean bioavailability of 55%.
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    Antipyrine kinetics in undernourished diabetics (1991)
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    European journal of clinical pharmacology 41 (1991), S. 359-361 
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    ISSN: 1432-1041
    Keywords: Diabetes ; Antipyrine ; undernutrition ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insulin dependent diabetes (NIDDM) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits. The AUC of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes per se may not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.
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    Lack of effect of paracetamol on the pharmacokinetics and metabolism of codeine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 379-382 
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    ISSN: 1432-1041
    Keywords: Codeine ; paracetamol ; codeine-6-glucuronide ; pharmacokinetics ; metabolism ; partial clearance ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (μmol·l−1·h) and CLR (ml·min−1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml·min−1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucoronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.
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    Relationship between renal function and disposition of oral cefixime (1991)
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    European journal of clinical pharmacology 41 (1991), S. 579-583 
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    ISSN: 1432-1041
    Keywords: Cefixime ; renal failure ; pharmacokinetics ; volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC. There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity. In normal subjects, the peak serum level (Cmax) was 2.50 μg·ml−1 at 2.83 h (tmax); the apparent elimination half-life (t1/2) was 3.73 h; the apparent total body clearance (CL·f−1) was 154 ml·min−1, the mean renal clearance (CLR) was 39.1 ml·min−1 and the apparent fraction of the dose recovered in 24 h urine was 0.22. In uraemic patients, Cmax and tmax were slightly increased and t1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min−1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CLR and creatinine clearance (CLCR). The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.
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    Pharmacokinetics of chlormezanone in elderly patients (1991)
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    European journal of clinical pharmacology 41 (1991), S. 603-607 
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    ISSN: 1432-1041
    Keywords: Chlormezanone ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.
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    Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 71-75 
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    ISSN: 1432-1041
    Keywords: Isosorbide-5-mononitrate ; sustained-release formulation ; pharmacokinetics ; cardiovascular effects ; chronopharmacology ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
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    Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency (1991)
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    European journal of clinical pharmacology 40 (1991), S. 87-93 
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    ISSN: 1432-1041
    Keywords: Pharmacotherapy ; renal insufficiency ; pharmacokinetics ; renal drug elimination ; drug monitoring ; dosage guidelines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As the renal elimination of most drugs is closely correlated with the endogenous creatinine clearance, it is possible to use this parameter of kidney function to adjust drug dosage in renal failure. However, this simple procedure neglects possible changes in the volume of distribution, plasma protein binding, drug metabolism, intestinal absorption, and pharmacodynamics in renal insufficiency, as well as the occurrence of biologically active drug metabolities. Because of these uncertainties in critical cases the validity of the dosage calculated using the creatinine clearance should be checked by clinical surveillance and measurements of drug blood concentrations. Further, pharmacokinetic dosage guidelines based on the individual creatinine clearance may not be applicable to diuretics and drugs which have markedly differing kinetics of pharmacodynamic effects and blood levels.
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    Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy subjects and in disease states (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 101-106 
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    ISSN: 1432-1041
    Keywords: Ximoprofen ; pharmacokinetics ; normal subjects ; hepatic disease ; renal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ximoprofen, a potent new non-steroidal anti-inflammatory agent, has been investigated in normal healthy subjects and in patients with hepatic or renal disease. After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml·min−1 and the volumes of distribution were 18.0 l Vz and 13.8 l Vss. Ximoprofen was 80–90% bound to plasma proteins. The systemic availabilities (f) of orally and rectally administered doses of 30 mg of ximoprofen were 98% and 56% respectively and, in the case of the rectal dose, absorption appeared to be prolonged leading to “flip-flop” kinetics. After single oral doses of 30 mg of ximoprofen to patients with hepatic disease, half-life (2.2 h), peak plasma concentrations (1.55 μg·ml−1 cf 1.04 μg·ml−1 in healthy subjects) and areas under the curve (6.12 μg·h·ml−1 cf 3.54 μg·h·ml−1 in healthy subjects) were significantly different from those in healthy subjects. After single oral doses of 30 mg of ximoprofen to patients with renal disease, pharmacokinetic parameters of half-life (4.0 h), mean residence time (6.0 h) and area under the curve (9.2 μg·h·ml−1) were significantly different from those in healthy subjects. There were no significant differences in pharmacokinetic parameters between patients having differing degrees of renal disease. These data nevertheless suggest that accumulation of ximoprofen in hepatic or renal disease would be of slight or negligible clinical relevance and that no alteration of the dose regimen (up to 15 mg twice daily) may be required when ximoprofen is administered in these disease states.
