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  • bioavailability  (130)
  • CR: 5.17  (98)
  • Springer  (228)
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  • Springer  (228)
  • American Institute of Physics (AIP)
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  • 1
    Electronic Resource
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    Springer
    Numerische Mathematik 43 (1984), S. 105-119 
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary A new formulation of the Dirichlet problem for the biharmonic operator is presented. This gives rise to a simple numerical method to solve the above problem. Convergence is proved in the unidimensional case. Numerical results in one and two dimensional test problems are presented.
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  • 2
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    Numerische Mathematik 43 (1984), S. 175-198 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65 L 10 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary We present a difference scheme for solving a semilinear singular perturbation problem with any number of turning points of arbitrary orders. It is shown that a solution of the scheme converges, uniformly in a perturbation parameter, to that of the continuous problem.
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  • 3
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65 N 30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Description / Table of Contents: Summary This paper uses Augmented Lagrangian techniques for the numerical solution of equilibrium problems of compressible hyperelastic bodies subjected to large deformations. The resulting method is illustrated by several numerical examples.
    Notes: Résumé Cet article applique les techniques de Lagrangien Augmenté à la résolution numérique des problèmes d'équilibre de corps hyperélastiques compressibles soumis à de grandes déformations. La méthode obtenue est illustrée par plusieurs exemples numériques.
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  • 4
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    Numerische Mathematik 45 (1984), S. 105-116 
    ISSN: 0945-3245
    Keywords: AMS(MOS) 65 N 30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary We study a superconvergence phenomenon which can be obtained when solving a 2nd order elliptic problem by the usual linear elements. The averaged gradient is a piecewise linear continuous vector field, the value of which at any nodal point is an average of gradients of linear elements on triangles incident with this nodal point. The convergence rate of the averaged gradient to an exact gradient in theL 2-norm can locally be higher even by one than that of the original piecewise constant discrete gradient.
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  • 5
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    Numerische Mathematik 45 (1984), S. 201-206 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Bulirsch and Stoer have shown how to construct asymptotic upper and lower bounds on the true (global) errors resulting from the solution by extrapolation of the initial value problem for a system of ordinary differential equations. It is shown here how to do this for any one-step method endowed with an asymptotically correct local error estimator. The one-step method can be changed at every step.
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  • 6
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    Numerische Mathematik 44 (1984), S. 191-200 
    ISSN: 0945-3245
    Keywords: AMS (MOS): Primary 65M05, 65M10, 65M15 ; Secondary: 35M05 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary We consider the numerical solution of the boundary value problem (1) $$(1) Lu = k(y)u_{xx} + u_{yy} - c(x,y)u = f, u|_{\Gamma _0 \cup \Gamma _1 } = 0,$$ where $$k(y) \gtreqless 0$$ for $$y \gtreqless 0$$ Г 0 andГ 1 are parts of the boundary of a bounded simply connected regionG inR 2.G is bounded fory〉0 by a piecewise smooth curveГ 0 which intersects the liney=0 at the pointsA(−1,0) andB(0, 0). Fory〈0,G is bounded by a piecewise smooth curveГ 1 throughA, which meets the characteristic of (1) issued fromB at pointC, and by the curveГ 2 which consists of the portionCB of the characteristic throughB. Using a weak formulation based on different spaces of test and trial functions, we construct a Galerkin procedure for the above boundary value problem. Existence, uniqueness and uniform stability of an approximate solution is proven and a priori error bounds are given.
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  • 7
    ISSN: 0945-3245
    Keywords: AMS: 65N10 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary The paper deals with such estimates of the rate of convergence of difference methods, which are compatible with the smoothness of the exact solutionu ∈ W 2 m (Ω),m〉0.5, of elliptic equations with mixed derivatives: The error in the norm of the discrete Sobolev spaceW 2 s (ω), ω denoting the set of grid points, is shown to be of the orderO(|h| m−s), 0≦s〈m.
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  • 8
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    Numerische Mathematik 44 (1984), S. 247-259 
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65L05 ; 65M05 ; 65M20 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary The aim of this paper is to study contractivity properties of two locally one-dimensional splitting methods for non-linear, multi-space dimensional parabolic partial differential equations. The term contractivity means that perturbations shall not propagate in the course of the time integration process. By relating the locally one-dimensional methods with contractive integration formulas for ordinary differential systems it can be shown that the splitting methods define contractive numerical solutions for a large class of non-linear parabolic problems without restrictions on the size of the time step.
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  • 9
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    Numerische Mathematik 43 (1984), S. 419-437 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary In this paper, we consider monotone explicit iterations of the finite element schemes for the nonlinear equations associated with the boundary value problem Δu=bu 2, based on piecewise linear polynomials and the lumping operator. These iterations construct the monotonically decreasing and increasing sequences, and convergence proofs are given. Finally, we present some numerical examples verifying the effectiveness of the theory.
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  • 10
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    Numerische Mathematik 43 (1984), S. 463-483 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary The method of lines is used to semi-discretize the non-linear Poisson equation over a domain with a free boundary. The resulting multipoint free boundary problem is solved with a line Gauss-Seidel method which is shown to converge monotonically. The method of lines solution is then shown to converge to the continuous solution of the variational inequality form of the obstacle problem. Some numerical results for the diffusion-reaction equation indicate that the method is applicable to more general free boundary problems for nonlinear elliptic equations.
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  • 11
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    Numerische Mathematik 43 (1984), S. 309-327 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65 N 30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Diffusion problems occuring in practice often involve irregularities in the initial or boundary data resulting in a local break-down of the solution's regularity. This may drastically reduce the accuracy of discretization schemes over the whole interval of integration, unless certain precautions are taken. The diagonal Padé schemes of order 2μ, combined with a standard finite element discretization, usually require an unnatural step size restriction in order to achieve even locally optimal accuracy. It is shown here that this restriction can be avoided by means of a sample damping procedure which preserves the order of the discretization and, in the case μ=1, does not increase the costs.
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  • 12
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    Numerische Mathematik 43 (1984), S. 343-360 
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65L05 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Retarded initial value problems are routinely replaced by an initial value problem of ordinary differential equations along with an appropriate interpolation scheme. Hence one can control the global error of the modified problem but not directly the actual global error of the original problem. In this paper we give an estimate for the actual global error in terms of controllable quantities. Further we show that the notion of local error as inherited from the theory of ordinary differential equations must be generalized for retarded problems. Along with the new definition we are led to developing a reliable basis for a step selection scheme.
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  • 13
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    Numerische Mathematik 43 (1984), S. 389-396 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L20 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Stability analysis of θ-methods for functional differential equations based on the test equation $$\begin{gathered} y'(t) = ay(t - \lambda ) + by(t),t 〉 0 \hfill \\ y(t) = \psi (t),t \in \left[ { - \lambda ,0} \right] \hfill \\ \end{gathered} $$ λ〉0, is presented. It is known thaty(t)→0 ast→∞ if and only if |b|〈−a and we investigate whether this property is inherited by the numerical solution approximatingy.
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  • 14
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    Numerische Mathematik 44 (1984), S. 75-102 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L10 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary This paper examines the concepts of feedback and adaptivity for the Finite Element Method. The model problem concernsC 0 elements of arbitrary, fixed degree for a one-dimensional two-point boundary value problem. Three different feedback methods are introduced and a detailed analysis of their adaptivity is given.
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  • 15
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    Numerische Mathematik 44 (1984), S. 201-217 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Description / Table of Contents: Resumé On présente une méthode d'approximation numérique des équations de Navier-Stokes possédant une direction de périodicité. Dans cette direction une méthode pseudospectrale basée sur des développements en série de Fourier est utilisée, dans les deux autres on applique une méthode d'éléments finis standard. On montre que la convergence est optimale et que les deux paramètres de discrétisation peuvent être choisis de façon indépendante.
    Notes: Summary We present a method for the numerical approximation of Navier-Stokes equations with one direction of periodicity. In this direction a Fourier pseudospectral method is used, in the two others a standard F.E.M. is applied. We prove optimal rate of convergence where the two parameters of discretization intervene independently.
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  • 16
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    Numerische Mathematik 44 (1984), S. 219-222 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary An analysis of the Babuška stability of bilinear/constant finite element pairs for viscous flow calculations is given. An unstable mode not of the checkerboard type is given for which the stability constant turns out to beO(h). Thus, the indicated spaces are not stable in general for numerical calculation.
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  • 17
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    Numerische Mathematik 44 (1984), S. 285-300 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary In this paper, we investigate the numerical asymptotic behavior of the finite element solutions for linear parabolic equations under some appropriate conditions. We also give some results of numerical experiments in the two dimensional problems to indicate the effectiveness of our results.
