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  • pharmacokinetics  (273)
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  • 1995-1999  (511)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Risk analysis 19 (1999), S. 711-726 
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
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  • 2
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
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  • 3
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    Journal of ornithology 140 (1999), S. 81-86 
    ISSN: 1439-0361
    Keywords: Reed Warbler ; timing of breeding ; spring arrival ; global climate change ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung In einem Untersuchungsgebiet am westlichen Bodensee (Halbinsel Mettnau) zeichnet sich zwischen 1976 und 1997 eine deutliche Zunahme früh ausgeflogener Teichrohrsänger ab, was auf ein früheres Brüten schließen läßt. Weiterhin hat sich die Erstankunft des Teichrohrsängers am Bodensee in den letzten 16 Jahren (1982–1997) im Vergleich zum Zeitraum 1961 bis 1980 um genau eine Woche verfrüht (im Mittel vom 26.4. auf den 19.4.). Während sich zwischen der jährlichen Erstankunft des Teichrohrsängers am Bodensee und der Zahl früh ausgeflogener Jungvögel kein statistisch gesicherter Zusammenhang finden läßt, ist die Temperatur in der ersten Maihälfte ein guter (statistisch signifikanter) Indikator für die Zahl früh ausgeflogener Teichrohrsänger. Die vorliegende Untersuchung zeigt, daß sich offenbar auch Langstreckenzieher an die sich abzeichnende Klimaveränderung anzupassen beginnen.
    Notes: Summary Data from a standardized mist-netting programme (the so-called "MRI-Programm") were used to assess the timing of breeding in Reed Warblers (Acrocephalus scirpaceus) at Lake Constance (South Germany). The number of Reed Warblers fledged early in the season increased significantly between 1976 and 1997 (rs=0.614; p〈0.01). This is most probably due to a long-term increase in spring temperature as suggested by the high correlation between the number of early-fledged Reed Warblers and mean temperature in the first half of May (rs=0.416; p〈0.01). While in the period from 1961 to 1980 the mean date of spring arrival was on the 26th of April, it shifted towards the 19th April from 1981 to 1997. However, the number of early-fledged Reed Warblers and the date of spring arrival are not significantly correlated. The lack of a significant correlation may be due to a number of reasons, for instance early arriving birds do not belong to the local population or there could be an observational bias among years. Yet, the most likely explanation is that the timing of breeding in Reed Warblers is triggered by vegetation growth and food supply rather than by the timing of spring arrival. There is growing body of evidence from this and other studies that the recent climate change is responsible for the shift in both the timing of migration and breeding in birds.
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  • 4
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    Entomologia experimentalis et applicata 88 (1998), S. 81-96 
    ISSN: 1570-7458
    Keywords: chlorogenic acid ; Heliothis virescens ; Manduca sexta ; Pseudoplusia includens ; rutin ; Spodoptera frugiperda ; temperature ; tomatine ; Trichoplusia ni
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Analysis of the combined effects of allelochemicals on insect herbivores is useful because there may be adverse additive or even synergistic effects. Analysis of the simultaneous effects of temperature and alleochemicals is also necessary because these factors may interact. We examined the effects of three allelochemicals found in tomato (chlorogenic acid, rutin and tomatine) and thermal regime (21:10 °C and 26:15 °C, representing spring and summer respectively) on five insect herbivores (a Solanaceae specialist, Manduca sexta, and the polyphagous Heliothis virescens, Pseudoplusia includens, Spodoptera frugiperda and Trichoplusia ni). There were allelochemical interactions and thermal regime-allelochemical interactions for all species, and so the patterns were complex. In some cases, paired allelochemicals or the combination of three allelochemicals showed adverse additive effects on insect performance. But that was not always the case, and there were only a few examples of synergism. Negative effects of the allelochemicals were sometimes, but not always, damped by the cooler thermal regime. Comparing the growth rates of the five species in this study with those of a previous study (a total of seven species) revealed five patterns. For two of three pairs of closely-related species, the paired species had distinctly different patterns. For example, for H. virescens, tomatine prevented development and chlorogenic acid slowed growth, whereas for Helicoverpa zea, tomatine just slowed growth and the phenolics had little effect. The specialist Manduca sexta had a pattern that was midway between patterns of the generalists; it was not the most tolerant of the allelochemicals.
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  • 5
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    Entomologia experimentalis et applicata 80 (1996), S. 481-489 
    ISSN: 1570-7458
    Keywords: reproductive compatibility ; hybrid inviability ; temperature ; Trichogramma ; biological control ; Hymenoptera ; Trichogrammatidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract In non-reciprocal cross-incompatibility (NRCI), the crossing of a female of a strain A with a male of a strain B results in hybrid offspring, whereas the reciprocal cross produces few or no hybrids. Only females are of hybrid origin in Hymenoptera because they arise from fertilized eggs; males arise from unfertilized (haploid) eggs. Crosses between many strains of Trichogramma deion showed some degree of NRCI. Crosses between a T. deion culture collected in Seven Pines, California (SVP) with one from Marysville, California (MRY) showed an extreme form of NRCI in which practically no female offspring was produced when MRY females were crossed with SVP males. The reciprocal cross produced a close to normal proportion of female and male offspring. Detailed studied of this cross indicated that 1) the female offspring produced in the compatible interstrain cross were not the result of parthenogenesis but were true hybrids, 2) the incompatible interstrain cross did not produce female offspring because fertilized eggs died during development, 3) the death of these eggs could not be prevented by either antibiotic or temperature treatment, 4) cytoplasmically inherited factors causing NRCI could be discounted because backcrossed females with the genome of MRY and the cytoplasm of SVP, exhibit the NRCI relationship characteristic of their genome. Therefore the NRCI between these strains appears to be caused by a modification coded for by the nuclear genes of MRY that results in incompatibility when SVP sperm fertilizes MRY eggs. In addition the level of incompatibility in crosses between the SVP females and MRY males is temperature sensitive, the higher the rearing temperature the lower the level of compatibility.