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    CSF Baclofen levels after intrathecal administration in severe spasticity (1991)
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    European journal of clinical pharmacology 40 (1991), S. 363-365 
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    ISSN: 1432-1041
    Keywords: Baclofen ; severe spasticity ; pharmacokinetics ; CSF ; intrathecal injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l·h−1. In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).
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    Evaluation of proposed sulphoxidation pathways of carbocysteine in man by HPLC quantification (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 387-392 
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    ISSN: 1432-1041
    Keywords: Carbocysteine ; pharmacogenetics ; drug metabolism ; sulphoxidation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A quantitative study has been made of the metabolism of S-carboxymethyl-L-cysteine (CMC) and its sulphoxides in volunteers by HPLC. Precolumn derivatization was applied prior to gradient reversed phase HPLC separation and fluorescence detection. For CMC and its metabolites containing a primary amino group the reagent 9-fluorenylmethylchloroformate was used. The other metabolites of CMC were derivatized at their carboxylic group with 1-pyrenyldiazomethane to give stable fluorescent products. Urine samples were collected for 8 h after oral administration of 1.125 g CMC to 33 healthy volunteers. Elimination of CMC in urine as sulphoxides did not account for more than 1% of the dose in any of the volunteers. Thus, CMC-sulphoxide metabolites are not quantitatively important. Recovery of the original substance in 8-hour urines ranged from 10 to 30% and a further 2 to 20% was recovered as the metabolite thiodiglycolic acid. Oral doses of 0.19, 1.125, and 2.25 g CMC in a second group of 12 healthy volunteers did not reveal dose dependence of the urinary excretion of the sulphoxides or of thiodiglycolic acid. Serum concentration-time-curves of CMC, (S)- and (R)-CMC sulphoxide were measured in a group of 9 healthy volunteers. The CMC sulphoxides in serum reached 1.5% of the parent substance after 4 hours. The ratio of CMC to its sulphoxide metabolites was similar in serum and urine. Pharmacogenetic polymorphism of sulphoxidation was not confirmed by the specific HPLC methods used.
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    Interaction of metoprolol with lorazepam and bromazepam (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 405-409 
    Details
    ISSN: 1432-1041
    Keywords: Metoprolol ; lorazepam ; bromazepam ; interaction ; psychomotor tests ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21–37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam AUC was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together.
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    Pharmacokinetics of ibuprofen in febrile children (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 427-428 
    Details
    ISSN: 1432-1041
    Keywords: Ibuprofen ; children ; fever ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibuprofen ranged from 17–42 μm·ml−1 at 5 mg·kg−1 and 25–53 μm·ml−1 at 10 mg·kg−1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean tmax, oral clearance and elimination half life were 1.1 h, 1.2 ml·min−1·kg−1, and 1.6 h, respectively in patients at 5 mg·kg−1 doses; the corresponding values were 1.2 h, 1.4 ml·min−1·kg−1, and 1.6 h in those receiving 10 mg·kg−1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.
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    Disposition of epirubicin and metabolites with repeated courses to cancer patients (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 481-487 
    Details
    ISSN: 1432-1041
    Keywords: Epirubicin ; pharmacokinetics ; plasma concentrations ; cancer patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38–50 mg·m−2, mean 49.2 mg·m−2, administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4′-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.
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    Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 155-162 
    Details
    ISSN: 1432-1041
    Keywords: Flecainide ; sparteine/debrisoquine polymorphism ; metabolism ; enantiomers ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min−1; S 379 ml·min−1) than in EMs (R 783 ml·min−1; S 828 ml·min−1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min−1; S 201 ml·min−1) relative to extensive metabolisers (R 533 ml·min−1; S 586 ml·min−1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min−1) than extensive (267 ml·min−1) metabolisers. The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml−1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.
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    The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 163-168 
    Details
    ISSN: 1432-1041
    Keywords: Tolbutamide ; diabetes mellitus ; non-insulin dependent ; pharmacokinetics ; pharmacodynamics ; glucose ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol·l−1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.