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  • 18
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    Numerische Mathematik 45 (1984), S. 283-300 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary This paper deals with the solution of partitioned systems of nonlinear stiff differential equations. Given a differential system, the user may specify some equations to be stiff and others to be nonstiff. For the numerical solution of such a system partitioned adaptive Runge-Kutta methods are studied. Nonstiff equations are integrated by an explicit Runge-Kutta method while an adaptive Runge-Kutta method is used for the stiff part of the system. The paper discusses numerical stability and contractivity as well as the implementation and usage of such compound methods. Test results for three partitioned stiff initial value problems for different tolerances are presented.
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  • 19
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    Numerische Mathematik 45 (1984), S. 51-74 
    ISSN: 0945-3245
    Keywords: MR65 M15 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary The error of the approximate solution obtained by discretising a functional equation can be shown under certain conditions to possess an asymptotic expansion in terms of some parameter which is usually a representative step-length. We consider the case of two-parameter expansions, which is particularly relevant to parabolic equations. We derive results for the existence of the expansion and for the application of the classical difference correction and of defect correction. The theory is illustrated by the discussion of a simple parabolic problem
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  • 20
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    European journal of clinical pharmacology 26 (1984), S. 513-520 
    ISSN: 1432-1041
    Keywords: xipamide ; electrolyte excretion ; bioavailability ; elimination ; extrarenal clearance ; chronic renal failure ; furosemide ; hydrochlorothiazide ; amiloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a single oral dose of 40 mg xipamide on urinary excretion of Na+, K+, Cl−, Ca2+ and Mg2+ in healthy subjects and in patients with varying degrees of renal impairment was compared with various conventional diuretics. Xipamide caused marked excretion of Na+ and Cl−, whereas the diuretic produced only moderate kaliuresis; urinary excretion of Ca2+ was increased in proportion to Na+, like the loop diuretics. Xipamide affected electrolyte excretion even in patients with a creatinine clearance below 30 ml/min, as do the loop diuretics, too. Therefore, the pharmacodynamic characteristics of xipamide are more like those of a loop diuretic than of a thiazide. Xipamide was good bioavailable, its t1/2β was 7 h and urinary recovery of the undegraded drug was 40% of the given dose. In renal insufficiency, t1/2β increased from 7 to only 9 h, yielding a moderate increase in the AUC. Urinary recovery of the drug was reduced in proportion to the reduction in the creatinine clearance of the patient. Therefore, significant extrarenal elimination of the diuretic must be postulated, which suffices to prevent significant drug accumulation in renal failure.
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  • 21
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    European journal of clinical pharmacology 27 (1984), S. 105-110 
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
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  • 22
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    European journal of clinical pharmacology 27 (1984), S. 595-602 
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; generic tablet formulations ; intrasubject variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intrasubject variation in bioavailability (rate and extent) and disposition of furosemide 40 mg was investigated using a repeated, randomized, double-blind cross-over study in 8 healthy subjects. Two generic tablet formulations (Lasix and Furix) and intravenous furosemide were compared on 6 separate days. Extensive intrasubject variability after oral administration was observed in AUC, mean absorption time (MAT) and urinary excretion. The variability (error variance) within the dosage forms was as large as that between the two generics. These variations most probably depended on the absorption process, since the repeated i.v. doses showed only marginal intrasubject variability. Absolute bioavailability was 56% for Lasix and 55% for Furix (AUC). The range was 20 to 84% between individuals and the maximal range within one individual was 20 to 61%. Confidence interval and Bayesian analysis showed a high probability of non-equivalence not only between but also within the generics when the separate cross-over experiments were analyzed (8 observations). When extending the analysis to 16 observations, bioequivalence was demonstrated for the two generic tablets. Rate of absorption, quantified as MAT, was 128 min for Lasix and 98 min for Furix (16 observations). Since MAT was significantly longer (p〈0.001) than the mean residence time after the i.v. dose (57 min), absorption was evidently the rate-limiting step in the overall kinetics of oral furosemide. Intraindividual variation in absorption is a confounding factor in bioavailability studies of furosemide using limited numbers of subjects. This is important to consider when designing and evaluating bioavailability studies for drugs showing these variations.
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  • 23
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    European journal of clinical pharmacology 26 (1984), S. 405-407 
    ISSN: 1432-1041
    Keywords: theophylline ; drug absorption ; bioavailability ; food intake ; sustained-release preparations ; Theolin Retard
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of theophylline from a sustained release tablet preparation (Theolin® Retard 300 mg) was studied in 10 subjects both when fasting and immediately after a standardized breakfast. Intravenous aminophylline was used as the reference material. Food did not influence the absorption from Theolin Retard. The bioavailability was complete (93% after 30 h) both with and without food, and no difference was found in the time to peak of the plasma concentration curve (7 h), or the mean residence time (14 h). The absorption characteristics, with predominantly zero order kinetics, did not change with concomitant intake of breakfast.
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  • 24
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    European journal of clinical pharmacology 27 (1984), S. 111-114 
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
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  • 25
    ISSN: 1432-1041
    Keywords: nitroglycerin ; plasma concentration ; transdermal administration ; bioavailability ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 µg/min yielded mean steady-state plasma concentrations of 0.5±0.02 and 0.82±0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 µg/min were 0.28±0.01 and 0.37±0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.
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  • 26
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    European journal of clinical pharmacology 26 (1984), S. 133-135 
    ISSN: 1432-1041
    Keywords: co-dergocrine mesylate ; geriatric patients ; hydergine ; bioavailability ; steady state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relative bioavailability of the newly developed formulation of co-dergocrine mesylate (Hydergine spezial, 1×4 mg) was determined in elderly patients under steady state conditions, with conventional Hydergine forte tablets (2×2 mg) as a reference. Both formulations were given once a day for 8 days in a randomised cross-over design. The areas under the curve showed that the bioavailability of the new tablet was about 30% higher (28±6.3%) than that of Hydergine forte. The peak plasma concentration was reached 3±0.9 h after administration. Because of its greater relative bioavailability higher plasma levels were found 2–24 hours after the Hydergine spezial formulation than after Hydergine forte tablets.
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  • 27
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    European journal of clinical pharmacology 26 (1984), S. 261-264 
    ISSN: 1432-1041
    Keywords: indomethacin capsules ; bioequivalence ; volunteers ; pharmacokinetics ; statistical significance ; bioavailability ; comparative bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.
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    European journal of clinical pharmacology 26 (1984), S. 463-470 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; 8′-hydroxy-dihydroergotamine ; plasma metabolites ; bioavailability ; receptor affinity ; healthy volunteers ; liver microsomal incubates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations and urinary excretion of dihydroergotamine and its metabolites have been measured after a single oral administration of 3 mg tritium-labelled drug to 6 male volunteers. The plasma level of non-volatile radioactivity declined biphasically with α- and β-phase half-lives of 2.1 h and 32.3 h, respectively. The peak plasma concentration was reached within 3.2h. Urinary excretion of total non-volatile radioactivity was low, amounting to 1.0% of the dose. The parent drug and four metabolites could be quantitated in urine and plasma samples. Metabolite 4 (8′-hydroxy-dihydroergotamine) was isolated from incubates of rat and monkey liver microsomal preparations. In human liver microsomal incubates, metabolite 4 was shown to be the primary metabolite of dihydroergotamine. In receptor binding studies performed with mammalian brain preparations, metabolite 4 had IC50-values at 6 monoaminergic binding sites similar to those of dihydroergotamine. Thus, it appears that the active principle consists at least of dihydroergotamine and its 8′-hydroxy derivative. As the concentration of metabolite 4 exceeded 5–7 times that of dihydroergotamine in urine and plasma, the bioavailability of dihydroergotamine should be reevaluated, taking into account the plasma concentrations of the parent drug and of its acitve metabolite, 8′-hydroxydihydroergotamine.
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  • 29
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    European journal of clinical pharmacology 26 (1984), S. 533-534 
    ISSN: 1432-1041
    Keywords: amiodarone ; bioavailability ; clearance estimation
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    Topics: Chemistry and Pharmacology , Medicine
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  • 30
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    European journal of clinical pharmacology 26 (1984), S. 125-127 
    ISSN: 1432-1041
    Keywords: nadolol ; pharmacokinetics ; plasma levels ; urinary excretion ; bioavailability ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 7 healthy subjects (3 males and 4 females), the kinetics of nadolol was investigated after oral doses of 60 and 120 mg. The t1/2 was 14.0±1.8 h. The peak plasma level was doubled on doubling the dose (from 69±15 to 132±27 ng/ml, respectively) and the urinary excretion (13.5%) rose similarly. The half-life of elimination was longer at night than in the day, probably because of the slower nocturnal flow of urine.
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  • 31
    ISSN: 1432-1041
    Keywords: cimetidine ; cystic fibrosis ; bioavailability ; renal clearance ; renal function differences
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of cimetidine were studied in five cystic fibrosis patients (mean age 12.6 years) after oral and intravenous administration. As compared to healthy adult volunteers, cystic fibrosis children had an elevated cimetidine total body clearance (474 vs 300 ml/min/m2) as well as renal clearance (293 vs 232 ml/min/m2) whether normalized for body weight or surface area differences. Cimetidine elimination was elevated in juvenile cystic fibrosis patients as compared to adult volunteers, however, it did not differ significantly from that previously seen in age matched children. There were no appreciable differences in cimetidine metabolism after either route of administration. Differences between adults and cystic fibrosis children were attributed to developmental and age related differences between the two groups. The recommended pediatric dose of 15 to 20 mg/kg, although four-fold greater than that used in adults, produces serum concentrations similar to those seen in adults, and is adequate for most juvenile cystic fibrosis patients.
