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  • 1
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    European journal of nutrition 36 (1997), S. 299-302 
    ISSN: 1436-6215
    Keywords: Energy retention ; protein retention ; fat retention ; growth ; body composition ; broilers ; Energieansatz ; Proteinansatz ; Fettansatz ; Wachstum ; Körperzusammensetzung ; Broiler
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Mit steigender Aufnahme erhöht sich der Körperfettgehalt und der Körperproteingehalt nimmt ab. Es wird oft angenommen, daß jede Zunahme im Ansatz mit mehr Fett und weniger Protein verbunden ist. Experimentelle Ergebnisse widerlegen jedoch diese Annahme. In zwei Experimenten mit männlichen Broilerhühnern wurden die Tiere auf einem Niveau von 60 % und 100 % der empfohlenen Energieaufnahme gefüttert. Die Körperzusammensetzung bei 1500 g zeigte, wie erwartet, daß sich bei steigenden Aufnahmen der Körperfettgchalt vergrößert und der Körperproteingehalt abnimmt. Fettund Proteinansatz waren linear mit der totalen Energieretention (ER) korreliert. Das bedeutet, daß jede Zunahme im Ansatz den gleichen Protein- und Fettgehalt besitzt. Wenn der Fettansatz gleich Null ist wird nur Protein, etwa 50 % des maximalen Ansatzes, retiniert. Wenn ER=O ist, wird Protein angesetzt und Fett mobilisiert. Energie-und N-Bilanzuntersuchungen bestätigen die konstante Zusammensetzung jeder Vergrößerung des Ansatzes. Die Ergebnisse beider Experimente zeigen, daß die ER aus zwei Komponenten besteht: einem basalen konstanten täglichen Proteinansatz und einer variablen zusätzlichen ER, die hauptsächlich aus Fett besteht. Der basale Proteinansatz beträgt etwa 50 % des maximalen Ansatzes. Mit steigenden Energieaufnahmen wird der basale Proteinansatz mit einer zusätzlichen Menge von Protein und Fett im konstanten Verhältnis ergänzt.
    Notes: Summary With increasing intakes the body fat content increases and that of protein decreases. It is most often assumed that this is brought about because each increment in retention contains more fat and less protein. Experimental results, however, showed that this explanation is not true. In two experiments male broiler chickens were fed at levels between 60 and 100 % of recommended energy intake. Body composition at 1500 g showed, as expected, that with increasing intakes body fat content increased and protein content decreased. Both fat and protein retention per day were linearly related to total energy retention (ER). This means that each increment in retention has the same protein and fat content. At zero fat retention only protein was retained, about 50 % of maximal retention. At zero ER protein was retained and fat mobilized. Energy and N balance experiments confirmed the constant composition of each increment in retention. The results of both experiments show that total ER consisted of two components: a basic constant daily protein retention and a variable additional ER, mainly consisting of fat. The basic protein retention is about half of maximal retention. With increasing energy intakes the basic protein retention is combined with an additional amount of protein and fat in a constant ratio.
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  • 2
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    European journal of nutrition 36 (1997), S. 332-335 
    ISSN: 1436-6215
    Keywords: Nutrient intake ; protein metabolism ; protein synthesis ; growth ; energy expenditures ; Nährstoffaufnahme ; Proteinstoffwechsel ; Proteinsynthese ; Wachstum ; Energieaufwand
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Eine Zunahme von fettfreiem Gewebe tritt auf, wenn die Proteinsynthese größer ist als der Proteinabbau. Obwohl während des Wachstums von der Geburt bis zur Reife die absoluten Proteinsynthese- und -abbauraten ansteigen, nehmen dagegen die fraktionellen Raten ab. Bcide Prozesse reagieren auf die Nährstoffaufnahme. Es gibt aber deutliche Unterschiede zwischen den verschiedenen Geweben. Protein, Kohlenhydrate und Fett können den Proteinansatz bei unreifen Tieren und Kindern stimulieren. Die zugrundeliegenden Mechanismen und die Energieaufwendungen scheinen jedoch unterschiedlich zu sein.
    Notes: Summary Lean tissue growth occurs when the rate of protein synthesis exceeds the rate of protein breakdown. Althoughabsolute rates of protein synthesis and breakdown rise during growth from birth to maturityfractional rates fall. Both these processes are sensitive to nutrient intake but responses to feeding vary greatly amongst different tissues. Protein, carbohydrate and fat can all stimulate body protein accretion in immature animals and in children but the mechanisms by which they do so, and the energy expenditures involved, seem to be different.
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  • 3
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    Acta biotheoretica 39 (1991), S. 1-14 
    ISSN: 1572-8358
    Keywords: Hematological diseases ; first order partial differential equations ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract To address the possibility that proliferative disorders may originate from interactions between multiple populations of proliferating and maturing cells, we formulate a model for this process as a set of coupled nonlinear first order partial differential equations. Using recent results for the asymptotic behaviour of the solutions to this model, we demonstrate that there exists a region of coupling coefficients, maturation rates, and proliferation rates that will guarantee the stable coexistence of coupled cellular populations. The analysis shows that increases in the coupling between populations may ultimately lead to a loss of stability. Furthermore, the analysis indicates that increases (decreases) in the maturation and/or proliferation rates above (below) critical levels will lead either to instability in the populations or the destruction of one population and the persistence of the other.
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  • 4
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    Catalysis letters 10 (1991), S. 225-232 
    ISSN: 1572-879X
    Keywords: VPI-5 ; stability ; molecular sieve ; post-synthesis treatments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Thorough washing of a VPI-5 synthesized with n-dipropylamine as template improves greatly its thermal stability while no major change is observed in the template content. A detailed study of the influence of the pretreatment conditions shows that in order to obtain a high thermal stability (up to at least 960 °C) two parameters are of importance. The removal of both the template and the adsorbed water requires either a low heating rate at atmospheric pressure or a low pressure (less than 3 Torr) when the heating rate is 300 ° per hour.
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  • 5
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    Positivity 1 (1997), S. 319-330 
    ISSN: 1572-9281
    Keywords: delay equations ; stability ; positive solutions ; spectral growth condition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We prove stability for a semilinear delay equation, whose nonlinearity is majorized by a linear positive operator. The key ingredients are a spectral condition, positivity of solutions to the linear problem, and lattice properties of the Banach space.
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  • 6
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    Set-valued analysis 5 (1997), S. 73-88 
    ISSN: 1572-932X
    Keywords: differential inclusion ; invariance ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract The properties of invariance, stability, asymptotic stability and attainability of a given compact set $$K \subset \mathbb{R}^n $$ with respect to a differential inclusion, have weak and strong versions: the weak version requires existence of a trajectory with the corresponding property, while the strong one requires this property for all trajectories. The following statement is proven in the paper (under slight restrictions) for each of the above-mentioned properties: if K has the weak property with respect to $$\dot x \in F(x) $$ , then there is a (regulation) mapping G such that G(x) ⊂ F(x) ∀ x and G has the strong property with respect to $${\dot x}$$ ε G(x). In addition, certain regularity of the set of solutions of the last inclusion is claimed.
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  • 7
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    Set-valued analysis 5 (1997), S. 365-375 
    ISSN: 1572-932X
    Keywords: set-valued mappings ; vector optimization ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We establish optimization results for set-valued mappings, with the image space given by a topological vector space partially ordered by a cone. Moreover, we obtain stability results relative to parametrized optimization problems. We use a weak semicontinuity concept related to the order structure of the image space and show how compactness assumptions used in previous papers can be lightened.
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  • 8
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    Queueing systems 27 (1997), S. 205-226 
    ISSN: 1572-9443
    Keywords: multiclass queueing networks ; ergodicity ; stability ; performance analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract We develop the use of piecewise linear test functions for the analysis of stability of multiclass queueing networks and their associated fluid limit models. It is found that if an associated LP admits a positive solution, then a Lyapunov function exists. This implies that the fluid limit model is stable and hence that the network model is positive Harris recurrent with a finite polynomial moment. Also, it is found that if a particular LP admits a solution, then the network model is transient.
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  • 9
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    Journal of dynamics and differential equations 9 (1997), S. 463-505 
    ISSN: 1572-9222
    Keywords: Difference equations ; random perturbation ; averaging ; diffusion approximation ; randomly perturbed iterations ; stability ; 3SR60 ; 60H15 ; 60J99
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract Let (X, ℬ) and (Y,C) be two measurable spaces withX being a linear space. A system is determined by two functionsf(X): X→ X andϕ:X×Y→X, a (small) positive parameterε and a homogeneous Markov chain {y n } in (Y,C) which describes random perturbations. States of the system, say {x n ɛ ∈X, n=0, 1,⋯}, are determined by the iteration relations:x n+1 ɛ =f(x n ɛ )+ɛϕ(x n ɛ ,Yn+1) forn≥0, wherex 0 ɛ =x 0 is given. Here we study the asymptotic behavior of the solutionx n ɛ asε → 0 andn → ∞ under various assumptions on the data. General results are applied to some problems in epidemics, genetics and demographics.
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  • 10
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    Set-valued analysis 5 (1997), S. 377-390 
    ISSN: 1572-932X
    Keywords: differential inclusions ; stability ; boundedness of solutions ; Lyapunov functions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract For Lipschitzian differential inclusions, we prove that the existence of suitable Lyapunov functions is necessary for uniform stability and uniform boundedness of solutions.