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    Pleiotropic effects of a nuclear restorer-of-fertility locus on mitochondrial transcripts in male-fertile and S male-sterile maize (1999)
    Springer
    Current genetics 35 (1999), S. 521-526 
    Details
    ISSN: 1432-0983
    Keywords: Key words Cytoplasmic male sterility ; Fertility restoration ; Zea mays ; Mitochondrial transcripts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Cytoplasmic male sterility (CMS) is encoded by the plant mitochondrial genome and can be reversed by nuclear restorer-of-fertility(Rf) alleles. In the CMS-S system of maize, reproductive failure and fertility restoration are gametophytic, occurring during the starch-filling stages of pollen development. Transcripts of the CMS-S-associated mitochondrial open reading frames (orf355 and orf77) are present from the early stages of microspore development through the aborted pollen stage. To investigate the molecular basis of fertility restoration, we compared mitochondrial-transcript accumulation in aborting CMS-S pollen and in CMS-S pollen restored to fertility by the Rf3 nuclear allele. In the presence of the Rf3 allele, novel, shorter transcripts of the orf355-orf77, cob and atp6 mitochondrial genes were created, and the relative abundance of larger transcripts was decreased for each of these loci. The altered transcript patterns cosegregated with male fertility conditioned by the Rf3 allele. The novel cob and atp6 transcripts were also observed in leaf-tissues of both normal and S-cytoplasm plants carrying the Rf3 allele. These observations support the hypothesis that the Rf3 allele encodes, or regulates, a modifier of mitochondrial transcript (Mmt) activity that affects both CMS and essential mitochondrial gene transcripts.
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    Nitrogen and phosphorus use in maize sole cropping and maize/cowpea mixed cropping systems on an Alfisol in the northern Guinea Savanna of Ghana (1991)
    Springer
    Biology and fertility of soils 10 (1991), S. 267-275 
    Details
    ISSN: 1432-0789
    Keywords: Vigna unguiculata ; Zea mays ; Nutrient competition ; Intercropping ; Nitrate depletion ; N2 fixation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary The use of N and P by mixed and by sole cropping (crop rotation) of maize and cowpeas were compared in a field experiment on an Alfisol at the Nyankpala Agricultural Experiment Station in the northern Guinea Savanna of Ghana, using two levels of N (0 and 80 kg N ha-1 year-1 as urea) and P application (0 and 60 kg P ha-1 year-1 as Volta phosphate rock). Maize grain yields were significantly reduced in the mixed cropping system. This yield difference became smaller with the application of N and P fertilizer. The N and P concentrations in maize ear leaves at silking indicated that a deficiency in N and P contributed to the maize yield depression in mixed cropping. Competition for soil and fertilizer N between maize and cowpeas was suggested by: (1) A similarity in total N uptake between the two cropping systems; (2) efficient use of soil nitrate by the cowpeas; and (3) low N2 fixation by the cowpeas, calculated with the aid of an extended-difference method. In general, N2 fixation was low, with the highest values in the sole cropping (53 kg ha-1) and a substantial reduction in the mixed cropping system. The application of N fertilizer further reduced N2 fixation. This was substantiated by nodule counts. The lower N2 fixation in the mixed cropping system was only partly explained by the lower density of cowpeas in this system. In addition, dry spells during the cropping season and shading by the maize component could have reduced the nodulation efficiency. No N transfer from the legume/rhizobium to the non-legume crop was observed. Impaired P nutrition in the mixed compared with the sole-cropped maize might have been due to less P mobility in the soil. This was indicated by lower soil moisture contents in the topsoil under mixed cropping, especially during the dry year of 1986. The results show that mixed cropping of maize and cowpeas did not lead to improved use of soil and fertilizer N and P or to an enhanced N2 fixation. On the contrary, an annual rotation of maize and cowpeas was clearly superior.
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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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    Shear band spacing in gradient-dependent thermoviscoplastic materials (1999)
    Springer
    Computational mechanics 23 (1999), S. 8-19 
    Details
    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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    Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 459-462 
    Details
    ISSN: 1432-1041
    Keywords: Levodopa/decarboxylase inhibitor ; Parkinson's Disease ; pharmacokinetics ; duration of therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.
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    Elimination of flecainide as a function of urinary flow rate and pH (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 61-63 
    Details
    ISSN: 1432-1041
    Keywords: Flecainide ; dose adjustment ; urinary pH ; urinary flow rate ; renal elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml · h−1) 2. acidic urine (pH 5) and a low fluid load (25 ml · h−1) 3. alkaline urine (pH 8) and a high fluid load (125 ml · h−1) 4. alkaline urine (pH 8) and a low fluid load (25 ml · h−1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml · min−1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng · ml−1 · h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml · min−1; AUC 976 vs 1480 ng · ml−1 · h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml · min−1; AUC 1045 vs 1540 ng · ml−1 · h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.