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  • 32
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    European journal of clinical pharmacology 26 (1984), S. 197-207 
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; pharmacokinetics ; oral administration ; i.v. administration ; drug absorption ; moment analysis ; food effect ; dissolution effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was administered to 8 healthy subjects as an i.v. bolus dose, as 1 tablet in the fasting state, and as 1 tablet and a solution after food intake. The i.v. data gave a total body clearance of 162±10.8 ml/min and a renal clearance of 117±11.3 ml/min; the volume of distribution at steady state was 8.3±0.61. Oral administration gave a bioavailability of the tablet (fasting) of 51%. Food intake slightly reduced the bioavailability, but not to a significant extent. There was no significant difference in availability between the tablet and the solution. Moment analysis gave a mean residence time after the i.v. dose, MRTi.v., of 51±1.5 min. The mean absorption times (MAT) for all oral doses were significantly longer than the MRTi.v., indicating absorption rate-limited kinetics of furosemide. On average, food delayed the absorption by 60 min. The MAT for the tablet in the postprandial state was significantly longer than for the solution, indicating dissolution rate-limited absorption of the tablet.
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    European journal of clinical pharmacology 26 (1984), S. 271-273 
    ISSN: 1432-1041
    Keywords: cimetidine ; prednisolone ; aluminium phosphate ; antacids ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten fasting subjects received 200 mg cimetidine orally either with water or 11 g aluminium phosphate mixture in a randomized, single dose, two-way cross-over study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There were no significant differences between the treatments with respect to peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, and urinary excretion. In 12 healthy subjects the absorption of prednisolone was investigated when given alone and together with 11 g aluminium phosphate. Blood samples were taken over 16 h and prednisolone in plasma was analysed by HPLC. There were no significant differences in the values of area under curve (AUC), Cmax and tmax. The results indicate that aluminium phosphate does not reduce the bioavailability of cimetidine and prednisolone.
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    European journal of clinical pharmacology 26 (1984), S. 347-355 
    ISSN: 1432-1041
    Keywords: cimetidine ; cirrhosis ; pharmacokinetics ; bioavailability ; clearance reduction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p〈0.01); renal clearance (Clr) 296±100 vs 588±181 ml/min (p〈0.01) and nonrenal clearance (Clnr) 97±111 vs 205±89 ml/min (p〈0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (Vdβ) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between Vdβ and total plasma clearance (r=0.72, p〈0.05). Volume of distribution in steady state (Vdss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.
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  • 35
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    European journal of clinical pharmacology 27 (1984), S. 105-110 
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
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  • 36
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    European journal of clinical pharmacology 27 (1984), S. 111-114 
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
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  • 37
    ISSN: 1432-1041
    Keywords: nitroglycerin ; plasma concentration ; transdermal administration ; bioavailability ; pharmacodynamics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 µg/min yielded mean steady-state plasma concentrations of 0.5±0.02 and 0.82±0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 µg/min were 0.28±0.01 and 0.37±0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.
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    European journal of clinical pharmacology 27 (1984), S. 367-369 
    ISSN: 1432-1041
    Keywords: flurbiprofen ; syrup ; suppository ; kinetics ; children ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight subjects, aged 6–12 years and weighing 18.8–36.7 kg, received single doses of flurbiprofen 50 or 75 mg (corresponding to 1.4–2.7 mg/kg) as syrup and suppository in a Latin square design. Half-life (2.7–3.2 h), elimination constant (0.22–0.26 h−1), area under the plasma level curve (72.4–77.3 µg·h·ml−1) and time to reach the concentration peak (1–0.75 h) were similar after the syrup and suppository. Flurbiprofen showed equivalent bioavailability after oral and rectal administration and the same pharmacokinetic profile was confirmed in children as observed in adults.
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    European journal of clinical pharmacology 27 (1984), S. 623-624 
    ISSN: 1432-1041
    Keywords: cimetidine ; bioavailability ; renal clearance
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    European journal of clinical pharmacology 26 (1984), S. 269-270 
    ISSN: 1432-1041
    Keywords: cyclophosphamide ; cytostatic drug ; cancer therapy ; female breast cancer ; bioavailability ; rapid release formulations ; gastric juice resistant formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cyclophosphamide (CP) is an alkylating cytostatic compound, which is activated to its cytotoxic form in the liver [1]. Since the therapeutic range of CP in the treatment of human tumours, is small like other cytostatics, a constant high bioavailability is essential for its oral administration. Although CP has become one of the most widely used cytostatics [2], there do not appear to have been any bioavailability investigations providing the necessary information. The development of a very sensitive gas chromatographic analytical method has now permited investigation of the pharmacokinetics of oral CP in conventional clinical doses [3, 4, 5, 6].
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    European journal of clinical pharmacology 27 (1984), S. 85-89 
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
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    European journal of clinical pharmacology 27 (1984), S. 85-89 
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
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  • 43
    ISSN: 1573-8744
    Keywords: hydrochlorothiazide ; triamterene ; hydroxytriamterene sulfate ; pharmacokinetics ; bioavailability ; renal clearance ; interaction
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate were monitored in the plasma and urine of 24 healthy young men taking single doses of a liquid preparation containing both hydrochlorothiazide and triameterene, liquid preparations containing either of these drugs alone, and a combination tablet recently formulated with a dose ratio of hydrochlorothiazide: triamterene (1∶1,5) found to give optimal potassium-sparing effect. In contradiction to a recent publication, no interaction between the drugs affecting the bioavailability or renal clearance of either could be demonstrated. The previous report of drug-drug interaction probably arose from formulationrelated problems with bioavailability from the two capsule and two tablet products which had been studied. A well-formulated hydrochlorothiazide-triamterene combination tablet promotes plasma concentrations and urinary excretion of hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate which are virtually identical to those seen after either a combination liquid dosage form or simple liquid forms containing only one of the two drugs.
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    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 289-313 
    ISSN: 1573-8744
    Keywords: protein binding ; pharmacokinetics ; bioavailability ; disopyramide ; heart failure
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10−7M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7X105 M−1 and 4.4X10 5 M−1, respectively (p 〈 0.05). The unbound clearance of disopyramide averaged 277ml/min and 209 ml/min in normal subjects and in patients (p 〈 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p 〈 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.
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    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 315-331 
    ISSN: 1573-8744
    Keywords: theophylline ; antacids ; interaction ; bioavailability ; steady state
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    Topics: Chemistry and Pharmacology
    Notes: Abstract We examined the influence of a large-volume, therapeutic antacid regimen, administered for three full days, on the steady-state bioavailability of a conventional-release and sustained-release theophylline product, Aminophyllin and Theodur, respectively. Nine stable asthmatics voluntarily completed a four-phase investigation requiring a total stay of 12 days in the Clinical Research Unit. The treatments consisted of administration of the formulations mentioned with and without antacids to each patient in a randomized sequence. Four patients participated in an additional phase where antacids were administered q2h around the clock for three days. After coadministration of theophylline plus antacids for two days, theophylline therapy was discontinued while numerous blood samples were obtained over 22 hr and analyzed for theophylline content via radioimmunoassay. Antacids had no predictable, consistent influence on theophylline absorption rate as determined by the absorption rate constant, the time to maximal theophylline concentration, or the lag time for theophylline absorption. Antacids had no detectable influence on theophylline elimination half-life and had no consistent, statistically significant effect on the extent of theophylline bioavailability, according to measurements of maximal concentration, AUCmeasured over the appropriate steady-state dosing interval, or elimination-rate adjusted AUC.The substantial intraindividual changes for all parameters of theophylline bioavailability that occurred for control and treatment phases likely represent spontaneous, random between-day variability in theophylline disposition independent of antacid administration, as evidenced by the comparability of the percent coefficient of variation for parameters of biovailability across all phases. Our data demonstrate that therapeutic antacid administration has no effect on steady-state theophylline bioavailability and does not alter the intrinsic variability in theophylline absorption. Based on the results of our data, it is unlikely that a clinically significant (〉20%) decrease in theophylline absorption would occur in any patient treated intensively with antacids concurrently.
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    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 83-91 
    ISSN: 1573-8744
    Keywords: bioavailability ; bioequivalence ; hypothesis tests ; sample size determination
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The clinical problem of testing for equivalence in comparative bioavailability trials is restated in terms of the proper statistical hypotheses. A simple t-test procedure for these hypotheses has been devloped that is more powerful than the methods based on usual (shortest) and symmetric confidence intervals. In this note, this new procedure is explained and an example is given, including the method for sample size determination.