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  • 11
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    Queueing systems 26 (1997), S. 343-363 
    ISSN: 1572-9443
    Keywords: retrial queues ; stability ; ergodicity ; renovation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract We consider the following Type of problems. Calls arrive at a queue of capacity K (which is called the primary queue), and attempt to get served by a single server. If upon arrival, the queue is full and the server is busy, the new arriving call moves into an infinite capacity orbit, from which it makes new attempts to reach the primary queue, until it finds it non-full (or it finds the server idle). If the queue is not full upon arrival, then the call (customer) waits in line, and will be served according to the FIFO order. If λ is the arrival rate (average number per time unit) of calls and μ is one over the expected service time in the facility, it is well known that μ 〉 λ is not always sufficient for stability. The aim of this paper is to provide general conditions under which it is a sufficient condition. In particular, (i) we derive conditions for Harris ergodicity and obtain bounds for the rate of convergence to the steady state and large deviations results, in the case that the inter-arrival times, retrial times and service times are independent i.i.d. sequences and the retrial times are exponentially distributed; (ii) we establish conditions for strong coupling convergence to a stationary regime when either service times are general stationary ergodic (no independence assumption), and inter-arrival and retrial times are i.i.d. exponentially distributed; or when inter-arrival times are general stationary ergodic, and service and retrial times are i.i.d. exponentially distributed; (iii) we obtain conditions for the existence of uniform exponential bounds of the queue length process under some rather broad conditions on the retrial process. We finally present conditions for boundedness in distribution for the case of nonpatient (or non persistent) customers.
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  • 12
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    Annals of global analysis and geometry 15 (1997), S. 277-297 
    ISSN: 1572-9060
    Keywords: mean curvature ; $$r$$ -mean curvature ; sphere ; stability ; stable
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract We deal with compact hypersurfaces immersed in space forms with constant $$r$$ -mean curvature. They are critical points for a variational problem. We show they are stable if and only if they are geodesic spheres, generalizing results on constant curvature hypersurfaces.
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  • 13
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    Acta applicandae mathematicae 49 (1997), S. 35-54 
    ISSN: 1572-9036
    Keywords: dynamical systems ; stability ; pseudo orbit tracing property ; nonstandard analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract It is known that it is not possible to introduce C0 -structural stability for whole systems in topological dynamics. Using the methods of Nonstandard Analysis, we suggest four different purely topological stability concepts for dynamical systems on compact subsets of Rn. Classically these amount to considering the space of all systems on a given subset of Rn as the fundamental entity when deforming a continuous system (instead of the space of all continuous systems as is normally done in topological dynamics). For two of the introduced stability concepts, we will show that all minimal flows are stable in this sense. Besides this, we will show that one of our stability concepts is related to what is called the pseudo orbit tracing property in a recently published book by Aoki and Hiraide and compare some of our results to the theory of dynamical systems as presented there.
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  • 14
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    Celestial mechanics and dynamical astronomy 67 (1997), S. 181-204 
    ISSN: 1572-9478
    Keywords: Hamiltonian systems ; symplectic mappings ; normal forms ; resonances ; stability ; three degrees of freedom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We analyze four-dimensional symplectic mappings in the neighbourhood of an elliptic fixed point whose eigenvalues are close to satisfy a third-order resonance. Using the perturbative tools of resonant normal forms, the geometry of the orbits and the existence of elliptic or hyperbolic one-dimensional tori (fixed lines) is worked out. This allows one to give an analytical estimate of the stability domain when the resonance is unstable. A comparison with numerical results for the four-dimensional Hénon mapping is given.
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    Celestial mechanics and dynamical astronomy 69 (1997), S. 271-281 
    ISSN: 1572-9478
    Keywords: restricted three-body problem ; libration points ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The existence and stability of triangular libration points in the relativistic restricted three-body problem has been studied. It is found that L4,5 are unstable in the whole range 0 ≤ µ ≤ 1/2 in contrast to the classical restricted three-body problem where they are stable for 0 〈 µ 〈 µ0, where µ is the mass parameter and µ0 = 0.03852....
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    Celestial mechanics and dynamical astronomy 69 (1997), S. 317-330 
    ISSN: 1572-9478
    Keywords: artificial satellite ; Nekhoroshev's theory ; normal form ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We investigate the significance of long time stabilty predictions in the light of Nekhoroshev's theory by studying the orbits of artificial satellites. As a simplified model problem we consider the so-called J2problem for an earth's satellite, neglecting luni-solar perturbations and nonconservative effects. We consider a wide range of orbits, excluding those which are too close to the critical inclination. Most of the orbits turn out to be stable for times larger than the estimated age of the solar system, thus proving that, as far as dissipation can be neglected, stability in Nekhoroshev's sense may be effective for physically realistic systems.
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    Entomologia experimentalis et applicata 61 (1991), S. 59-72 
    ISSN: 1570-7458
    Keywords: Consumption ; food utilization efficiencies ; growth ; Lycopersicon esculentum ; Manduca sexta ; Nicotiana tabacum ; potassium ; tobacco hornworm ; water regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Third instar tobacco hornworms (Manduca sexta L.: Sphingidae) on low dietary potassium had a lower relative growth rate than individuals on diets with potassium concentrations reflecting those in host-plants, due to decreased consumption rate, lower efficiencies of conversion of ingested and digested food (ECI and ECD), and a prolonged growth/feeding phase. Furthermore, these larvae, when placed on a diet with a moderate potassium concentration through the fourth stadium, ended up being smaller due to lower ECI and less biomass gained, and had a prolonged growth phase, which suggest an irreversible cost of the previous low potassium diet. Third instar hornworms on high potassium diets had lower ECI and ECD, and they had a prolonged growth phase. These individuals, when placed on a moderate potassium diet in the fourth stadium, gained less biomass, than those previously offered hostplant-like-potassium diets. Body potassium concentrations (% dw) at the end of the third stadium were similar among treatment groups. With increasing potassium concentrations in the diet, utilization efficiencies of potassium decreased and potassium concentrations in the frass increased. Correspondingly, water content (% fw) of the newly-molted fourth instar larvae declined with increasing potassium, indicating a passive loss of water during potassium excretion. Low and high dietary potassium reduced survivorship of third instar larvae; fourth instar caterpillars previously fed the low potassium diet also had poor survivorship. We conclude that, within the normal range of potassium concentrations in the hostplants, caterpillar performance is largely unaffected by potassium concentration, but that potassium-poor and potassium-rich diets, such as those hornworms may sometimes experience, can reduce growth and survivorship.
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    Archive of applied mechanics 67 (1997), S. 447-456 
    ISSN: 1432-0681
    Keywords: Key words rotation ; stability ; energy criterion ; variational analysis ; functional analysis ; eigenvalue problem
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Summary Stability of a heavy rotating rod with a variable cross section is studied by energy method. Bifurcation points for the system of equilibrium equations are analyzed. It is shown that for the case when the rotation speed exceeds the critical one, the trivial solution ceases to be the minimizer of the potential energy, so that rod loses stability, according to the energy criteria. Also, a new estimate of the maximal rod deflection in the post-critical state is obtained.
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  • 19
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    Biology and fertility of soils 25 (1997), S. 163-168 
    ISSN: 1432-0789
    Keywords: Key words Arbuscular mycorrhiza ; Ectomycorrhiza ; Benomyl ; Colonization ; External hyphae ; Field study ; Glomales ; Zea mays ; Pisolithus tinctorius
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Arbuscular mycorrhizal (AM) grasses compete for nutrients with ectomycorrhizal (EM) pine in the southeastern United States. Our objective was to determine if benomyl could be used to selectively inhibit the function of AM and thereby reduce grass competition in the field. The effects of Benlate (active ingredient: benomyl) in the greenhouse and field were evaluated. No effect was observed on pine inoculated with Pisolithus tinctorius in the greenhouse. Colonized root length of benomyl-treated Zea mays L. plants inoculated with Glomus sp. in the greenhouse remained static over time and the response was not dose dependent at concentrations of 0, 20, 60 and 150kg benomyl ha–1 equivalent. In contrast, colonization of nontreated plants increased over time. In the field, a minimal reduction of grass colonization was observed following four applications of benomyl ranging from 5 to 20kgha–1. We conclude that benomyl can successfully inhibit development of AM fungi under controlled conditions in the greenhouse with no inhibitory effects on the EM fungus P. tinctorius; however, in the field several factors may interfere with the effect of benomyl on AM fungi. These factors include: (a) the presence of ground cover which obstructs penetration of the fungicide to the soil, (b) timing of application in relation to mycorrhizal development, and (c) the application method of benomyl, a soil drench being preferable to a foliar spray.