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    Kinetics of cholinesterase inhibition by eptastigmine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 83-84 
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    ISSN: 1432-1041
    Keywords: Eptastigmine ; cholinesterase inhibitor ; Alzheimer's disease ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00280116
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    Pharmacokinetic investigation of oral and IV dihydroergotamine in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 597-602 
    Details
    ISSN: 1432-1041
    Keywords: Dihydroergotamine mesilate ; pharmacokinetics ; urinary excretion ; prolonged half-life ; deep compartment ; RIA ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized crossover trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz=33 l/kg) and a high plasma clearance (CLP=2l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8′-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.
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    Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 615-617 
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    ISSN: 1432-1041
    Keywords: Piperine ; Propranolol ; Theophylline ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.
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    Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 141-145 
    Details
    ISSN: 1432-1041
    Keywords: Platelet activating ; Factor RP 48740 ; platelet aggregation ; PAF-antagonist ; dose-response relationship ; adverse effects ; pharmacokinetics ; dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and exvivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg·l−1. There were no clinical or biological adverse reactions to RP 48740 during the study.
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    Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 481-484 
    Details
    ISSN: 1432-1041
    Keywords: Disopyramide ; pharmacokinetics ; protein binding ; enantiomers ; metabolism ; metabolite kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h−1.kg−1 for R-disopyramide and 0.58 l.h−1.kg−1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h−1.kg−1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.
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    Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 495-496 
    Details
    ISSN: 1432-1041
    Keywords: Asthma ; Salbutamol ; Asians ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients. Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean Cmax was 4.2 ng·ml−1 and 7.7 ng·ml−1 after 4 and 8 mg, respectively. In 5 patients the steady state mean Cmax, Cmin and tmax were 8.1 ng·ml−1 and 4.7 ng·ml−1 and 6 h for the 4 mg tablets and 14.1 ng·ml−1 and 7.1 ng·ml−1 and 4 h for the 8 mg tablets. It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.
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    Relation between plasma concentration and clinical efficacy after sublingual single dose apomorphine in Parkinson's disease (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 493-494 
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    ISSN: 1432-1041
    Keywords: Parkinson's disease ; Apomorphine ; pharmacokinetics ; adverse effect ; on-off effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with Parkinson's disease were given a single sublingual dose of apomorphine in 3 mg tablets (2 patients received 18 mg and 3 patients took 39 mg). The therapeutic effect appeared within 33.0 min and lasted 137 min. There was a significant correlation between peak concentration, area under the curve, dose (mg/kg) and the duration of the therapeutic effect.
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    Therapeutic monitoring of cyclosporin — an update (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 273-283 
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    ISSN: 1432-1041
    Keywords: Cyclosporin A ; therapeutic monitoring ; assay techniques ; pharmacokinetics ; dose-response relationships
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The success of organ transplantation is closely related to clinical use of the immunosuppressive drug cyclosporin (CsA). The dosage of CsA is complicated by the large intra- and interindividual variability in its pharmacokinetics, as well as by the narrow concentration range between insufficient immunosuppression and toxicity. Potential sources of error in the sampling procedure and the advantages and disadvantages of the available analytical methods are discussed. Traditionally, 12 or 24 hour trough concentrations of CsA are monitored. Recently, peak concentrations or estimation of AUCs by a limited sampling strategy have been tried to improve the relatively weak concentration-effect and concentration-toxicity relationships found with trough CsA concentration monitoring. Studies of the CsA concentration-effect relationships for various treatment indications are reviewed.
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    URL: http://dx.doi.org/10.1007/BF00314952
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    Verapamil in the prophylaxis of bronchial asthma (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 317-319 
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    ISSN: 1432-1041
    Keywords: Asthma ; Verapamil ; histamine-induced bronchoconstriction ; calcium antagonists ; plasma levels ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi〉100%) in the responders 5 h after the oral dose. The relationship of the bronchoprotective effect to the plasma level of verapamil was also examined. Responders and non-responders did not differ significantly in the peak plasma level or the time course of the plasma verapamil concentration. The protective effect was not correlated with the peak plasma level of verapamil or with the baseline bronchial hyperreactivity.
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  • 78
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    Pharmacokinetics of paroxetine in patients with cirrhosis (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 351-354 
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    ISSN: 1432-1041
    Keywords: Paroxetine ; Cirrhosis ; pharmacokinetics ; multiple-dose study ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20–30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSS min) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng · ml−1 per mg paroxetine and 89 vs 43 h (ng) · ml−1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.