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    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 437-450 
    ISSN: 1573-8744
    Keywords: first-pass ; bioavailability ; Michaelis-Menten ; volume of distribution ; absorption rate constant
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Two approaches used for bioavailability determination of drugs with Michaelis-Menten elimination kinetics were examined by computer simulation. The first method involved treating the drug as though its clearance remained constant during elimination, and the conventional method of taking the ratio of areas under the curve resulting from the oral and intravenous doses was used to calculate bioavailability. The second approach involved using the Michaelis parameters, Vmax and Km,to determine concentration dependent clearance values, but based these calculations on peripheral drug concentrations rather than on concentrations entering or in the liver. We have developed a simulation method that was used to test the accuracy of the above two methods. In the simulations described, Vmax, Km,and hepatic blood flow were chosen to represent a drug with an extraction ratio of 0.9 under linear conditions, but with Michaelis-Menten kinetics occurring at the doses given. Absorption was assumed to be first-order, and metabolism was assumed to occur only in the liver. These simulations showed that the most accurate determination of bioavailability requires knowledge of the direct contribution of oral absorption to the concentration of drug entering the liver. Unexpectedly, the results also showed that if a drug has a large volume of distribution or a large absorption rate constant, or both, use of the much simpler conventional method of bioavailability determination may be appropriate even in cases where the degree of saturation is substantial.
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    European journal of nutrition 22 (1983), S. 185-194 
    ISSN: 1436-6215
    Keywords: sugar substitutes ; D-glucose ; bioavailability ; D-glucitol (D-sorbitol) ; D-mannitol ; Palatinit® ; D-glucosyl-α(1→1)-D-mannitol ; D-glucosyl-α(1→6)-D-glucitol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Zur Vertiefung des Verständnisses vom Stoffwechsel des Zuckeraustauschstoffes Palatinit® wurden seine zwei Bestandteile D-Glucosyl-α(1→1)-D-mannit und D-Glucosyl-α(1→6)-D-glucit [D-Glucosyl-α(1→6)-D-sorbit] nach dem Verfahren von Karimzadegan et al. auf ihre Glucose-Bioverfügbarkeit an ketotischen Ratten untersucht. Bei Umwandlungsraten in Glucose von 6 bzw. 20 % für Mannit und Glucit (Sorbit) sowie von 39 bzw. 42% für Glucosylmannit und Glucosylglucit erhält demnach der metabolische Glucose-Pool nicht das volle Glucose-Äquivalent aus diesen Verbindungen. Von dem Anteil an präformierter Glucose in den Glucosylhexiten — theoretisches Maximum 50 % — sind nur 36 % aus Glucosylmannit bzw. 32 % aus Glucosylglucit bioverfügbar. Die im Vergleich zur Theorie verminderte Bioverfügbarkeit von Glucose aus Palatinit® wird auf partiellen mikrobiellen Abbau in unteren Darmabschnitten zurückgeführt. Die an Ratten erhaltenen Ergebnisse werden auch für alle anderen Spezies gelten, welche in Caecum und/oder Colon Kohlenhydrate vergären. Die Unterschiede zwischen D-Glucosyl-α(1→1)-D-mannit und D-Glucosyl-α(1→6)-D-glucit werden durch unterschiedliche Verzögerung der Glucoseresorption im Dünndarm, wo auch D-Glucit angreift, bedingt. Die Ermittlung der Glucose-Bioverfügbarkeit gewährt weitgehende Einblicke in das Schicksal von Kohlenhydraten einschließlich der Symbiose zwischen Säugetier und Mikroorganismen im Dickdarm. Da ein ziemlich vollständiger Überblick über die metabolischen Konsequenzen nach ihrer Zufuhr erhalten wird, sollte das Verfahren zur Messung der Bioverfügbarkeit von Glucose daher bei Abschätzungen der Lebensmittelsicherheit anderer Zuckeraustauschstoffe ebenfalls angewandt werden.
    Notes: Summary For the sake of metabolic insight into the fate of the sugar substitute Palatinit®, its two components D-glucosyl-α(1→1)-D-mannitol and D-glucosyl-α(1→6)-D-glucitol [D-glucosyl-α-(1→6)-D-sorbitol] were assayed for glucose bioavailability by the procedure of Karimzadegan et al. using ketotic rats. With conversion rates into glucose of 6 and 20 %, respectively, for free mannitol and glucitol (sorbitol), 39 % for glucosylmannitol and 42 % for glucosylglucitol, the metabolic glucose pool of the rat does not receive the full carbohydrate complement of these compounds. The preformed glucose moiety of the glucosylhexitols is bioavailable by 36 and 32 %, respectively, from glucosylmannitol and glucosylglucitol, with 50 % as theoretical maximum. Less than theoretical bioavailability of glucose from Palatinit® is ascribed to microbial attack in the hindgut. The data on rats are held valid also for other species demonstrating carbohydrate fermentation in the caecum and/or colon. Differences between D-glucosyl-α(1→1)-D-mannitol and D-glucosyl-α(1→6)-D-glucitol are caused by a differential delay of glucose absorption in the small intestine, also exerted by D-glucitol. The deep metabolic insight offered by the glucose bioavailability assay into the fate of carbohydrates includes the mammal-microbial symbiosis in the large bowel. Since a rather complete survey of the metabolic consequences after their intake can be obtained, the assay system should be generally applied in assessments of food safety also of other sugar substitutes.
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    Numerische Mathematik 41 (1983), S. 373-398 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary The paper introduces a new semi-implicit extrapolation method especially designed for the numerical solution of stiff systems of ordinary differential equations. The existence of a quadratic asymptotic expansion in terms of the stepsize is shown. Moreover, the new discretization is analyzed in the light of well-known stability models. The efficiency of the new integrator is clearly demonstrated by solving a series of challenging test problems including real life examples.
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    Numerische Mathematik 41 (1983), S. 345-371 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Maximum-norm stability and error estimates of best approximation and nonsmooth data types are derived for the approximate solution of a parabolic equation in one space variable, using the continuous in time Galerkin method based on piecewise polynomial approximating functions on a quasi-uniform mesh.
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    Keywords: AMS(MOS): 65L05 ; CR: 5.17
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    Notes: Summary We study the difference equations obtained when a linear multistep method is applied to the scalar test equationdy/dt=λy and constant stepsizeh. LetS be the region of the absolute stability of the method, and letD be a closed subset ofS (on the Riemann sphere $$\mathbb{C}$$ ). It is shown that the solutions of these difference equations are bounded forn≧0, uniformly for λh∈D.S is itself closed in $$\mathbb{C}$$ iff ∂S is free of cusps. The question is studed by means of contractivity analysis and a matrix theorem, derived from the matrix theorem of Kreiss.
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    Numerische Mathematik 41 (1983), S. 399-422 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary The paper presents a new theory for joint order and stepsize control in extrapolation methods. This theory defines a locally optimal order that can be determined along any trajectory to be computed. In addition, Shannon's information theory is applied to derive some ideal convergence model that is expected to describe the behavior of an extrapolation method over a large set of test problems. Extensive numerical comparisons document a drastic acceleration in stiff integration and a mild acceleration in non-stiff integration by the new device. Moreover, a significant increase in reliability, robustness, and portability of the extrapolation codes is achieved.
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    Numerische Mathematik 42 (1983), S. 299-310 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary A new approach to the problem of numerically integrating stiff differential systems is described. In this approach a linear multistep method (the basic method) is split into a kind of predictor-corrector scheme, where the predictor is also implicit. If this splitting is done in an appropriate manner, the modified method has considerably better stability properties than the basic method. As a result, splitting methods are particularly useful for problems where conventional integration methods experience stability difficulties. In particular some highly stable split linear multistep methods based on backward differentiation formulae are derived and a highly stable variable step implementation is proposed.
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    Numerische Mathematik 42 (1983), S. 311-322 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65 N 30 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary This paper presents Galerkin approximations for solutions of two dimensional interface problems by solving corresponding boundary integral equations. These are obtained by simple layer potential operators only. Due to the strong ellipticity of the integral equations the Galerkin procedure converges with optimal order. Smoothness of the given data implies high convergence rates for the layers.
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    Numerische Mathematik 42 (1983), S. 349-357 
    ISSN: 0945-3245
    Keywords: AMS(MOS) 65L05 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary In this paper theD-stability properties of some classes of perturbed collocation methods are investigated. Among others we show the implicit Runge-Kutta methods described by Ehle-Chipman to beD-stable. We also give implicit Runge-Kutta methods that are bothD-stable andA-stable but notB-stable. Finally we indicate in what senseB-stability is stronger thanA-stability together withD-stability. The results of this paper are based on recent results of Nørsett and Wanner on perturbed collocation methods.