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    Biology and fertility of soils 25 (1997), S. 142-146 
    ISSN: 1432-0789
    Keywords: Key words Denitrification ; Tillage systems ; Maize ; Zea mays ; Hot spots ; Denitrifying populations ; N2O emission
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Denitrification losses show an irregular pattern through the year, often being caused by climatic conditions and management practices. The objectives of the present work were to quantify denitrification losses and to determine the influence of tillage system on the factors that control denitrification in fertilized soils. The modal profile of the soil was an Vertic Argiudoll, clay loam texture, located in Buenos Aires province, Argentina. The treatments were: (a) fertilized, (b) incorporated fertilization and (c) without fertilization for both no tillage and conventional tillage systems. Chambers were placed in the field to measure denitrification. In this clayish soil the estimated mean values of accumulated denitrification during the crop cycle (90 days) were 0.190kgNha–1 for conventional tillage and 0.350kgNha–1 for no tillage. In treatments with no tillage, losses by denitrification were approximately twice those of conventional tillage. These differences were also evidenced by the number of microorganisms, which were significantly higher (P〈〉;5%) for no tillage on all dates, except for at flowering. The increase at flowering coincided with the period of highest rainfall and consequently the highest water contents in the soil. The highest denitrification losses, except for sowing, were measured when soil moisture content was more than 30% (v/v). Denitrification increased in conjunction with an increase in the availability of carbon that is consumed by the heterotrophic microorganisms (including the denitrifiers).
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  • 21
    ISSN: 1432-0789
    Keywords: Key wordsAlternaria alternata ; Arbuscular mycorrhizas ; Fusarium equiseti ; Glomus mosseae ; Lactuca sativa ; Lettuce ; Maize ; Saprophytic fungi ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The effect of inoculation with the saprophytic fungi Alternaria alternata or Fusarium equiseti on maize (Zea mays) and lettuce (Lactuca sativa) with or without arbuscular mycorrhizal (AM) colonization by Glomus mosseae was studied in a greenhouse trial. Plant dry weights of non-AM-inoculated maize and lettuce were unaffected by the presence of A. alternata and F. equiseti. In contrast, A. alternata and F. equiseti decreased plant dry weights and mycorrhization when inoculated to the rhizosphere before G. mosseae. The saprophytic fungi inoculated 2 weeks after G. mosseae did not affect the percentage of root length colonized by the AM endophyte, but did affect its metabolic activity assessed as succinate dehydrogenase activity. Although F. equiseti inoculated at the same time as G. mosseae did not affect mycorrhization of maize roots, its effect on AM colonization of lettuce roots was similar to that with A. alternata. In the rhizosphere of both plants, the population of saprophytic fungi decreased significantly, but was not affected by the presence of G. mosseae. Our results suggest that there may have been a direct effect of the saprophytic fungi on the mycorrhizal fungi in the extramatrical phase of the latter, and when the AM fungus was established in the root the AM fungus was less affected by the saprophytic fungi.
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  • 22
    ISSN: 1432-0789
    Keywords: Key words Corn stubble decomposition ; N-fertilization ; Carbon light fraction ; Humic acids ; Microbial activity ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The variation in stubble decomposition due to fertilizer incorporation was determined in a typical Argiudoll of the Argentinian rolling pampas. The experiment was conducted for 15 years, which included a no till system under maize (Zea mays L.) and a soybean rotation (Glycine max) with 0 and 45kg N ha–1 nitrogen fertilization treatments, called NFS and FS, respectively. A higher proportion of residues with a high N content was found in the FS plots. The different substrate quality proved to be the regulating factor for mineralization. This activity was indicated by the increase in soil microbial activity and soil carbon light fraction in FS compared to NFS. This carbon light fraction mineralizes rapidly but does not contribute to the most stable components, which are related to synthesis and polymerization of humic acids. No significant differences in humic acid content were found.
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    Biology and fertility of soils 24 (1997), S. 266-273 
    ISSN: 1432-0789
    Keywords: Key words Green manure ; Lime ; K deficiency ; Oxisol ; Sweet corn ; Zea mays ; Mn toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Effects of local green manure (GM) and lime on soil productivity in a low-input agricultural system were evaluated by growing three successive crops of sweet corn (Zea mays) on an acid Oxisol (Typic acrorthox, Togitogiga series) in Western Samoa. The soil was amended with coral lime at 0, 5, and 10Mgha–1 and with cowpea GM at 0, 7.5, and 15Mgha–1. Commercial NPK fertilizers at 50kgha–1 each of N, P, and K were included for comparison. The amendments were applied only once prior to planting of the first crop. Response parameters measured included nutrient composition of leaves at tasseling and grain yield of each crop, and selected soil chemical properties at each planting. Yields of the first crop were nearly tripled with GM additions and doubled with lime additions. Such yield increases were caused mainly by better K nutrition and to a lesser extent by enhanced P nutrition. Yields of subsequent crops were much lower than those of the first, and the declines were much steeper for the GM treatments than for the lime treatments. Thus, the enhancement effect on K nutrition did not last beyond one crop. Poor growth of the second and third crops was caused by K deficiency; probably coupled with Mn toxicity. Significant yield reductions were found when Mn-to-K ratios in leaves exceeded 0.010. As for effects on soil, soil pH was increased significantly by lime but only slightly by GM. Given the variable charge property of this Oxisol, each unit pH increase corresponds to a cation exchange capacity (CEC) increase of 5cmolckg–1. Having greater CEC, the amended soil retained K more effectively, thereby causing yield increases, especially of the first corn crop, which required at least 0.75cmolckg–1 of exchangeable soil K or 7% of CEC for adequate growth.
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    European journal of nutrition 36 (1997), S. 205-213 
    ISSN: 1436-6215
    Keywords: Frying ; growth ; liver lipids ; lipaemia ; olive oil ; pregnancy ; rat ; Fritierung ; Wachstum ; Leberfett ; Olivenöl ; Schwangerschaft ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Um Informartionen über den Zusammenhang zwischen der Aufnahme von Fett, das zum Fritieren benutzt wurde, und dem Fetthaushalt während Perioden starken Körperaufbaus zu haben, wurde der Einfluß der Aufnahme von frischem Olivenöl (Gehalt polarer Verbindungen, 2 %; Ölsäure 78,9 mg/100 mg Öl, und Linolsäure 7 mg/100 mg Öl) und von Olivenöl, das 15 mal in Folge für das Fritieren von Kartoffeln benutzt worden war (Gehalt polarer Verbindungen 9 %; Ölsäure 75,8 mg/100mg Öl und Linolsäure 6,2 mg/100mg Öl) während der Gravidität, untersucht. Dazu wurden trächtige Wistar Ratten in zwei Gruppen geteilt, die beide eine isokalorische Diät bekamen, deren Fettanteil 15 % von frischem (unbenutztem) (P1) bzw. fritiertem (benutztem) (P2) Olivenöl stammte mit nicht trächtigen Ratten verglichen. Die Gravidität erhöhte (p〈0,01) die Futteraufnahme, das Körpergewicht, die Gewichtszunahmen und die Futterverwertung. Die Ölqualität beeinflußte dagegen diese Parameter nicht. Während der Gravidität stiegen die Serumwerte der Triglyceride (TG) (p〈0,01) und des Cholesterins (TC) (p〈0,05) an, während die der Phosphatide (PH) sanken (p〈0,01). Ein signifikanter Effekt der Ölqualität und eine Wechselwirkung zwischen Gravidität und Öl wurde für TG und PH festgestellt. Das Gewicht und der Fettgehalt der Leber der trächtigen Ratten stiegen signifikant an (p.〈0.05), Leber TC, TG und PH stiegen während der Gravidität (ungefähr um das 3-fache der Ausgangswerte), aber es traten keine signifikanten Unterschiede zwischen der Aufnahme von benutztem und nicht benutztem Öl (P2 vs P1) auf. Die Ergebnisse zeigen, daß die Aufnahme von leicht verdorbenem Olivenöl als alleinige Fettquelle der Nahrung keine besonderen Folgen für die Gravidität hat, was die Gewichtszunahme der Mütter und der Feten, die Lipämie und die Zusammensetzung des Leberfetts betrifft.
    Notes: Summary The effect of the consumption of unused olive oil (polar content, 2 %; oleic acid, 78.9 mg/100 mg oil, and linoleic acid 7 mg/100 mg oil) and olive oil used discontinuously for frying potatoes 15 times (polar content, 9 %; oleic acid, 75.8 mg/100 mg oil and linoleic acid 6.2 mg/100 mg oil) was studied in pregnant rats with the aim of better understanding the relationship between the consumption of fat used in frying and lipid metabolism during periods of intense anabolism. Trials were performed in pregnant Wistar rats, divided into 2 groups and fed isocaloric diets in which the fat content (15 % wt/wt) consisted of unused olive oil (P1) or oil previously used for frying (P2), and the results were compared with those of nonpregnant rats fed unused olive oil (NP1) and olive oil used for frying (NP2). Pregnancy increased (p〈0.01) food intake, body weight, weight gain, and food efficiency ratio (P2 vs NP2 and P1 vs NP1, respectively), but the treatment of oil included in the diets did not alter these parameters. Gestation significantly increased the serum triglyceride (TG) (p〈0.01) and total cholesterol (TC) (p〈0.05) concentrations and diminished that of phospholipids (PH) (p〈0.01). A significant effect of the type of oil consumed and a pregnancy x oil interaction on Tg and PH levels was observed. The weight of the liver and its fat content increased significantly (p〈0.05) as a result of pregnancy. Liver TC, TG, and PH increased (approximately 3 times the original values) during gestation, but no significant differences due to the intake of used or unused oil (P2 vs P1) were observed. The results indicate that the consumption of moderately altered olive oil, as the sole source of fat, does not alter the effect of pregnancy on the mothers' weight gain, lipaemia, and hepatic fat composition to any important degree.