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  • 79
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    Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 363-368 
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    ISSN: 1432-1041
    Keywords: Benzoic acid ; hippuric acid ; pharmacokinetics ; hyperammonaemia ; ureagenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentration-time data for benzoic and hippuric acids and urinary excretion-time data for hippuric acid were analyzed simultaneously after oral doses of 40, 80 or 160 mg/kg sodium benzoate administered at least one week apart to 6 healthy subjects. The mean AUCs of benzoic acid after the doses of 80 and 160 mg/kg of sodium benzoate were 3.7- and 12.0-times greater, respectively, than after 40 mg/kg. However, the mean AUC of hippuric acid was roughly proportional to the benzoate doses. The observed data were explained by a one-compartment model with first-order rate absorption and Michaelis-Menten elimination of benzoic acid, together with a one-compartment model with first-order elimination for hippuric acid. Although the maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2 and 28.8 mg·kg−1·h−1 among the six individuals, the mean value (23.0 mg·kg−1·h−1) was fairly close to that provided by daily maximum dose (0.5 g·kg−1·day−1) recommended in the treatment of hyperammonaemia in patients with inborn errors of ureagenesis. The individual maximum rate of metabolism can be estimated from the urinary excretion rate of hippuric acid 1.5 to 3 h after the single oral dose of 80 to 160 mg·kg−1 sodium benzoate. The justification of this concept requires further studies in patients with inborn errors of urea synthesis.
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  • 80
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    Pharmacokinetics of intramuscular nicomorphine and its metabolites in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 375-378 
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    ISSN: 1432-1041
    Keywords: Nicomorphine ; 6-nicotinoylmorphine ; morphine ; intramuscular administration ; metabolism ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After i.m. injection nicomorphine is relatively slowly absorbed from the muscular depot and is found in the serum for approximately 1 h. The rate of absorption differs between patients and governs the overall pharmacokinetic profile of the compound. The relative AUCs were nicomorphine 18%, 6-nicotinoylmorphine 17%, and morphine 65%. Nicomorphine and 6-nicotinoylmorphine have significantly higher AUCs after i.m. injection than after i.v. injection, while the AUC of morphine and the total AUC show no difference between the two modes of administration.
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  • 81
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    Decreased and variable systemic availability of zidovudine in patients with AIDS if administered with a meal (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 305-308 
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    ISSN: 1432-1041
    Keywords: Zidovudine ; acquired immunodeficiency syndrome (AIDS) ; pharmacokinetics ; bioavailability ; food intake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of oral zidovudine has been studied in 13 patients with the acquired immunodeficiency syndrome (AIDS) dosed either fasting or with breakfast. The mean peak plasma concentration and AUC of zidovudine were significantly 2.8- and 1.4-times higher in fasting patients than in those treated during meal. In both conditions the mean half-life was about 1.5 h and the period of plasma zidovudine concentrations 〉1 μmol · l−1 was 2 h (NS). It is concluded that if zidovudine is taken on an empty stomach, high peak plasma concentrations and decreased variation in pharmacological parameters may be expected. Whether or not this will influence toxicity and efficacy remains to be shown.
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    Absorption of theophylline from a new theophylline controlled-release capsule (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 319-320 
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    ISSN: 1432-1041
    Keywords: Theophylline ; controlled-release formulation ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00315219
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  • 83
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    Diuretic effect and disposition of furosemide in cystic fibrosis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 333-341 
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    ISSN: 1432-1041
    Keywords: Furosemide ; cystic fibrosis ; pharmacokinetics ; diuretic effect ; baseline urine flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis. The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug. The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects. The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.
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    The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous, intramuscular, and subcutaneous injection (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 399-403 
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    ISSN: 1432-1041
    Keywords: Lisuride ; pharmacokinetics ; prolactin concentrations ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 μg lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min−1·kg−1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.
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    Disposition of oral quinine in acute falciparum malaria (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 49-52 
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    ISSN: 1432-1041
    Keywords: Quinine ; pharmacokinetics ; falciparum malaria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l−1 compared to 5.7 mg·l−1 in convalescence. There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg−1·min−1, which was significantly lower than in convalescence — 2.67 ml·kg−·min−1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg−1·min−1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of α1 acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l−1 compared to 1.05 g·l−1 during convalescence. Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.