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    Numerische Mathematik 41 (1983), S. 55-62 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary The finite element method with Laplace transform of time variable is proposed for the solution of hyperbolic equations. Error estimates in Hardy spaces of functions with values in Sobolev spaces are derived. Due to the isometric isomorphism of Hardy spaces with weighted Hilbert spaces these estimates are valid also for original formulations of hyperbolic equations.
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    Numerische Mathematik 41 (1983), S. 165-175 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65LO5 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary The extrapolated midpoint rule is a popular way to solve the initial value problem for a system of ordinary differential equations. As originally formulated by Gragg, the results are smoothed to remove the weak instability of the midpoint rule. It is shown that this smoothing is not necessary. A cheaper smoothing scheme is proposed. A way to exploit smoothing to increase the robustness of extrapolation codes is formulated.
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    Numerische Mathematik 41 (1983), S. 255-279 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L15 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Some methods for evaluating the characteristic exponents in connection with Newton's iteration are applied for solving the eigenvalue problem related to the finite Hill's differential equation or, in particular, Mathieu's equation. By using these methods a high accuracy is achieved, furthermore a complete error analysis, which yields rather realistic error bounds, is possible.
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  • 59
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    Numerische Mathematik 42 (1983), S. 15-30 
    ISSN: 0945-3245
    Keywords: AMS: 65L10 ; 34C25 ; 34K10 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary An iterative method is presented which starting from a lower or from an upper periodic solution, provides a monotone sequence converging to a periodic solution of (1). With some restrictions on the growth off, the method extends to functional differential equations of type (1′). Two numerical examples with an “a posteriori” error analysis are given.
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  • 60
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    Numerische Mathematik 42 (1983), S. 51-64 
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65N99 ; 35L05 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Engquist and Majda [3] proposed a pseudodifferential operator as asymptotically valid absorbing boundary condition for hyperbolic equations. (In the case of the wave equation this boundary condition is valid at all frequencies.) Here, least-squares approximation of the symbol of the pseudodifferential operator is proposed to obtain differential operators as boundary conditions. It is shown that for the wave equation this approach leads to Kreiss well-posed initial boundary value problems and that the expectation of the reflected energy is lower than in the case of Taylor- and Padé-approximations [3, 4]. Numerical examples indicate that this method works even more effectively for hyperbolic systems. The least-squares approach may be used to generate the boundary conditions automatically.
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    Numerische Mathematik 42 (1983), S. 77-95 
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    Keywords: AMS(MOS): 65N99 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Brakhage and Werner, Leis and Panich suggested to reduce the exterior Dirichlet boundary value problem for the Helmholtz equation to an integral equation of the second kind which is uniquely solvable for all frequencies by seeking the solution in the form of a combined double- and single-layer potential. We present an analysis of the appropriate choice of the parameter coupling the double- and single-layer potential in order to minimize the condition number of the integral operator.
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  • 62
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    Numerische Mathematik 42 (1983), S. 65-76 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65 N 20 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary We consider here a general class of algorithms for the numerical solution of variational inequalities. A convergence proof is given and in particular a multi-grid method is described. Numerical results are presented for the finite-difference discretization of an obstacle problem for minimal surfaces
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  • 63
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    Numerische Mathematik 42 (1983), S. 119-123 
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    Keywords: AMS(MOS): 65N10 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Many difference methods for the numerical solution of elliptic boundary value problems lead to systems of linear equations whose matrices areM-matrices and which therefore have nonnegative inverses. In this paper it is shown, that these difference methods are at most consistent of second order.
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  • 64
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    Numerische Mathematik 42 (1983), S. 173-194 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65N30 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary We consider the stationary Navier-Stokes equations, written in terms of the primitive variables, in the case where both the partial differential equations and boundary conditions are inhomogeneous. Under certain conditions on the data, the existence and uniqueness of the solution of a weak formulation of the equations can be guaranteed. A conforming finite element method is presented and optimal estimates for the error of the approximate solution are proved. In addition, the convergence properties of iterative methods for the solution of the discrete nonlinear algebraic systems resulting from the finite element algorithm are given. Numerical examples, using an efficient choice of finite element spaces, are also provided.
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  • 65
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    Numerische Mathematik 42 (1983), S. 271-290 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65J10, 65L20, 65M10 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary Consider a linear autonomous system of ordinary differential equations with the property that the norm |U(t)| of each solutionU(t) satisfies |U(t)|≦|U(0)| (t≧0). We call a numerical process for solving such a system contractive if a discrete version of this property holds for the numerical approximations. A givenk-step method is said to be unconditionally contractive if for each stepsizeh〉0 the numerical process is contractive. In this paper a general theory is given which yields necessary and sufficient conditions for unconditional contractivity. It turns out that unconditionally contractive methods are subject to an order barrierp≦1. Further the concept of a contractivity threshold is studied, which makes it possible to compare the contractivity behaviour of methods with an orderp〉1 as well. Most theoretical results in this paper are formulated for differential equations in arbitrary Banach spaces. Applications are given to numerical methods for solving ordinary as well as partial differential equations.
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    Numerische Mathematik 42 (1983), S. 359-377 
    ISSN: 0945-3245
    Keywords: AMS 65L05 ; 65L07 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary This paper is concerned with the stability of multistep methods for ordinary initial-value problems on grids with variable mesh-sizes. A necessary and sufficient condition for stability is given from which generalizations of recent results by Gear et al. and by Zlatev can be obtained as special cases. As an application the stability of the variable BDF-formulas is treated.
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    Numerische Mathematik 42 (1983), S. 379-389 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L20 ; 15A60 ; 65M20 ; CR: 5.17
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    Topics: Mathematics
    Notes: Summary If the field of values of a matrixA is contained in the left complex halfplaneH and a functionf mapsH into the unit disc then ∥f(A)∥2≦1 by a theorem of J.v. Neumann. We prove a theorem of this type, only the field of values ofA is used for functions which are absolutely bounded by one in only part ofH. An extension can be used to show norm-stability of single step methods for stiff differential equations. The results are applicable among others to several subdiagonal Padé approximations which are notA-stable.
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    European journal of clinical pharmacology 24 (1983), S. 127-136 
    ISSN: 1432-1041
    Keywords: statistical analysis ; nonparametric statistical methods ; bioavailability ; confidence interval ; ANOVA
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary For a two-way cross-over design, which appears to be the most common experimental design in bioavailability studies, 95%-confidence limits for expected bioavailability can be obtained by classical analysis of variance (ANOVA). If symmetry of the confidence interval is desired about zero (differences) or unity (ratios) rather than about the corresponding point estimator, Westlake's modification can be used. Two nonparametric methods and their adaptations to bioavailability ratios are reviewed, one based on Wilcoxon's signed rank test (Tukey), and the other on Pitman's permutation test. The necessary assumptions and the merits of these procedures are discussed. The methods are illustrated by an example of a comparative bioavailability study. A FORTRAN program facilitating the procedures is available from the authors upon request.
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    European journal of clinical pharmacology 24 (1983), S. 791-796 
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; diuretic effect ; urine sodium ; urine potassium ; power of ANOVA ; tablet formulations ; urinary flow rate ; normal volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relative bioavailability and diuretic effect of 2 commercially available tablet preparations of furosemide 40 mg was examined in 10 healthy male volunteers. A close linear relationship between the urinary excretion rate of furosemide and the rate of sodium ion excretion in urine and/or flow rate of urine was demonstrated. There were no significant differences in the urinary excretion of furosemide, sodium and potassium ions or urinary volume following the oral doses. The difference in drug content affected the urinary recovery of furosemide over 24 h but had no effect on the pharmacological response. The analytical power of ANOVA using the various parameters of the responses to furosemide was no lower than when the parameters of urinary excretion of furosemide were used.
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    European journal of clinical pharmacology 25 (1983), S. 237-241 
    ISSN: 1432-1041
    Keywords: triamterene ; bioavailability ; pharmacokinetics ; metabolism ; hydroxy triamterene sulphate ; urinary excretion ; i.v. administration ; first-pass-effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.
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    European journal of clinical pharmacology 25 (1983), S. 449-453 
    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
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    European journal of clinical pharmacology 24 (1983), S. 103-108 
    ISSN: 1432-1041
    Keywords: dexamethasone ; bioavailability ; pharmacokinetics ; ‘first-pass’ effect ; pre-systemic elimination
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and oral biovailability of dexamethasone were studied in 6 patients with neurological disease being treated with high dosages of the drug. A specific high performance liquid chromatographic assay was used to measure dexamethasone concentrations. Unlike the previously published mean figure of 0.78 for the oral bioavailability of the drug given in single doses to healthy volunteers, the mean bioavailability of dexamethasone in the patients studied was 0.53±SD 0.40. It appeared more likely that this incomplete bioavailability was due to presystemic elimination than to poor absorption. The intravenous clearance of the drug was relatively high (0.4902±SD 2291 l kg−1, approximately 65% of expected hepatic plasma flow), the oral clearance higher (2.5804±SD 3.2181 l kg−1 h−1) while the absorption rate constant (4.8729±8.4998 h−1), suggested rapid absorption after oral administration. Prior phenytoin and possibly prior dexamethasone therapy is likely to have contributed to the higher clearance values of the drug in these patients than the values reported in healthy volunteers after single dose studies.