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  • 25
    ISSN: 1436-6215
    Keywords: Body composition ; fat ; growth ; somatotropin ; pig ; Körperzusammensetzung ; Fett ; Wachstum ; Somatotropin -Schwein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung An 78 männlichen Kastraten und weiblichen Schweinen der Kreuzung Pietrain x (Deutsches Edelschwein x Deutsche Landrasse) wurden Untersuchungen zum Einfluß einer porcinen Somatotropin (pST)-Behandlung während des Wachstums auf die chemische Körperzusammensetzung der Tiere, das Adipozyten-Wachstum und das Fettsäure-Profil des Rückenspecks untersucht. Die intramuskulären Injektionen (1 oder 3 mg pST) wurden täglich ab durchschnittlich 65 kg Lebendgewicht bis zum Schlachten verabreicht. Nach der pST-Behandlung wurden bei den Kastraten in allen untersuchten Merkmalen signifikante Unterschiede festgestellt, während sich bei den weiblichen Tieren nur leichte Reaktionen zeigten. Das pST verursachte eine Zunahme des Wasserund Proteingehaltes bei gleichzeitiger Reduzierung des Lipidgehaltes besonders in den fettreichen Körperteilen der Tiere. Im Rückenspeck war der Gehalt an ungesättigten Fettsäuren erhöht und der Fettzelldurchmesser erniedrigt.
    Notes: Summary Seventy eight growing-finishing pigs (male castrates and females) of the cross-breed Pietrain x (Large White x German Landrace) were used to investigate the effects of pST treatment on the chemical composition of the body, the growth of adipocytes, and the fatty acid profile of the backfat. Intramuscular injections (1 or 3 mg pST) were administered daily from an average weight of 65 kg up to slaughter. After pST treatment significant changes in all studied characteristics were observed in barrows, whereas the females exhibited very small responses. The pST caused an increase of water and protein contents and a simultaneous decrease of lipid content especially in body parts rich in fat. Furthermore, the proportion of unsaturated fatty acids increased and the fat cell diameter decreased in the backfat.
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  • 26
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    Microchimica acta 104 (1991), S. 467-482 
    ISSN: 1436-5073
    Keywords: prediction ; stability ; multivariate methods ; graphical analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sizeable data bases are now being routinely generated in a variety of contexts in chemical industry. Statistical investigations of such data bases are aimed both at initially uncovering structure and eventually proposing models, in particular for predicting product quality by the mix or characteristics of the chemical compounds. “Online Multivariate Exploratory Graphical Analysis” (OMEGA) stands for a structured exploratory study of the relationships in a multivariate data set, where, rather than testing for one specific property, as many clues as possible for interesting structures are searched for by different dimension reductions and succeeding interactive graphical analyses. The stability of the projections obtained by the different dimension reduction methods is assessed by simulation producing graphical displays particularly supporting the identification of influential points. The variation of the predictions obtained by the different dimension reduction methods is assessed by cross-validation delivering misclassification rates or cross-validated R2 values. The interpretation of the new coordinates corresponding to dimension reduction is supported by loading simplifications and graphical displays for judging its adequacy. The OMEGA strategy has been found to be an effective tool for routine searching for structure.
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  • 27
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    Journal of productivity analysis 8 (1997), S. 293-310 
    ISSN: 1573-0441
    Keywords: growth ; USagriculture ; externalities ; spill-overs ; public R and D
    Source: Springer Online Journal Archives 1860-2000
    Topics: Economics
    Notes: Abstract Growth in U.S. agriculture is linked to the non-farm economy through domestic terms of trade and factor market adjustments. With almost stable input growth, the relatively large contributions from growth in Total Factor Productivity (TFP) are passed on to intermediate and final consumers in the form of declining real prices for primary farm products. The resulting net growth in the real value of farm output (GDP) is relatively low (0.25% per annum). The decomposition of TFP suggests that public agricultural stock of knowledge and infrastructure are “robustly” associated with TFP growth, while spill-overs from private agricultural and economy wide research and development (R and D) are positive but, relatively small.
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  • 28
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    K-Theory 4 (1991), S. 363-397 
    ISSN: 1573-0514
    Keywords: Nonabelian K 1 ; noncommutative homotopy ; general linear group ; superspecial linear groups ; descending central series ; stability ; relative normal subgroups ; nilpotent sandwich classifications ; quasi-finite algebras
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A functorial filtration GL n =S−1L n $$ \supseteq$$ S0L n $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n $$ \supseteq$$ ⋯ $$ \supseteq$$ E n of the general linear group GL n, n ⩾ 3, is defined and it is shown for any algebra A, which is a direct limit of module finite algebras, that S−1 L n (A)/S0L n (A) is abelian, that S0L n (A) $$ \supseteq$$ S1L n (A) $$ \supseteq$$ ⋯ is a descending central series, and that S i L n (A) = E n(A) whenever i ⩾ the Bass-Serre dimension of A. In particular, the K-functors k 1 S i L n =S i L n /E n are nilpotent for all i ⩾ 0 over algebras of finite Bass-Serre dimension. Furthermore, without dimension assumptions, the canonical homomorphism S i L n (A)/S i+1 L n (A)→S i L n+ 1(A)/S i+1 L n + 1 (A) is injective whenever n ⩾ i + 3, so that one has stability results without stability conditions, and if A is commutative then S0L n (A) agrees with the special linear group SL n (A), so that the functor S0L n generalizes the functor SL n to noncommutative rings. Applying the above to subgroups H of GL n (A), which are normalized by E n(A), one obtains that each is contained in a sandwich GL′ n (A, ρ) $$ \supseteq$$ H $$ \supseteq$$ E n(A, ρ) for a unique two-sided ideal ρ of A and there is a descending S0L n (A)-central series GL′ n (A, ρ) $$ \supseteq$$ S0L n (A, ρ) $$ \supseteq$$ S1L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ E n(A, ρ) such that S i L n (A, ρ)=E n(A, ρ) whenever i ⩾ Bass-Serre dimension of A.
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  • 29
    ISSN: 1573-0832
    Keywords: Candida albicans ; ammonium ; physiology ; medium ; growth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Candida albicans strain B 311-10 with and without starvation was cultivated in the minimal synthetic medium of Shepherd et al. [18], modified without biotin, aminoacids, low glucose concentration [20] and with decreasing amounts of (NH4)2SO4, to determine the optimal growth requirement for this strain. All the experiments were carried out under sterile conditions at 25 °C in a thermostat with initial O.D.s (675 nm) of 0.500 and 0.100. Cell growth was generally monitored everyday for six days with a spectrophotometer by determining the absorbance of the cultures at 675 nm. All the experiments were repeated three times and a statistical analysis of the data with a probability of 99% and 1% of error was performed to confirm the validity of the results. Best growth was obtained with starved cells at an initial O.D. of 0.100 and with a 0.1 g/L concentration of (NH4)2SO4. At this concentration, the growth of C. albicans B 311-10 was best between the first and the fourth day with the maximum at the third day. With (NH4)2SO4 concentrations of 0.05 and 0.5 g/L, cell growth was the same.
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    Journal of statistical physics 88 (1997), S. 691-711 
    ISSN: 1572-9613
    Keywords: Quasicrystals ; nonperiodic tilings ; classical lattice-gas models ; ground states ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We give strong evidence that noncrystalline materials such as quasicrystals or incommensurate solids are not exceptions, but rather are generic in some regions of phase space. We show this by constructing classical lattice-gas models with translation-invariant finite-range interactions and with a unique quasiperiodic ground state which is stable against small perturbations of two-body potentials. More generally, we provide a criterion for stability of nonperiodic ground states.
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  • 31
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    Journal of intelligent and robotic systems 20 (1997), S. 131-155 
    ISSN: 1573-0409
    Keywords: robot adaptive control ; basis function-like networks ; stability ; discrete variable structure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Stable neural network-based sampled-data indirect and direct adaptivecontrol approaches, which are the integration of a neural network (NN)approach and the adaptive implementation of the discrete variable structurecontrol, are developed in this paper for the trajectory tracking control ofa robot arm with unknown nonlinear dynamics. The robot arm is assumed tohave an upper and lower bound of its inertia matrix norm and its states areavailable for measurement. The discrete variable structure control servestwo purposes, i.e., one is to force the system states to be within the stateregion in which neural networks are used when the system goes out of neuralcontrol; and the other is to improve the tracking performance within the NNapproximation region. Main theory results for designing stable neuralnetwork-based sampled data indirect and direct adaptive controllers aregiven, and the extension of the proposed control approaches to the compositeadaptive control of a flexible-link robot is discussed. Finally, theeffectiveness of the proposed control approaches is illustrated throughsimulation studies.