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    Lack of effect of omeprazole treatment on steady-state plasma levels of metoprolol (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 61-65 
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    ISSN: 1432-1041
    Keywords: Omeprazole ; substituted benzimidazole ; metoprolol ; interaction ; cytochrome P450 ; debrisoquine hydroxylase ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomised double-blind crossover study, seven healthy males were concomitantly given metoprolol 100 mg o. d. as a controlled release formulation, and omeprazole 40 mg o. d. or placebo, for 8 days. Plasma levels of the R- and S-enantiomers of metoprolol were determined on the 8th day of each treatment. The subjects were also characterised by their metabolic capacity to hydroxylate debrisoquine. Concomitant omeprazole treatment had no significant influence on the steady-state plasma levels of the two enantiomers of metoprolol. All subjects were characterised by extensive debrisoquine hydroxylation, i.e. extensive metoprolol metabolism. As metoprolol is metabolised to a great extent by debrisoquine hydroxylase (IID6), it is concluded that concomitant omeprazole treatment will probably have a negligible influence on the metabolism of the relatively large number of drugs mainly metabolised by this isoenzyme of the cytochrome P450 family.
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    Is there a need for more precise definitions of bioavailability? (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 123-126 
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    ISSN: 1432-1041
    Keywords: bioavailability definition ; health authorities ; pharmacokinetics ; drug registration Participants: L. P. Balant (Geneva, Switzerland), L. Z. Benet (San Francisco, USA), H. Blume (Eschborn, FRG), G. Bozler (Biberach, FRG), D. D. Breimer (Leiden, The Netherlands), M. Eichelbaum (Stuttgart, FRG), U. Gundert-Remy (Berlin, FRG), J. L. Hirtz (Paris, France), E. Mutschler (Frankfurt, FRG), K. K. Midha (Saskatoon, Canada), A. G. Rauws (Bilthoven, The Netherlands), W. A. Ritschel (Cincinnati, USA), L. N. Sansom (Adelaide, Australia), J. P. Skelly (Rockville, USA), and K.-O. Vollmer (Freiburg, FRG)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for “more precise” definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future “targeted drugs”. Thus, the FDA definition might be modified as follows: “Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action”.
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    Changes in gentamicin pharmacokinetic profiles induced by mechanical ventilation (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 297-302 
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    ISSN: 1432-1041
    Keywords: Gentamicin ; pharmacokinetics ; mechanical ventilation ; therapeutic dose range
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of controlled mechanical ventilation (CMV) on the pharmacokinetic profile of gentamicin has been examined in 23 patients after elective open heart surgery. A parallel design was adopted in two groups of patients: 13 patients requiring CMV for at least 32 h after surgery, all of whom were able to breath spontaneously (SB) after 72 h (study group), and 10 patients who required CMV for only a brief period and who showed SB at 32 h postsurgery. Haemodynamic parameters remained stable throughout the study. Apparent volume of distribution (Vz), half-life (t1/2), total clearance (CL), peak (C max ss ) and trough (C min ss ) plasma levels at steady-state for target levels (6–8 μg/ml), were measured. In the study group significant differences between CMV and SB conditions were found in Vz (mean 0.36 and 0.25 l/kg), t1/2 (mean 3.63 and 2.90 h) and C max ss (mean 4.30 and 5.53 μg/ml) while C min ss (mean 1.06 μg·ml−1 and 0.92 μg·ml−1) did not change significantly. In contrast, the pharmacokinetics in the control group showed no differences. It appears that CMV leads to an increase in gentamicin Vz, which accounts for the fall in C max ss below the therapeutic dose range (〈5 μg/ml) recommended for gentamicin. It seems advisable to use a larger dose of gentamicin in patients receiving CMV, even before the level is assessed.
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    Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 65-68 
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    ISSN: 1432-1041
    Keywords: Chlordesmethyldiazepam ; pharmacokinetics ; i.v./p.o. administration ; renal failure ; protein binding ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients. After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l · kg−1) and a reduced clearance (5.0 vs. 10.5 ml · min−1 · kg−1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.
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    Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 209-214 
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    ISSN: 1432-1041
    Keywords: Furosemide ; renal transplant recipients ; kidney donors ; naproxen ; dehydration ; pharmacokinetics ; salt-regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg · 6 h−1. While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml/min; P〈0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P〈0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors. Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients. In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.