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  • 73
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    Keywords: oxmetidine ; pharmacokinetics ; bioavailability ; plasma half-life ; clearance ; oral dose ; i.v. dose
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration curves and urinary excretion of oxmetidine after administration of single i.v. (100 mg) and oral (200 mg) doses have been studied in 11 patients with peptic ulcer disease. The mean bioavailability of the drug was 70% (range 53–91%). After intravenous administration, the mean plasmat 1/2β was 3.0 h, the mean apparent volume of distribution 0.7 l/kg, the mean total plasma clearance 12.3 l/h and the mean plasma renal clearance was 0.7 l/h. Following intravenous and oral administration an average of 6% and 3%, respectively, of unchanged drug was found in the urine. The plasma concentration curve after oral administration in most patients exhibited two maxima, with peak concentrations appearing between 45 and 210 min after dosing.
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    European journal of clinical pharmacology 25 (1983), S. 689-693 
    ISSN: 1432-1041
    Keywords: amiodarone ; bioavailability ; calculation ; linear pharmacokinetics ; absorption
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Methods for estimating the bioavailability of drugs with long elimination half-lives are examined. Provided both absorption and disposition are linear a simple linear regression method is developed which can be used to calculate bioavailability in situations where only an incomplete estimate of the area under the curve (AUC) is available. The regression method and the traditional method of comparing the AUC following an oral dose to the AUC following an i.v. dose were applied to simulated data. It was found that the AUC ratio method works well as long as absorption is complete within the time over which the AUC is computed. The regression method is less precise than the AUC ratio method but is more accurate for drugs with long absorption half-lives. When applied to published data on a beta blocker the two methods produced comparable results. The bioavailability of amiodarone in three human subjects was calculated to be 0.20, 0.44 and 0.98 using the regression method with similar results from the ratio method. It is not possible to estimate the clearance of amiodarone from single dose data.
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  • 75
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    Keywords: chlorambucil ; prednimustine ; plasma concentrations ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlorambucil has been investigated in a cross over study after oral administration of the free drug (10 mg) and its prednisolone ester (prednimustine, 100 mg). The bioavailability of chlorambucil was about five times lower when given as prednimustine as compared to administration of the free drug. The peak plasma concentration was about twice as high and it was obtained more rapidly when the free drug was given. No intact prednimustine could be detected in plasma.
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    European journal of clinical pharmacology 24 (1983), S. 563-568 
    ISSN: 1432-1041
    Keywords: indomethacin ; multi-dose kinetics ; controlled release formulation ; capsule formulation ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a controlled release (CR) formulation of indomethacin 75 mg (Indocid-Retard®) given once daily was compared with a conventional 25 mg indomethacin capsule (Indocid®) given 3 times daily for 7 days, to 14 healthy volunteers, using a randomized, cross-over, multiple-dose study design. The following differences in plasma indomethacin profiles after the 2 treatments were observed: average peak concentrations (Cmax) for the CR regimen were higher and the time to peak (Tmax) was significantly delayed. Trough (pre-morning dose) plasma concentrations (Cmin) on Days 2, 5, 6 and 7 were significantly lower after the CR-formulation. No statistically significant differences between preparations for area under the plasma concentration time curve (AUC0–24h) or for renal clearance were observed. Average steady-state plasma concentrations (C p ss ) on Day 7 of the multiple dose regimens averaged 0.477 and 0.427 µg/ml for the 75 mg CR once daily and the conventional 25 mg t.i.d. treatments, respectively. These results show that the bioavailability of the CR and conventional indomethacin formulations under these multiple-dose conditions was not significantly different.
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    European journal of clinical pharmacology 24 (1983), S. 537-542 
    ISSN: 1432-1041
    Keywords: morphine ; analgesic activity ; tablets solution ; pharmacokinetics ; bioavailability ; pain score ; dose-response relationship ; chronic pain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20–40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7–240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.
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  • 78
    ISSN: 1432-1041
    Keywords: metoprolol ; bioavailability ; young ; elderly ; metoclopramide ; probanthine ; gut motility
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of metoprolol was studied in eight healthy young and seven healthy elderly volunteers. Large interindividual differences in the bioavailability of metoprolol were observed in both groups. However, there was no significant difference in AUC, peak plasma concentration or elimination half-life between young and elderly, but time to peak concentration was significantly longer in the elderly. Pretreatment with metoclopramide had no effect on AUC but caused significant increases in peak concentration and decreases in time to peak concentration in both groups. Probanthine pretreatment (only to the young) resulted in a significant decrease in peak concentration of metoprolol and a significant increase in time to peak concentration but had no effect on the AUC. These results suggest that alterations in gastric emptying and gut motility due to ageing or other drugs have no effect on the overall availability of metoprolol to the systemic circulation but may have significant effects on the time to peak plasma concentration and peak concentration achieved after a single oral dose.
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    European journal of clinical pharmacology 25 (1983), S. 419-424 
    ISSN: 1432-1041
    Keywords: dihydrocodeine ; pharmacokinetics ; acid metabolites ; radioimmunoassay ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum concentrations of dihydrocodeine and its acid metabolites have been determined in seven human volunteers (6 male) who received the drug orally (30 mg and 60 mg) and intravenously (30 mg) on separate occasions, and in twenty-four patients (12 male) receiving 25 mg or 50 mg of the drug intravenously. The concentrations were estimated by radioimmunoassay on reconstituted extracts from serum after an extraction process which effectively separates dihydrocodeine from its polar acidic metabolites. The intravenous data show that dihydrocodeine kinetics followed a two-compartment distribution model. The concentration curves after oral administration indicated relatively rapid absorption with mean peak concentrations at 1.6h–1.8h. The mean half-lives varied between 3.3h–4.5h. From the AUC, the mean bioavailability of orally administered drug was 21% (range 12–34%). The peak levels of the acidic metabolites occurred between 1.8h–2.0h after oral administration and 2.2h–2.5h after i.v. administration, and they were significantly greater after oral administration. The low bioavailability of dihydrocodeine, together with the earlier and higher plasma levels of the acid metabolites after oral administration is suggestive of substantial first-pass metabolism.
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    European journal of clinical pharmacology 25 (1983), S. 467-473 
    ISSN: 1432-1041
    Keywords: hydralazine ; heart failure ; pharmacokinetics ; bioavailability ; metabolism ; hypertension ; dapsone ; acetylator phenotype
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of various disease states, other than hypertension, on the pharmacokinetic behaviour of hydralazine is not completely known. In the present study the pharmacokinetics of oral hydralazine has been evaluated in 7 patients with severe, chronic heart failure, using 8 compensated hypertensives as controls. The pharmacokinetics was evaluated by measuring the plasma concentrations of hydralazine (“apparent” and “real” hydralazine) and hydralazine pyruvate hydrazone, and by assessing acetylator phenotype after a small dose of dapsone. The AUC (area under the plasma concentration curve) following a single, oral 50 mg dose was significantly larger in patients with chronic heart failure NYHA Class III–IV than in patients with essential hypertension without cardiac decompensation. A decreased rate of hepatic elimination of hydralazine is suggested as a major contributory factor to this finding.
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    European journal of clinical pharmacology 25 (1983), S. 553-556 
    ISSN: 1432-1041
    Keywords: Endralazine ; pharmacokinetic ; acetylator phenotype ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Endralazine (E), a new hydralazine-like antihypertensive was given intravenously (0.05 mg/kg) to 10 normal volunteers (5 slow and 5 fast acetylators). Plasma levels were fitted to a 3 compartment model and pharmacokinetic parameters (area under curve [AUC 0 ∞ ], clearance, volume of distribution, half-lives) obtained in the usual way. Bioavailabilities of 5 and 10 mg oral doses of E were determined from the AUC 0 ∞ generated in a previous study of oral E given to the same subjects. E had high system bioavailability (73.5–99.1%) suggesting that it was almost completely absorbed without undergoing appreciable first-pass metabolism. Furthermore, dose size and acetylator phenotype did not significantly affect the bioavailability of E. This behaviour contrasts with that of hydralazine where systemic bioavailability was 〈40%, and 2 to 3 times higher in slow acetylators than in fast acetylators. It is concluded that the bioavailability of E is high and not influenced by acetylator phenotype; these properties suggest some clinical advantages for the drug.