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  • 32
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    Journal of intelligent and robotic systems 19 (1997), S. 411-436 
    ISSN: 1573-0409
    Keywords: assembly planning ; stability ; robot ; forward ; operations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract The paper presents an approach to sequence planning consisting in determining assembly sequences defined in terms of mating and non-mating operations and based on a dynamic expansion of the assembly tree obtained using a knowledge base management system. The planner considers the case of a single-robot assembly workcell. The use of stability and the detailed definition of sequences also by means of several non-mating operations are shown to be powerful instruments in the control of the tree expansion. Forward assembly planning has been chosen, in order to minimize the number of stability checks. Backtracking is avoided by combining precedence relations and stability analysis. Hard and soft constrains are introduced to drive the tree expansion. Hard constraints are precedence relations and stability analysis. All operations are associated to costs, which are used as soft constraints. The operation based approach enables one to manage even non-mating operations and to easily overcome the linearity constraint. Costs enable the planner to manage the association among tools and components. The first section of the paper concerns Stability Analysis that is subdivided into Static and Dynamic Stability Analysis. The former is mainly involved in analyzing gravity effects; the latter is mainly involved in evaluate inertia effects due to manipulation. Stability Analysis is implemented in a simplified form. Fundamental assumptions are: no rotational equilibrium condition is considered; for each reaction force only direction and versus, but not magnitude, are considered; friction is neglected. The second section discusses the structure of the planner and its implementation. The planner is a rule based system. Forward chaining and hypothetical reasoning are the inference strategies used. The knowledge base and the data base of the system are presented and the advantages obtained using a rule based system are discussed. The third section shows two planning examples, showing the performance of the system in a simple case and in an industrial test case, the assembly of a microwave branching filter composed of 26 components.
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  • 33
    ISSN: 1432-1939
    Keywords: Key words Agrostis canina ; CO2 vents ; photosynthesis ; lignification ; growth
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    Topics: Biology
    Notes: Abstract  The aim of this study was to characterise growth and photosynthetic capacity in plants adapted to long-term contrasting atmospheric CO2 concentrations (C a). Seeds of Agrostis canina L. ssp. monteluccii were collected from a natural CO2 transect in central-western Italy and plants grown in controlled environment chambers at both ambient and elevated CO2 (350 and 700 μmol mol−1) in nutrient-rich soil. Seasonal mean C a at the source of the plant material ranged from 610 to 451 μmol CO2 mol−1, derived from C4 leaf stable carbon isotope discrimination (δ13C). Under chamber conditions, CO2 enrichment stimulated the growth of all populations. However, plants originating from elevated C a exhibited higher initial relative growth rates (RGRs) irrespective of chamber CO2 concentrations and a positive relationship was found between RGR and C a at the seed source. Seed weight was positively correlated with C a, but differences in seed weight were found to explain no more than 34% of the variation in RGRs at elevated CO2. Longer-term experiments (over 98 days) on two populations originating from the extremes of the transect (451 and 610 μmol CO2 mol−1) indicated that differences in growth between populations were maintained when plants were grown at both 350 and 700 μmol CO2 mol−1. Analysis of leaf material revealed an increase in the cell wall fraction (CWF) in plants grown at elevated CO2, with plants originating from high C a exhibiting constitutively lower levels but a variable response in terms of the degree of lignification. In vivo gas exchange measurements revealed no significant differences in light and CO2 saturated rates of photosynthesis and carboxylation efficiency between populations or with CO2 treatment. Moreover, SDS-PAGE/ LISA quantification of leaf ribulose bisphosphate carboxylase/oxygenase (Rubisco) showed no difference in Rubisco content between populations or CO2 treatments. These findings suggest that long-term adaptation to growth at elevated CO2 may be associated with a potential for increased growth, but this does not appear to be linked with differences in the intrinsic capacity for photosynthesis.
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  • 34
    ISSN: 1432-2048
    Keywords: Ammonium compartmentation ; Cytoplasm ; Vacuole ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We show that the pH dependence of the base-catalysed exchange rate of the ammonium ion provides a basis for discriminating between the cytoplasmic and vacuolar pools of ammonium in plant tissues. In vivo, 14N-nuclear magnetic resonance spectra were recorded with and without 1H-decoupling and information on the subcellular distribution of NH 4 + was obtained from a lineshape analysis of the 1H-coupled spectrum. We applied this method to maize (Zea mays L.) root tissues and found that: (i), the cytoplasmic ammonium concentration was low, which was in accord with the large activity of glutamine synthetase present in the roots; and (ii), inhibition of glutamine synthetase with methionine sulphoximine increased the cytoplasmic ammonium concentration, and led to the appearance of ammonium in the xylem sap.
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  • 35
    ISSN: 1432-203X
    Keywords: wheat ; rye ; embryogenesis ; growth ; tissue culture
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    Topics: Biology
    Notes: Summary The influence of the short arm of rye chromosome 1 (1RS) from Secale cereale var. Imperial on the growth and differentiation of callus cultures from wheat Triticum aestivum var. Chinese Spring immature embryos was analysed. This chromosome arm was found to stimulate both embryogenesis and the rate of growth of calli. Recombinant lines carrying segments of 1RS were used to delineate the regions of 1RS responsible for the tissue culture effects. The enhancement of embryogenesis and the stimulation of growth were shown to be associated with two distinct genetic regions of the chromosome arm; the former is located between the centromere and the Sec 1 locus, while the latter is situated in the immediate vicinity of the Sec 1 locus.
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  • 36
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    Sexual plant reproduction 4 (1991), S. 12-16 
    ISSN: 1432-2145
    Keywords: In vitro fertilization ; Egg cell ; Sperm cell ; Electrofusion ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Electrofusion-mediated in vitro fertilization of maize using single sperm and egg cells was performed. Sperm cells were released from pollen grains after rupture of the latter by osmotic shock in the fusion medium (0.55 M mannitol). Egg cells were isolated by enzyme treatment (pectinase, pectolyase, hemicellulase, and cellulase) followed by mechanical isolation. The conditions generally used for the electrical fusion of protoplasts of somatic cells were also applied to the protoplasts of gametic cells of maize. Electrofusion was performed with single pairs of gametes under microscopic observation. The mean fusion frequency was 79%. Isolated egg cells of maize showed protoplasmic streaming during 22 days of culture, but they did not divide. However, after fusion of the sperm with the egg cells, these fused cells did develop, with a mean division frequency of 83%, and grew to multicellular structures. Egg cells and fusion products were cultivated with a maize feeder-cell system.
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  • 37
    ISSN: 1432-1041
    Keywords: Alpidem ; Anxiolytics ; pharmacokinetics ; tolerance ; metabolites ; sedation ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, placebo-controlled, crossover experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0–54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1–4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng · ml−1, respectively. In 50% of the subjects cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng · ml−1 · h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18,1 and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related. Thus the kinetics of alpidem and its three major metabolites were linear after doses of 25 to 200 mg. The drug was well tolerated by most of the subjects. Sedation and dizziness occurred mainly after the 100 and 200 mg doses.
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  • 38
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    European journal of clinical pharmacology 41 (1991), S. 449-452 
    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; Caffeine ; pharmacokinetics ; P-450 mono-oxygenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diabetes may alter the pharmacokinetics of aminopyrine and antipyrine, which are used to assess liver function. Caffeine has recently been used to test liver function, but the effect of diabetes on caffeine kinetics is not known. The kinetics of caffeine has been examined in patients with decompensated Type I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the apparent caffeine clearance, half-life, and apparent volume of distribution were similar to controls. It is concluded that decompensated diabetes does not influence the cytochrome P-448 mono-oxygenase system responsible for caffeine metabolism.
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  • 39
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    European journal of clinical pharmacology 40 (1991), S. 593-597 
    ISSN: 1432-1041
    Keywords: Dopamine ; Newborns ; critically ill patients ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 μg · kg−1 · min−1, for presumed or proven sepsis and hypotensive shock. Steady-state concentrations of dopamine ranged from 0.013–0.3 μg/ml. Total body clearance averaged 115 ml · kg−1 · min−1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg−1 and 6.9 min, respectively. No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate. Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.
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  • 40
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    European journal of clinical pharmacology 40 (1991), S. 619-624 
    ISSN: 1432-1041
    Keywords: Inulin ; pharmacokinetics ; half life ; distribution ; concentration-dependent clearance ; healthy subjects ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml·min−1) following intravenous infusion of 70 mg·kg−1 over 5 min. Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg·l−1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%. The concentration-dependent renal clearance of inulin was confirmed in “step-up” and “step-down” constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg·l−1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time. Under these conditions the mean plasma half life, volume of distribution (Vss) and total body clearance of inulin in the healthy males, healthy females and patients with chronic renal failure were 73.2, 65.5 and 172.4 min, 10.5, 9.6 and 8.81·70 kg−1 and 113.3, 111.5 and 43.3 ml·min−1·70 kg−1 respectively. There were no sex differences in any of the kinetic variables. The mechanism of the concentration-dependent clearance of inulin is unknown but the findings are consistent with saturable renal tubular reabsorption. Care is required with the use of inulin for measurement of the glomerular filtration rate by the single injection technique.
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  • 41
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    European journal of clinical pharmacology 40 (1991), S. 631-633 
    ISSN: 1432-1041
    Keywords: Mefloquine ; ampicillin ; Thai subjects ; pharmacokinetics ; enterohepatic recycling ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day). These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.
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  • 42
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    European journal of clinical pharmacology 40 (1991), S. 637-638 
    ISSN: 1432-1041
    Keywords: Roxatidine acetate ; sucraflate ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
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    European journal of clinical pharmacology 52 (1997), S. 235-237 
    ISSN: 1432-1041
    Keywords: Key words Itraconazole ; Coca Cola; acidic beverage ; absorption ; pharmacokinetics ; drug concentration ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.
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  • 44
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    European journal of clinical pharmacology 52 (1997), S. 289-292 
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
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  • 45
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    European journal of clinical pharmacology 52 (1997), S. 379-381 
    ISSN: 1432-1041
    Keywords: Key words Nitroglycerin; transdermal nitrate ; pharmacokinetics ; patch renewal ; exercise test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. Results and conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.