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    Monitoring of the free concentration of cyclosporine in plasma in man (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 571-575 
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    ISSN: 1432-1041
    Keywords: Cyclosporine ; free drug in plasma ; therapeutic drug monitoring ; renal transplantation ; plasma binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The free fraction of cyclosporine A (CsA) and its total plasma concentration as determined by HPLC(CsAT) were prospectively monitored in 66 recipients of renal transplants. The free CsA levels (CsAu) were calculated. The variability in free CsA levels was no less than for total CsAT levels. The correlation between CsAu and CsAT was high (r=0.90). Both CsAT and CsAu covaried with serum triglycerides and apolipoprotein A1. Fourty-four of the 66 patients suffered acute rejection episodes on 69 occasions. CsAT and CSAu both decreased and to a similar extent at the occurrence of acute rejection (42% and 59% decrease, respectively; significant vs baseline. Notsignificant difference in decrease in CsATvsCsAu). Acute nephrotoxicity occurred on 11 occasions in 10 patients. Both CsAT and CSAu were approximately twice as high at the time of acute nephrotoxicity as compared to one week previously. Both CsAT and CsAu were higher during the first month after transplantation in patients with than in patients without systemic infection. Thus, plasma CsAu gave no additional clinical information or guidance compared to CsAT in renal transplant recipients. Due to the complexity of its assay, which requires two consecutive analyses, there does not appear to be any need for routine monitoring of CsAu in renal transplant recipients.
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    Flecainide: evidence of non-linear kinetics (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 57-59 
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    ISSN: 1432-1041
    Keywords: Flecainide ; pharmacokinetics ; ventricular arrhythmias
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flecainide has been studied in 12 patients with ventricular arrhythmias, both after single administration and during chronic treatment. Both the half-life and the AUC were significantly increased during chronic treatment. This suggests that the kinetics of flecainide might be non-linear also in patients with normal kidney and liver function. The increase in plasma flecainide levels during chronic treatment could not be predicted, so close monitoring of its plasma levels is advisable.
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    Pharmacokinetic profile and tolerability of pimobendan in patients with terminal renal insufficiency (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 107-111 
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    ISSN: 1432-1041
    Keywords: Pimobendan ; pharmacokinetics ; tolerability ; renal impairment ; adverse effects ; haemodynamic actions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of an i.v. bolus of pimobendan (P) 2.5 mg and 5.0 mg, its tolerability and the effect on heart rate and blood pressure have been studied in 12 subjects (42–70 y) suffering from severe terminal renal impairment. Plasma level data were compared with those obtained in a previous investigation in healthy volunteers. Pharmacokinetics were dose linear and were comparable to those in healthy subjects. No adjustment of the dose of P is necessary in patients with severe renal impairment. Tolerability of P, observed by means of blood pressure monitoring, clinical chemistry tests, electrocardiography and subjective judgement resulted in 4 complaints out of 12 patients: three suffered from orthostatic problems and vomiting, and one patient had nausea. Mean heart rate was elevated by 19% (2.5 mg) and 16% (5.0 mg). Blood pressure was significantly reduced after 2.5 mg P (23% systolic and 26% diastolic pressure), and after 5.0 mg P by 25% systolic and 23% diastolic pressure.
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    Clinical pharmacokinetics of 3-day continuous infusion cisplatin and daily bolus 5-Fluorouracil (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 115-117 
    Details
    ISSN: 1432-1041
    Keywords: Cisplatin ; 5-Fluorouracil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315150
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  • 95
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    Electronic Resource
    Continuous infusion of high-dose metoclopramide: comparison of pharmacokinetically adjusted and standard doses for the control of cisplatin-induced acute emesis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 283-286 
    Details
    ISSN: 1432-1041
    Keywords: Metoclopramide cancer chemotherapy ; emesis ; continuous infusion ; pharmacokinetics ; cisplatin ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Metoclopramide was administered by continuous infusion to two groups each of 14 patients on chemotherapy, randomized to receive either doses adjusted to individual pharmacokinetic parameters or doses adjusted as usual to body weight. The mean plasma concentration at the end of the infusion in the adjusted group was 1.01 mg · 1−1, close to that aimed for (1.20 mg · 1−1). It was significantly different from that in the other group, v0.54 mg · 1−1. Antiemetic efficacy, defined as ⩽2 emetic events in the 24 h following cisplatin, was similar in both groups (being found in 12/14 (86%) and 10/14 patients (71%), respectively). Analysis of the cumulative percentage of responders according to plasma concentration showed a clear plasma concentration-effect relationship. Routine MCP pharmacokinetic dosage adjustment is not indicated, but this therapeutic approach can be used to optimize antiemetic therapy in poor responder patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315210