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  • 82
    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; children ; sustained-release ; diurnal ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute oral bioavailability of a sustained release theophylline tablet (Nuelin-SR250), given 12 hourly was determined in 14 asthmatic children aged 5 to 13 years. In 4 of the patients, mean bioavailability of the fourth dose was 38.9±8.4% and that of the sixth dose was 67.9±25.9% (p〈0.05) in the other ten patients. This suggests steady-state had not been achieved after four doses. In the initial study with 9 patients, a significant diurnal variation in predose plasma theophylline concentrations was observed, as the mean morning predose concentrations were 2.9 fold greater than the mean evening predose concentrations (p〈0.005). Dual peak plasma concentrations occurred in 5 out of the 9 patients. The mechanism of this diurnal variation was investigated in a further 5 asthmatic children (10.8 years ±1.6). Morning and night steady-state plasma theophylline concentrations during a continuous intravenous infusion of aminophylline were not different (14.9±5.3 mg/l vs. 15.6±5.9 mg/l), demonstrating that there was no diurnal variation in the plasma clearance of theophylline. The diurnal variation in predose concentrations with Neulin-SR250 was confirmed with the morning concentrations again being 2.6 fold greater than those in the evening. However, bioavailability was not significantly different for day (09.00–21.00) and night (21.00–09.00) dosing intervals after doses 6 and 7 respectively of Nuelin-SR250. The plasma concentration versus time profiles suggested that the diurnal variation in predose concentrations was due to slower absorption of the evening dose.
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    European journal of clinical pharmacology 24 (1983), S. 509-515 
    ISSN: 1432-1041
    Keywords: cibenzoline ; pharmacokinetics ; bioavailability ; urinary excretion ; antiarrhythmic drug ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of cibenzoline (UP 339.01), a new antiarrhythmic drug, was studied after i.v. and oral administration to 5 healthy subjects. Cibenzoline levels in plasma and urine cibenzoline were measured by a GLC method. After i.v. administration, the total clearance was 826 ml · min−1. The fraction of cibenzoline excreted unchanged in the urine was 0.602 and it was correlated with the creatinine clearance. After i.v. and oral administration, the renal clearances were 499 ml · min−1 and 439 ml · min−1, and the half-lives were 4 h 01 min and 3 h 24 min, respectively. The differences were not significant. Availability by the oral route was 0.92, the maximum plasma concentration being observed at 1 h 36 min. The results were compared with those for other antiarrhythmic drugs.
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    European journal of clinical pharmacology 25 (1983), S. 281-283 
    ISSN: 1432-1041
    Keywords: dyphylline ; pharmacokinetics ; bioavailability ; drug levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of 3 oral dyphylline preparations, solution (S), regular (R) and sustained release (SR), were studied in 8 healthy subjects (mean age 25 years). A single dose of each preparation, 20 mg·kg−1, was given at one week intervals and multiple serum samples obtained over 24 h. Drug levels were measured by high performance liquid chromatography. No adverse effects were found. The dyphylline half-life for the solution was 2.16±0.18 h and for the tablet 2.59±0.56 h. The mean clearance rate for S was 13.6±1.7 h−1 and volume of distribution 43.0±3.91. Peak concentration (Cmax, µg·ml−1), time of peak (Tmax, h), area under the curve (AUC, µg·ml−1·h) and relative bioavailability (RB, %), were determined for three preparations: The data confirm the short half-life of dyphylline, demonstrate a lack of toxicity for the 20 mg·kg−1 dose and establish bioequivalence for the products studied.
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    European journal of clinical pharmacology 25 (1983), S. 357-359 
    ISSN: 1432-1041
    Keywords: pindolol ; bioavailability ; fluorimetric assay ; GLC-ECD assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute oral bioavailability of pindolol has been estimated by two analytical methods, fluorimetry and GLC-ECD. The study was carried out in six healthy subjects who received either i.v. or oral pindolol in random order. The results obtained by both methods were similar and confirm the high bioavailability (about 75%) of pindolol. The present findings are compared with previous publications and emphasize the importance of undertaking bioavailability studies in the same subjects.
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  • 86
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    European journal of clinical pharmacology 24 (1983), S. 21-30 
    ISSN: 1432-1041
    Keywords: clonidine ; bioavailability ; blood pressure ; elimination half-life ; pharmacokinetics ; plasma catecholamines ; rebound phenomenon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using considerably improved analytical methods, the kinetics and effects of clonidine were observed in healthy volunteers over periods of time more than 3 times longer than those previously reported. The high sensitivity and small work load of the newly developed method permitted the performance of low-dose and multipledose trials. 1. The complete bioavailability of clonidine and its elimination half-life (20 to 25.5 h) remained constant after single and multiple doses. 2. Approximately 62% of a given dose was excreted unchanged in the urine, independent of the quantity administered (0.075, 0.15, 0.2, 0.25 or 0.3 mg), the drug formulation (solution, tablet, Perlonget) or of the mode of administration (i.v., p.o.; single or multiple doses). 3. As the pharmacokinetics of the drug were affected by entero-hepatic circulation, it cannot be described by a conventional, open one or two compartment model. 4. The time courses of the plasma clonidine concentration and its drug effects ran asynchronously. 5. On cessation of chronic clonidine administration, blood pressure and plasma catecholamine levels increased to pretreatment levels without exhibiting any “overshoot” reaction.
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  • 87
    ISSN: 1432-1041
    Keywords: theophylline ; smoking ; sustained release formulation ; dosage forms ; multidose pharmacokinetics ; bioavailability ; circadian variation in kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of theophylline following 10 days of multiple doses of a plain uncoated (640 mg, q.i.d.) and a sustained-release tablet formulation (600 mg, b.i.d.) were related to habitual smoking in 11 healthy adult male volunteers, who had previously taken part in a single-dose study of an intravenous preparation of theophylline and of the same oral dosage form. There were significant differences (p〈0.05 to 0.01) in the steady-state mean and minimum theophylline concentration and AUC between the groups (6 smokers versus 5 nonsmokers), but not between other variables. A difference (p〈0.05) in peak time was also found between the dosage forms. The mean elimination t1/2 was significantly (p〈0.05) shorter in smokers than in nonsmokers. The intersubject variability in plasma theophylline concentration observed on the final trial day in the smoking group was larger and diverged more from simulation curves generated from the mean pharmacokinetic parameters of the single-dose study of the same formulations as compared to that of the nonsmoking group. There was no significant difference between the two groups in the mean accumulation ratio and absolute bioavailability of the two dosage forms. The mean morning (7 a.m.) trough theophylline concentrations after both formulations were significantly (p〈0.05 to 0.01) greater than the evening (7 p.m.) values within the same group. The average number of reported side-effects was significantly (p〈0.001) greater during the earlier period (Days 1 to 3) than the later period of the trial. A trend was observed suggesting that the incidence of side-effects was less in smokers than in nonsmokers. The results indicate that smoking is a determinant not only of enhanced elimination of theophylline but that it also produces more variability in the plasma level, irrespective of the dosage form administered or the dosing scheme employed. There may be circadian variation in theophylline kinetics.
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  • 88
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    European journal of clinical pharmacology 24 (1983), S. 415-419 
    ISSN: 1432-1041
    Keywords: prednisolone ; bioavailability ; non-linear pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of prednisolone after oral and intravenous administration of 10 and 20 mg have been studied. Serum protein binding of prednisolone was also measured after the i.v. injections. The bioavailability after oral administration was 84.5% after 10 mg and 77.6% after 20 mg (p〉0.05). Dose dependent pharmacokinetics were found, the VDss and Clt being significantly larger (p〈0.01) after 20 mg i.v. than after 10 mg i.v. The protein binding of prednisolone in all subjects was non-linear, and is the most likely cause of the dose dependent pharmacokinetics, as there was no dose dependent variation in elimination half-time.
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  • 89
    ISSN: 1432-1041
    Keywords: ranitidine ; duodenal ulceration ; pharmacokinetics ; non-responders ; therapeutic response ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of orally administered ranitidine were studied in 17 male patients with chronic duodenal ulceration. The patients were divided into 2 groups, 10 responders and 7 nonresponders, on the basis of their endoscopic response to ranitidine treatment. The 10 responders were studied both after a single 150 mg dose (SD) and after multiple dosing (MD) with ranitidine 150 mg twice daily for 4 weeks. The area under the curve (AUC) and maximum concentration (Cmax) were significantly higher (p〈0.01 andp〈0.05, respectively) after MD than after SD, but the half-life (t1/2) and minimum concentration (Cmin) 12 h postdosing did not differ. The non-responders were studied after MD only and their pharmacokinetic characteristics were compared with those of responders. No differences between the 2 groups were found. However, 2 non-responders had particularly low plasma ranitidine levels and high acid output. Such patients may need larger doses of ranitidine for adequate suppression of gastric acid. Five patients (4 responders and 1 non-responder) received ranitidine 20 mg i.v. The drug followed a two-compartment model, with mean values for t1/2β, volume of distribution steady-state and total plasma clearance of 80 min, 701 and 680 ml/min, respectively. The oral bioavailability of ranitidine in these 5 patients showed wide variation (27–76%; mean 51%).