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  • 46
    ISSN: 1432-1041
    Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
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  • 47
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    European journal of clinical pharmacology 51 (1997), S. 359-366 
    ISSN: 1432-1041
    Keywords: Key words Sufentanil ; pharmacokinetics ; haemo dynamics ; different infusion rates ; coronary surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract    Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg−1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg−1 · min−1, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min−1 · kg−1), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg−1) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean Cmax values of 421 (group I), 125 (group II), and 53 (group III) ng · ml−1 and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg−1 tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate.
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  • 48
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    European journal of clinical pharmacology 51 (1997), S. 415-419 
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Fluconazole ; CYP3A4 ; interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0–3, AUC0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0–3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
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  • 49
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    European journal of clinical pharmacology 51 (1997), S. 421-425 
    ISSN: 1432-1041
    Keywords: Key words Warfarin ; Meloxicam ; interaction ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.
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  • 50
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    European journal of clinical pharmacology 52 (1997), S. 391-396 
    ISSN: 1432-1041
    Keywords: Key words Lansoprazole ; CYP2C19; genotype ; hydroxy lation ; polymorphism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. Results: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1. Conclusion: The hydroxylation of lansoprazole to 5-hydroxylansoprazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/m2).
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  • 51
    ISSN: 1432-1041
    Keywords: Halofantrine ; Malaria falciparum ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax)=896 and 491 ng·ml−1; time to reach the Cmax (tmax)=15 and 56 h; elimination half-life (t1/2)=91 and 79 h and the mean residence time (MRT)=71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.
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  • 52
    ISSN: 1432-1041
    Keywords: Fosinopril ; fosinoprilat ; CAPD ; ACE-inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml−1, 4.8 h, and 3.19 μg·h·ml−1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng·ml−1, tmax of 9 h, and AUC of 18.1 μg·h·ml−1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min−1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.
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  • 53
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    European journal of clinical pharmacology 41 (1991), S. 171-174 
    ISSN: 1432-1041
    Keywords: Bisoprolol ; pharmacokinetics ; obesity ; blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single i. v. dose of dlbisoprolol 0.16 mg·kg−1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight). Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (Vz) (182 vs 135 1) and a decrease in Vz per kg body weight (2 vs 2.7 l·kg−1). There was a negative correlation between Vz l·kg−1 and the percentage of ideal body weight (r=−0.672). Total body clearance was increased, but t1/2 and renal clearance was unchanged. It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.
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  • 54
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    European journal of clinical pharmacology 41 (1991), S. 175-178 
    ISSN: 1432-1041
    Keywords: Bopindolol ; pharmacokinetics ; beta-adrenoceptor blocker ; age ; hydrolysed bopindolol
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Steady-state pharmacokinetic parameters of the new, long-acting beta-adrenoceptor blocker bopindolol have been measured in 17 young and 20 elderly healthy men. The t1/2β and the AUC(0→24 h) of hydrolysed bopindolol (the active metabolite) were both increased (40% and 26%, respectively) in the elderly subjects but tmax, Cmax and CL/f were not altered. However, after adjusting the parameters to allow for the different average body weights of the two groups, Cmax and CL/f became significantly different (+29% and −30%, respectively). AUC(0→24 h) was increased by 41%. The changes of up to 41% in pharmacokinetic parameters were smaller than the alterations of 50–100% usually seen when titrating doses of antihypertensive drugs. The clinical relevance of the effects was not examined, but similar changes have been reported for other beta-blockers which did not appear to be clinically relevant and did not affect the dosage required to treat hypertension.
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  • 55
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    European journal of clinical pharmacology 41 (1991), S. 179-183 
    ISSN: 1432-1041
    Keywords: Cefadroxil ; saturable absorption ; saturable renal tubular reabsorption ; cephalexin ; competitive inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg−1. As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg−1, the peak plasma concentrations, normalized to 5 mg · kg−1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l−1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l−1. When the same subjects were given 5 mg·kg−1 of cefadroxil together with 45 mg·kg−1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil. Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil. The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg−1 was significantly increased by the simultaneous administration of high-dose cephalexin. The renal clearance of cefadroxil ranged from 98 ml·min·l−1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l−1 to 156 mg·l−1 at concentrations greater than 40 mg·l−1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.
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  • 56
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    European journal of clinical pharmacology 41 (1991), S. 245-250 
    ISSN: 1432-1041
    Keywords: Org 10172 ; Digoxin ; heparinoid ; pharmacokinetics ; pharmacodynamics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potential pharmacokinetic and pharmacodynamic interactions between a new low molecular weight heparinoid Org 10172 (bolus injection of 3250 anti-Xa units) and digoxin (0.25 mg once daily for 8 days) were studied in 6 healthy male volunteers using an open, randomised three-way cross-over design. Digoxin produced a slight increase in clearance of anti-Xa activity from 4.3 to 4.8 ml·min−1, while plasma anti-thrombin and thrombin generation inhibiting (TGI) activity remained unchanged. Digoxin did not affect the actions of Org 10172 on the clotting tests. In the presence of Org 10172 there was a reduction in the AUC of digoxin during one dosing interval after the seventh digoxin tablet from 20 to 17 ng·ml−1·h, and a significant reduction in the average serum digoxin conentration. Since renal digoxin clearance was not significantly changed this probably might be due to a change in the non-renal clearance of digoxin. Atrio-ventricular node conduction, as measured by PR-time intervals, remained unchanged during all three treatments. In conclusion, although the pharmacokinetics of Org 10172 and digoxin were slightly changed by the combination, it is probably safe to administer Org 10172 and digoxin simultaneously. The clinical relevance of the slight decrease in plasma anti-Xa activity levels cannot yet be defined.
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  • 57
    ISSN: 1432-1041
    Keywords: Tiaprofenic acid ; children ; pharmacokinetics ; NSAID
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg · kg−1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC. No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age; tmax=2.12h, Cmax=8.78mg · l−1, AUC(0→8 h) 33.9mg · h · l−1, AUC=39.3 mg · h · l−1, t1/2=2.35 h, Vz=0.319 l · kg−1, CL=0.094 l · h−1 · kg−1. Renal clearance was 14 ml · h−1. kg−1. 33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates. The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg · kg−1 TA. Volume of distribution and t1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3–11 year-old children from that in adults.
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  • 58
    ISSN: 1432-1041
    Keywords: Midazolam ; pharmacokinetics ; intranasal ; intravenous ; children ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg−1 either by the intravenous (IV) or intranasal (IN) routes. After IN administration the rapid onset of absorption was observed (tmax 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration. The results are consistent with an estimated mean bioavailability of 55%.
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  • 59
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    European journal of clinical pharmacology 41 (1991), S. 359-361 
    ISSN: 1432-1041
    Keywords: Diabetes ; Antipyrine ; undernutrition ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insulin dependent diabetes (NIDDM) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits. The AUC of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes per se may not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.
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  • 60
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    European journal of clinical pharmacology 41 (1991), S. 379-382 
    ISSN: 1432-1041
    Keywords: Codeine ; paracetamol ; codeine-6-glucuronide ; pharmacokinetics ; metabolism ; partial clearance ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (μmol·l−1·h) and CLR (ml·min−1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml·min−1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucoronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.
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  • 61
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    European journal of clinical pharmacology 41 (1991), S. 579-583 
    ISSN: 1432-1041
    Keywords: Cefixime ; renal failure ; pharmacokinetics ; volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC. There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity. In normal subjects, the peak serum level (Cmax) was 2.50 μg·ml−1 at 2.83 h (tmax); the apparent elimination half-life (t1/2) was 3.73 h; the apparent total body clearance (CL·f−1) was 154 ml·min−1, the mean renal clearance (CLR) was 39.1 ml·min−1 and the apparent fraction of the dose recovered in 24 h urine was 0.22. In uraemic patients, Cmax and tmax were slightly increased and t1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min−1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CLR and creatinine clearance (CLCR). The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.
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  • 62
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    European journal of clinical pharmacology 41 (1991), S. 603-607 
    ISSN: 1432-1041
    Keywords: Chlormezanone ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.
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  • 63
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
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  • 64
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    European journal of clinical pharmacology 52 (1997), S. 307-310 
    ISSN: 1432-1041
    Keywords: Key words Artemether ; Thai males; malaria ; dihydroartemisinin ; pharmacokinetics ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).
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  • 65
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    European journal of clinical pharmacology 52 (1997), S. 403-406 
    ISSN: 1432-1041
    Keywords: Key words Oxybutynin ; Itraconazole; N-desethyloxy‐butynin; drug interaction ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.
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  • 66
    ISSN: 1432-1041
    Keywords: Key wordsDraflazine ; Population analysis; nucleoside transport inhibitor ; non-linear red blood cell partition ing ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant K d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1. Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.