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  • 96
    Electronic Resource
    Electronic Resource
    Cyclosporine pharmacokinetics in liver transplant recipients: evaluation of results using both polyclonal radioimmunoassay and liquid chromatographic analysis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 513-519 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine ; liver transplant recipients ; radioimmunoassay ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic variables were derived from cyclosporine measurements using liquid chromatography (HPLC) and radioimmunoassay with a non-selective polyclonal antibody (PARIA) in 11 orthotopic liver transplant recipients studied in paired oral and intravenous studies both before and after permanent clamping of the biliary T-tube. After oral drug administration, mean areas under blood cyclosporine concentration versus time curves before clamping were around 5.2-fold greater by PARIA than HPLC but 2.9-fold greater after clamping and closer to comparable values after intravenous cyclosporine (2.5 and 2.3-fold, respectively). Cyclosporine clearance was smaller by PARIA than HPLC (mean 7.3 versus 3.3 ml · min−1 · kg−1, respectively, before clamping). Both values decreased by 25% after clamping (to 5.5 and 2.4 ml · min−1 · kg−1, respectively), although there was no significant change in distribution or elimination half-lives (around 0.5 and 8 h, respectively). The mean bioavailability of oral cyclosporine increased significantly after clamping in 9 patients (from 10.6% to 28.1% by HPLC and from 14.8 to 35.1% by PARIA) but in two patients who developed the vanishing bile duct syndrome values fell to 〈 10% and the proportional overestimation of cyclosporine concentrations by PARIA increased. Clamping had no significant effect on the mean apparent volumes of distribution but values of Vz were approximately twice those of Vss (around 2.6 and 1.3 l · kg−1 by PARIA and HPLC respectively). Mean half lives after clamping were shorter following oral than intravenous cyclosporine (t1/2λ2 around 15 h enterally versus 8 h parenterally). These data suggest delays in cyclosporine absorption and significant first pass metabolism which may contribute to higher PARIA:HPLC ratios after oral dosing and to reduced bioavailability before clamping.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315232
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  • 97
    Electronic Resource
    Electronic Resource
    Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 585-591 
    Details
    ISSN: 1432-1041
    Keywords: Morphine ; metabolites ; clinical trial ; pharmacokinetics ; controlled release formulation ; cancer patients ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279975
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  • 98
    Electronic Resource
    Electronic Resource
    Sublingual captopril — a pharmacokinetic and pharmacodynamic evaluation (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 393-398 
    Details
    ISSN: 1432-1041
    Keywords: Captopril ; sublingual ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22–35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril. Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: Cmax, 234 ng·ml−1; tmax, 45 min; AUC (0–3 h), 15.1 μg·ml−1. min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were: Cmax, 228 ng·ml−1; tmax, 75 min; AUC (0–3 h), 17.0 μg·ml−1. min. tmax was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent. The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP. tmax for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265850
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  • 99
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of SUN 1165, a new antiarrhythmic agent, in renal dysfunction (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 411-414 
    Details
    ISSN: 1432-1041
    Keywords: SUN 1165 ; renal failure ; antiarrhythmic agent ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg. The apparent volume of distribution at steady state was 1.48 1 · kg−1, the absorption rate constant was 2.2 h−1, and plasma protein binding was 26.8% in subjects with normal renal function. These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration. The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml · min−1 · 1.48 m−2). Dosage adjustment of SUN 1165 is necessary in renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265853
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  • 100
    Electronic Resource
    Electronic Resource
    Analysis of stable two-dimensional patterns in contractile cytogel (1991)
    Springer
    Journal of nonlinear science 1 (1991), S. 289-311 
    Details
    ISSN: 1432-1467
    Keywords: cytogel ; mechanochemical ; two-dimensional patterns ; cellular differentiation ; pattern formation ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Physics
    Notes: Summary Contractile actomyosin systems play a central role in the generation of intracellular patterns. Models for pattern formation have benefited greatly from the application of mechanochemical theory. However, investigations of the patterns have been primarily qualitative in nature; the two-dimensional nature of the evolving patterns has not yet been addressed mathematically, nor has the evolution of stable heterogeneous steady-state solutions. We consider these issues, supporting our analytical predictions with numerical simulations in one and two spatial dimensions. We show how, for certain gels, the two and three-dimensional tensor equation which describes a balance of forces can be reduced to a reaction-diffusion equation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01238816
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