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  • 90
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    European journal of clinical pharmacology 24 (1983), S. 761-767 
    ISSN: 1432-1041
    Keywords: theophylline ; bioavailability ; sustained release tablet ; pharmacokinetics ; Theograd-250
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of theophylline after oral administration of a new sustained release tablet Theograd®-250 mg was studied in 7 healthy volunteers, under fasting and non-fasting conditions. Whilst fasting the bioavailability was moderate at 64±22% (mean±SD), whereas in the non-fasting state the relatively high bioavailability of 90±13% was found. The drug appeared to be significantly more slowly absorbed when a tablet was taken after a meal, than when it was ingested on an empty stomach. In the former case, the peak level was reached after 6.9±1.0 h, whereas in the fasting state the maximum serum concentration occurred 4.0±1.7 h after administration of the drug. Despite the slow absorption, the peak non-fasting level of 4.4±1.4 mg·l−1 was significantly higher than the 3.1±1.0 mg·l−1 observed in the fasting state. The profiles of the serum concentration-time curves showed that the concentration remained above 75% of Cmax for 8.7±1.3 h in the fasting and 9.0±1.1 h in the non-fasting state. It was concluded that to define the optimal dosage regime for sustained release oral dosage forms of theophylline, the influence of food on absorption from these preparations should be taken into account. Based on the present results, Theograd®-250 mg tablets have predictable absorption and a high (90%) bioavailability if taken after a meal.
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  • 91
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    European journal of clinical pharmacology 25 (1983), S. 69-72 
    ISSN: 1432-1041
    Keywords: levodopa ; intestinal absorption ; small intestine ; bioavailability ; benserazide ; presystemic clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In four healthy subjects the intestinal absorption of levodopa (l-dopa) was investigated by measuring the plasma concentration of the amino acid following the administration of l-dopa at three different sites in the small intestine. In order to minimize presystemic clearance of l-dopa, the subjects were pretreated with the peripheral decarboxylase inhibitor benserazide 3×50 mg every 8 h on the previous day and 1×50 mg 2 h prior to administration of the l-dopa. L-dopa 100 mg dissolved in 0.05 N HCl and 50 mg benserazide dissolved in 0.05 N HCl were coadministered. Under these conditions no difference in tmax, cmax or AUC of l-dopa was observed between administration of the drug into the proximal or the distal part of duodenum, or into the upper part of jejunum. The results indicate that in healthy subjects, during inhibition of peripheral decarboxylase, the rate and extent of l-dopa absorption does not differ at any site in the upper small intestine.
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  • 92
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    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 561-576 
    ISSN: 1573-8744
    Keywords: methylprednisolone ; bioavailability ; pharmacokinetics ; oral and parenteral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study was conducted to evaluate the influence of route of administration upon the bioavailability and pharmacokinetics of methylprednisolone sodium succinate. Fourteen healthy adult male volunteers received 40 mg doses of methylprednisolone as the following treatments after an overnight fast in a 4-way crossover design: (a) as a 1 ml i.v. bolus;(b) as a 1 ml i.m. injection;(c) administered as an oral solution;and (d) as 5×8 mg oral tablets. Both the ester and free methylprednisolone were determined in plasma and urine. Study results indicate that the ester is rapidly and extensively converted to free methylprednisolone after all routes. The extent of methylprednisolone absorption was equivalent after i.v. and i.m. administration. Both orally administered treatments resulted in a lower extent of absorption attributed to a first-pass effect. Although a slightly lower extent of absorption was demonstrated following the oral administration of the methylprednisolone sodium succinate solution relative to the methylprednisolone oral tablets, this average difference of 9% would probably be of minimal therapeutic importance.
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  • 93
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    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 205-214 
    ISSN: 1573-8744
    Keywords: bioavailability ; clearance ; V area ; V ss
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The limitations of using estimates of extent of bioavailability (F) based on the assumption that either clearance (CL) or Varea remain, constant are discussed in relation to the situation where CL changes between doses. When estimates of F assume CL to remain constant, the entent of the error is the same for all drugs where the percentage change in CL is the same. Assuming Varea to remain constant, the error in F will vary between drugs for similar percentage changes in CL and is related to the extent to which the kinetics of the disposition process deviate from a one compartment body model. A noncompartmental method is described where, provided the reference dose is given intravenously, F can be estimated based on the assumption that Vss remains constant between doses. This method is more accurate than those based on the assumption that either CL or Varea remain, constant when CL changes between doses, but is subject to error when the terminal loglinear slope of Cp vs. time better reflects the process of absorption rather than elimination.
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  • 94
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    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 529-545 
    ISSN: 1573-8744
    Keywords: bioavailability ; nitrofurantoin ; capacity-limited elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of route of administration on the absolute bioavailability and GI tract absorption of nitrofurantoin was investigated in rabbits. The disposition of nitrofurantoin was described by a one-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics, and bioavailability was estimated by nonlinear assessment. The plasma levels following oral administration were significantly lower than those after intravenous administration, and absolute Fvalues for oral administration were approximately 0.3. However, Fvalues following intraduodenal administration and portal vein infusion were nearly unity, and it was concluded that the reduction of bioavailability following oral administration could not be attributed to metabolism by intestinal microflora or to the hepatic first-pass effect. Thus, reduction of Fvalues following oral administration is probably due to gastric degradation of the drug. The effects of factors influencing bioavailability, such as water volume taken with the drug, change of gastric emptying rate and effect of particle size, were also investigated. Increase of volume of water administered tended to improve the bioavailability, and a particle size dependency was also observed.
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  • 95
    ISSN: 1436-5057
    Keywords: 65L05 ; CR: 5.17 ; Numer. Analysis ; verallgemeinerte Runge-Kutta-Methoden ; steife Probleme
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Description / Table of Contents: Abstract Adaptive Runge-Kutta-methods are considered. Investigations of stability for these linear implicit methods are studied. For the application a LS-stable method of order four with an adaptive stepsize control is proposed. Test results for 25 stiff initial value problems for different tolerances are discussed.
    Notes: Zusammenfassung Es werden adaptive Runge-Kutta-Verfahren betrachtet und Stabilitätsuntersuchungen für diese linear impliziten Methoden durchgeführt. Für die Anwendung wird ein LS-stabiles Verfahren vierter Ordnung mit einer angepaßten Schrittweitenkontrolle vorgeschlagen. Testergebnisse von 25 stiff Anfangswertproblemen für verschiedenen Toleranzen werden diskutiert.
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  • 96
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    Numerische Mathematik 40 (1982), S. 179-199 
    ISSN: 0945-3245
    Keywords: AMS(MOS) ; Primary 65N30 ; Secondary 35R35 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Two problems are considered in the paper: the first of them is connected with elliptic variational inequalities and consists in developing a moving obstacle algorithm for approximating the unknown free boundary; the other problem is linked with numerical solution of the Stefan problem, which is formulated in the similar way as in the elliptic case. Some computational aspects are also discussed in the paper.
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  • 97
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    Numerische Mathematik 40 (1982), S. 207-227 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65M30 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary Several regularization methods for parabolic equations backwards in time together with the usual additional constraints for their solution are considered. The error of the regularization is estimated from above and below. For a “boundary value problem in time”-method, finite elements as well as a time discretization are introduced and the error with respect to the regularized solution is estimated, thus giving an overall error of the discrete regularized problem. The algorithm is tested in simple numerical examples.
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  • 98
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    Numerische Mathematik 39 (1982), S. 221-230 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L05 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary In this paper Adams type methods for the special case of neutral functional differential equations are examined. It is shown thatk-step methods maintain orderk+1 for sufficiently small step size in a sufficiently smooth situation. However, when these methods are applied to an equation with a “non-smooth” solution the order of convergence is only one. Some computational considerations are given and numerical experiments are presented.
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  • 99
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    Numerische Mathematik 39 (1982), S. 309-324 
    ISSN: 0945-3245
    Keywords: AMS (MOS): 65L10 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary A method for improvement of the numerical solution of differential equations by incorporation of asymptotic approximations is investigated for a class of singular perturbation problems. Uniform error estimates are derived for this method when implemented in known difference schemes and applied to linear second order O.D.E.'s. An improvement by a factor ofε n+1 can be obtained (where ɛ is the “small” parameter andn is the order of the asymptotic approximation) for a small amount of extra work. Numerical experiments are presented.
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  • 100
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    Numerische Mathematik 39 (1982), S. 341-350 
    ISSN: 0945-3245
    Keywords: AMS(MOS): 65L10 ; CR: 5.17
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Summary We discuss the construction of three-point finite difference approximations and their convergence for the class of singular two-point boundary value problems: (x α y′)′=f(x,y), y(0)=A, y(1)=B, 0〈α〈1. We first establish a certain identity, based on general (non-uniform) mesh, from which various methods can be derived. To obtain a method having order two for all α∈(0,1), we investigate three possibilities. By employing an appropriate non-uniform mesh over [0,1], we obtain a methodM 1 based on just one evaluation off. For uniform mesh we obtain two methodsM 2 andM 3 each based on three evaluations off. For α=0,M 1 andM 2 both reduce to the classical second-order method based on one evaluation off. These three methods are investigated, theirO(h 2)-convergence established and illustrated by numerical examples.
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