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  • 67
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    European journal of clinical pharmacology 40 (1991), S. 71-75 
    ISSN: 1432-1041
    Keywords: Isosorbide-5-mononitrate ; sustained-release formulation ; pharmacokinetics ; cardiovascular effects ; chronopharmacology ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
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  • 68
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    European journal of clinical pharmacology 40 (1991), S. 87-93 
    ISSN: 1432-1041
    Keywords: Pharmacotherapy ; renal insufficiency ; pharmacokinetics ; renal drug elimination ; drug monitoring ; dosage guidelines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As the renal elimination of most drugs is closely correlated with the endogenous creatinine clearance, it is possible to use this parameter of kidney function to adjust drug dosage in renal failure. However, this simple procedure neglects possible changes in the volume of distribution, plasma protein binding, drug metabolism, intestinal absorption, and pharmacodynamics in renal insufficiency, as well as the occurrence of biologically active drug metabolities. Because of these uncertainties in critical cases the validity of the dosage calculated using the creatinine clearance should be checked by clinical surveillance and measurements of drug blood concentrations. Further, pharmacokinetic dosage guidelines based on the individual creatinine clearance may not be applicable to diuretics and drugs which have markedly differing kinetics of pharmacodynamic effects and blood levels.
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  • 69
    ISSN: 1432-1041
    Keywords: Ximoprofen ; pharmacokinetics ; normal subjects ; hepatic disease ; renal disease
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ximoprofen, a potent new non-steroidal anti-inflammatory agent, has been investigated in normal healthy subjects and in patients with hepatic or renal disease. After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml·min−1 and the volumes of distribution were 18.0 l Vz and 13.8 l Vss. Ximoprofen was 80–90% bound to plasma proteins. The systemic availabilities (f) of orally and rectally administered doses of 30 mg of ximoprofen were 98% and 56% respectively and, in the case of the rectal dose, absorption appeared to be prolonged leading to “flip-flop” kinetics. After single oral doses of 30 mg of ximoprofen to patients with hepatic disease, half-life (2.2 h), peak plasma concentrations (1.55 μg·ml−1 cf 1.04 μg·ml−1 in healthy subjects) and areas under the curve (6.12 μg·h·ml−1 cf 3.54 μg·h·ml−1 in healthy subjects) were significantly different from those in healthy subjects. After single oral doses of 30 mg of ximoprofen to patients with renal disease, pharmacokinetic parameters of half-life (4.0 h), mean residence time (6.0 h) and area under the curve (9.2 μg·h·ml−1) were significantly different from those in healthy subjects. There were no significant differences in pharmacokinetic parameters between patients having differing degrees of renal disease. These data nevertheless suggest that accumulation of ximoprofen in hepatic or renal disease would be of slight or negligible clinical relevance and that no alteration of the dose regimen (up to 15 mg twice daily) may be required when ximoprofen is administered in these disease states.
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  • 70
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    European journal of clinical pharmacology 40 (1991), S. 363-365 
    ISSN: 1432-1041
    Keywords: Baclofen ; severe spasticity ; pharmacokinetics ; CSF ; intrathecal injection
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l·h−1. In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).
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  • 71
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    European journal of clinical pharmacology 40 (1991), S. 387-392 
    ISSN: 1432-1041
    Keywords: Carbocysteine ; pharmacogenetics ; drug metabolism ; sulphoxidation ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A quantitative study has been made of the metabolism of S-carboxymethyl-L-cysteine (CMC) and its sulphoxides in volunteers by HPLC. Precolumn derivatization was applied prior to gradient reversed phase HPLC separation and fluorescence detection. For CMC and its metabolites containing a primary amino group the reagent 9-fluorenylmethylchloroformate was used. The other metabolites of CMC were derivatized at their carboxylic group with 1-pyrenyldiazomethane to give stable fluorescent products. Urine samples were collected for 8 h after oral administration of 1.125 g CMC to 33 healthy volunteers. Elimination of CMC in urine as sulphoxides did not account for more than 1% of the dose in any of the volunteers. Thus, CMC-sulphoxide metabolites are not quantitatively important. Recovery of the original substance in 8-hour urines ranged from 10 to 30% and a further 2 to 20% was recovered as the metabolite thiodiglycolic acid. Oral doses of 0.19, 1.125, and 2.25 g CMC in a second group of 12 healthy volunteers did not reveal dose dependence of the urinary excretion of the sulphoxides or of thiodiglycolic acid. Serum concentration-time-curves of CMC, (S)- and (R)-CMC sulphoxide were measured in a group of 9 healthy volunteers. The CMC sulphoxides in serum reached 1.5% of the parent substance after 4 hours. The ratio of CMC to its sulphoxide metabolites was similar in serum and urine. Pharmacogenetic polymorphism of sulphoxidation was not confirmed by the specific HPLC methods used.
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  • 72
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    European journal of clinical pharmacology 40 (1991), S. 405-409 
    ISSN: 1432-1041
    Keywords: Metoprolol ; lorazepam ; bromazepam ; interaction ; psychomotor tests ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21–37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam AUC was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together.
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  • 73
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    European journal of clinical pharmacology 40 (1991), S. 427-428 
    ISSN: 1432-1041
    Keywords: Ibuprofen ; children ; fever ; pharmacokinetics ; adverse effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibuprofen ranged from 17–42 μm·ml−1 at 5 mg·kg−1 and 25–53 μm·ml−1 at 10 mg·kg−1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean tmax, oral clearance and elimination half life were 1.1 h, 1.2 ml·min−1·kg−1, and 1.6 h, respectively in patients at 5 mg·kg−1 doses; the corresponding values were 1.2 h, 1.4 ml·min−1·kg−1, and 1.6 h in those receiving 10 mg·kg−1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.
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  • 74
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    European journal of clinical pharmacology 40 (1991), S. 481-487 
    ISSN: 1432-1041
    Keywords: Epirubicin ; pharmacokinetics ; plasma concentrations ; cancer patients
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38–50 mg·m−2, mean 49.2 mg·m−2, administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4′-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.
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  • 75
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    European journal of clinical pharmacology 40 (1991), S. 155-162 
    ISSN: 1432-1041
    Keywords: Flecainide ; sparteine/debrisoquine polymorphism ; metabolism ; enantiomers ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min−1; S 379 ml·min−1) than in EMs (R 783 ml·min−1; S 828 ml·min−1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min−1; S 201 ml·min−1) relative to extensive metabolisers (R 533 ml·min−1; S 586 ml·min−1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min−1) than extensive (267 ml·min−1) metabolisers. The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml−1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.
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  • 76
    ISSN: 1432-1041
    Keywords: Tolbutamide ; diabetes mellitus ; non-insulin dependent ; pharmacokinetics ; pharmacodynamics ; glucose ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol·l−1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.
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  • 77
    ISSN: 1432-0789
    Keywords: Vigna unguiculata ; Zea mays ; Nutrient competition ; Intercropping ; Nitrate depletion ; N2 fixation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences , Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary The use of N and P by mixed and by sole cropping (crop rotation) of maize and cowpeas were compared in a field experiment on an Alfisol at the Nyankpala Agricultural Experiment Station in the northern Guinea Savanna of Ghana, using two levels of N (0 and 80 kg N ha-1 year-1 as urea) and P application (0 and 60 kg P ha-1 year-1 as Volta phosphate rock). Maize grain yields were significantly reduced in the mixed cropping system. This yield difference became smaller with the application of N and P fertilizer. The N and P concentrations in maize ear leaves at silking indicated that a deficiency in N and P contributed to the maize yield depression in mixed cropping. Competition for soil and fertilizer N between maize and cowpeas was suggested by: (1) A similarity in total N uptake between the two cropping systems; (2) efficient use of soil nitrate by the cowpeas; and (3) low N2 fixation by the cowpeas, calculated with the aid of an extended-difference method. In general, N2 fixation was low, with the highest values in the sole cropping (53 kg ha-1) and a substantial reduction in the mixed cropping system. The application of N fertilizer further reduced N2 fixation. This was substantiated by nodule counts. The lower N2 fixation in the mixed cropping system was only partly explained by the lower density of cowpeas in this system. In addition, dry spells during the cropping season and shading by the maize component could have reduced the nodulation efficiency. No N transfer from the legume/rhizobium to the non-legume crop was observed. Impaired P nutrition in the mixed compared with the sole-cropped maize might have been due to less P mobility in the soil. This was indicated by lower soil moisture contents in the topsoil under mixed cropping, especially during the dry year of 1986. The results show that mixed cropping of maize and cowpeas did not lead to improved use of soil and fertilizer N and P or to an enhanced N2 fixation. On the contrary, an annual rotation of maize and cowpeas was clearly superior.
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  • 78
    ISSN: 1432-1041
    Keywords: Levodopa/decarboxylase inhibitor ; Parkinson's Disease ; pharmacokinetics ; duration of therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.
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  • 79
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    European journal of clinical pharmacology 41 (1991), S. 61-63 
    ISSN: 1432-1041
    Keywords: Flecainide ; dose adjustment ; urinary pH ; urinary flow rate ; renal elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml · h−1) 2. acidic urine (pH 5) and a low fluid load (25 ml · h−1) 3. alkaline urine (pH 8) and a high fluid load (125 ml · h−1) 4. alkaline urine (pH 8) and a low fluid load (25 ml · h−1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml · min−1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng · ml−1 · h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml · min−1; AUC 976 vs 1480 ng · ml−1 · h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml · min−1; AUC 1045 vs 1540 ng · ml−1 · h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.
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    European journal of clinical pharmacology 41 (1991), S. 83-84 
    ISSN: 1432-1041
    Keywords: Eptastigmine ; cholinesterase inhibitor ; Alzheimer's disease ; pharmacokinetics ; adverse effects
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  • 81
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    European journal of clinical pharmacology 41 (1991), S. 597-602 
    ISSN: 1432-1041
    Keywords: Dihydroergotamine mesilate ; pharmacokinetics ; urinary excretion ; prolonged half-life ; deep compartment ; RIA ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized crossover trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz=33 l/kg) and a high plasma clearance (CLP=2l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8′-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.
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  • 82
    ISSN: 1432-1041
    Keywords: Piperine ; Propranolol ; Theophylline ; pharmacokinetics ; drug interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.
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  • 83
    ISSN: 1432-1041
    Keywords: Key words Paracetamol ; Renal failure; polar conjugates ; non-insulin-dependent diabetes mellitus (NIDDM) ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A single oral dose of paracetamol (20 mg · kg−1) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min−1 · 1.73 m−2. The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur.
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  • 84
    ISSN: 1432-1041
    Keywords: Platelet activating ; Factor RP 48740 ; platelet aggregation ; PAF-antagonist ; dose-response relationship ; adverse effects ; pharmacokinetics ; dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and exvivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg·l−1. There were no clinical or biological adverse reactions to RP 48740 during the study.
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  • 85
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    European journal of clinical pharmacology 41 (1991), S. 481-484 
    ISSN: 1432-1041
    Keywords: Disopyramide ; pharmacokinetics ; protein binding ; enantiomers ; metabolism ; metabolite kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h−1.kg−1 for R-disopyramide and 0.58 l.h−1.kg−1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h−1.kg−1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.
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  • 86
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    European journal of clinical pharmacology 41 (1991), S. 495-496 
    ISSN: 1432-1041
    Keywords: Asthma ; Salbutamol ; Asians ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients. Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean Cmax was 4.2 ng·ml−1 and 7.7 ng·ml−1 after 4 and 8 mg, respectively. In 5 patients the steady state mean Cmax, Cmin and tmax were 8.1 ng·ml−1 and 4.7 ng·ml−1 and 6 h for the 4 mg tablets and 14.1 ng·ml−1 and 7.1 ng·ml−1 and 4 h for the 8 mg tablets. It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.
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  • 87
    ISSN: 1432-1041
    Keywords: Parkinson's disease ; Apomorphine ; pharmacokinetics ; adverse effect ; on-off effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with Parkinson's disease were given a single sublingual dose of apomorphine in 3 mg tablets (2 patients received 18 mg and 3 patients took 39 mg). The therapeutic effect appeared within 33.0 min and lasted 137 min. There was a significant correlation between peak concentration, area under the curve, dose (mg/kg) and the duration of the therapeutic effect.
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  • 88
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    European journal of clinical pharmacology 41 (1991), S. 273-283 
    ISSN: 1432-1041
    Keywords: Cyclosporin A ; therapeutic monitoring ; assay techniques ; pharmacokinetics ; dose-response relationships
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The success of organ transplantation is closely related to clinical use of the immunosuppressive drug cyclosporin (CsA). The dosage of CsA is complicated by the large intra- and interindividual variability in its pharmacokinetics, as well as by the narrow concentration range between insufficient immunosuppression and toxicity. Potential sources of error in the sampling procedure and the advantages and disadvantages of the available analytical methods are discussed. Traditionally, 12 or 24 hour trough concentrations of CsA are monitored. Recently, peak concentrations or estimation of AUCs by a limited sampling strategy have been tried to improve the relatively weak concentration-effect and concentration-toxicity relationships found with trough CsA concentration monitoring. Studies of the CsA concentration-effect relationships for various treatment indications are reviewed.
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  • 89
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    European journal of clinical pharmacology 41 (1991), S. 317-319 
    ISSN: 1432-1041
    Keywords: Asthma ; Verapamil ; histamine-induced bronchoconstriction ; calcium antagonists ; plasma levels ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi〉100%) in the responders 5 h after the oral dose. The relationship of the bronchoprotective effect to the plasma level of verapamil was also examined. Responders and non-responders did not differ significantly in the peak plasma level or the time course of the plasma verapamil concentration. The protective effect was not correlated with the peak plasma level of verapamil or with the baseline bronchial hyperreactivity.
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  • 90
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    European journal of clinical pharmacology 41 (1991), S. 351-354 
    ISSN: 1432-1041
    Keywords: Paroxetine ; Cirrhosis ; pharmacokinetics ; multiple-dose study ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20–30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSS min) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng · ml−1 per mg paroxetine and 89 vs 43 h (ng) · ml−1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.
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  • 91
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    European journal of clinical pharmacology 41 (1991), S. 363-368 
    ISSN: 1432-1041
    Keywords: Benzoic acid ; hippuric acid ; pharmacokinetics ; hyperammonaemia ; ureagenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentration-time data for benzoic and hippuric acids and urinary excretion-time data for hippuric acid were analyzed simultaneously after oral doses of 40, 80 or 160 mg/kg sodium benzoate administered at least one week apart to 6 healthy subjects. The mean AUCs of benzoic acid after the doses of 80 and 160 mg/kg of sodium benzoate were 3.7- and 12.0-times greater, respectively, than after 40 mg/kg. However, the mean AUC of hippuric acid was roughly proportional to the benzoate doses. The observed data were explained by a one-compartment model with first-order rate absorption and Michaelis-Menten elimination of benzoic acid, together with a one-compartment model with first-order elimination for hippuric acid. Although the maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2 and 28.8 mg·kg−1·h−1 among the six individuals, the mean value (23.0 mg·kg−1·h−1) was fairly close to that provided by daily maximum dose (0.5 g·kg−1·day−1) recommended in the treatment of hyperammonaemia in patients with inborn errors of ureagenesis. The individual maximum rate of metabolism can be estimated from the urinary excretion rate of hippuric acid 1.5 to 3 h after the single oral dose of 80 to 160 mg·kg−1 sodium benzoate. The justification of this concept requires further studies in patients with inborn errors of urea synthesis.
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  • 92
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    European journal of clinical pharmacology 41 (1991), S. 375-378 
    ISSN: 1432-1041
    Keywords: Nicomorphine ; 6-nicotinoylmorphine ; morphine ; intramuscular administration ; metabolism ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After i.m. injection nicomorphine is relatively slowly absorbed from the muscular depot and is found in the serum for approximately 1 h. The rate of absorption differs between patients and governs the overall pharmacokinetic profile of the compound. The relative AUCs were nicomorphine 18%, 6-nicotinoylmorphine 17%, and morphine 65%. Nicomorphine and 6-nicotinoylmorphine have significantly higher AUCs after i.m. injection than after i.v. injection, while the AUC of morphine and the total AUC show no difference between the two modes of administration.
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  • 93
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    European journal of clinical pharmacology 40 (1991), S. 305-308 
    ISSN: 1432-1041
    Keywords: Zidovudine ; acquired immunodeficiency syndrome (AIDS) ; pharmacokinetics ; bioavailability ; food intake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of oral zidovudine has been studied in 13 patients with the acquired immunodeficiency syndrome (AIDS) dosed either fasting or with breakfast. The mean peak plasma concentration and AUC of zidovudine were significantly 2.8- and 1.4-times higher in fasting patients than in those treated during meal. In both conditions the mean half-life was about 1.5 h and the period of plasma zidovudine concentrations 〉1 μmol · l−1 was 2 h (NS). It is concluded that if zidovudine is taken on an empty stomach, high peak plasma concentrations and decreased variation in pharmacological parameters may be expected. Whether or not this will influence toxicity and efficacy remains to be shown.
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  • 94
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    European journal of clinical pharmacology 40 (1991), S. 319-320 
    ISSN: 1432-1041
    Keywords: Theophylline ; controlled-release formulation ; absorption ; pharmacokinetics
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  • 95
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    European journal of clinical pharmacology 40 (1991), S. 333-341 
    ISSN: 1432-1041
    Keywords: Furosemide ; cystic fibrosis ; pharmacokinetics ; diuretic effect ; baseline urine flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis. The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug. The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects. The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.
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  • 96
    ISSN: 1432-1041
    Keywords: Lisuride ; pharmacokinetics ; prolactin concentrations ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 μg lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min−1·kg−1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.
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  • 97
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    European journal of clinical pharmacology 52 (1997), S. 229-234 
    ISSN: 1432-1041
    Keywords: Key words Ranitidine ; Renal impairment; dose adjustment ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (CCr) ranging from 0 to 213 ml · min−1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min−1, correlated with CPAH (r 2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when CCr〈50 ml · min−1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when CCr〈10 ml · min−1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.
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  • 98
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    European journal of clinical pharmacology 52 (1997), S. 241-242 
    ISSN: 1432-1041
    Keywords: Key words Citalopram ; Cimetidine; drug ; drug interac‐tion ; pharmacokinetics
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  • 99
    ISSN: 1432-1041
    Keywords: Key words Nisoldipine ; Hypertension; Ca antagonist ; pharmacokinetics ; pharmacodynamics ; PK/PD modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.
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  • 100
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    European journal of clinical pharmacology 40 (1991), S. 49-52 
    ISSN: 1432-1041
    Keywords: Quinine ; pharmacokinetics ; falciparum malaria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l−1 compared to 5.7 mg·l−1 in convalescence. There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg−1·min−1, which was significantly lower than in convalescence — 2.67 ml·kg−·min−1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg−1·min−1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of α1 acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l−1 compared to 1.05 g·l−1 during convalescence. Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.
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