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  • 6
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    Entomologia experimentalis et applicata 85 (1997), S. 231-236 
    ISSN: 1570-7458
    Keywords: Glossina fuscipes fuscipes ; vegetation ; biconical trap ; temperature ; light ; relative humidity ; monitor lizard
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Glossina fuscipes fuscipes Newstead was sampled in isolated thickets and forest patches near Lake Victoria, Kenya using unbaited biconical traps, between March 1992 and June 1993. Traps set at 1 m from the forest edge caught 3.3 times as many males and 5 times as many females as those set inside or 10 m away. The corresponding figures at 1 m from the edge of thicket were about 1.43 and 1.64 times, respectively. Hourly catches of males and females were positively correlated with temperature, light intensity and host (monitor lizard) prevalence, and negatively correlated with relative humidity. Light intensity and temperature were the most important variables affecting the catches of each sex. The results are discussed in relation to control and monitoring of G. f. fuscipes using traps.
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  • 7
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    Entomologia experimentalis et applicata 86 (1998), S. 13-24 
    ISSN: 1570-7458
    Keywords: Drosophila ; cytoplasmic incompatibility ; Wolbachia ; temperature ; antibiotics ; density
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The effects of high temperatures, antibiotics, nutrition and larval density on cytoplasmic incompatibility caused by a Wolbachia infection were investigated in Drosophila simulans. Exposure of larvae from an infected stock to moderate doses of tetracycline led to complete incompatibility when treated females were crossed to infected males; the same doses only caused a partial restoration of compatibility when treated males were crossed to uninfected females. In crosses with treated females, there was a strong correlation between dose effects on hatch rates and infection levels in embryos produced by these females. Ageing and rearing males at a high temperature led to increased compatibility. However, exposing infected females to a high temperature did not influence their compatibility with infected males. Male temperature effects depended on conditions experienced at the larval stage but not the pupal stage. Exposure to 25 °C reduced the density of Wolbachia in embryos compared with a 19 °C treatment. Low levels of nutrition led to increased compatibility, but no effect of larval crowding was detected. These findings show the ways environmental factors can influence the expression of cytoplasmic incompatibility and suggest that environmental effects may be mediated by bacterial density.
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  • 8
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    Entomologia experimentalis et applicata 86 (1998), S. 49-58 
    ISSN: 1570-7458
    Keywords: aphids ; Sitobion ; population ; chromosomal race ; mean relative growth rate ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Chromosomal races of the aphid Sitobion miscanthi (Takahashi), and a closely-related species S. near fragariae (Aphididae: Macrosiphini) show seasonal differences in abundance in eastern Australia. We tested whether this was related to differences in temperature response, using controlled laboratory conditions. Intrinsic rate of increase, rm, mean relative growth rate (MRGR), and longevity were compared at different temperatures, and rates of increase were compared outdoors under ambient conditions. Using laboratory data, we simulated population growth, for comparison with outdoor populations. There were significant differences in responses to temperature regimes both in the laboratory and outdoors. Outdoor populations fell well short of predicted sizes. S. miscanthi (2n=18) showed evidence of adaptation to warmer conditions. In contrast, S. nr fragariae showed consistent evidence for adaptation to cooler conditions, and S. miscanthi 2n=17 was approximately intermediate. These data indicate that temperature responses are important in the ecology, evolution and pest status of S. miscanthi clones and S. nr fragariae in Australia.
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  • 9
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    Entomologia experimentalis et applicata 80 (1996), S. 511-519 
    ISSN: 1570-7458
    Keywords: sweet potato whitefly ; temperature ; relative humidity ; migration and dispersal ; virus transmission ; Homoptera ; Aleyrodidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The ability of the sweet potato whitefly, Bemisia tabaci Gennad., to survive a range of environmental conditions was investigated in the laboratory. The range of temperature and humidity investigated corresponds to the normal climatic range during B. tabaci's summer migration in Israel. Adult whiteflies confined to small test cages were exposed to combinations of temperature (25, 30, 35, and 41 °C) and relative humidity (20, 50, 80, and 100%) for periods of 2, 4, or 6 h. A logistic regression model describing the four-dimensional surface defining percent survival as a function of time, temperature, and humidity was developed. Using stepwise regression to exclude non-significant terms, the linear predictor included temperature, and the products of temperature and time, and humidity and time. The model accounted for 75% of the variance. A reparameterization of the fitted regression model suggests that survival potential is conditioned by temperature conditions prevailing during the previous 10 h. Whitefly survival after 2 h exposure ranged from ≈ 90% survival at 20°C and 100% RH, to 〈2% survival at 41°C and 20% r.h.. No whiteflies survived more than 2 h exposure at these latter extremes of temperature and humidity. Survival rates decreased slightly after experimental whiteflies were kept in a cage with food a further 20 h at 25±2°C, 55±5% r.h. Investigations of the effects of hunger and virus infection, showed that both increased mortality.
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  • 10
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    Entomologia experimentalis et applicata 83 (1997), S. 171-180 
    ISSN: 1570-7458
    Keywords: within-plant heterogeneity ; tent caterpillars ; temperature ; circular statistics ; Lepidoptera ; Yponomeutidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The caterpillars of Yponomeuta mahalebella Latr. (Lepidoptera: Yponomeutidae) are monophagous on Prunus mahaleb (Rosaceae) leaves. Adult females deposit eggs in batches, which determines larval gregarious behaviour. Coupled with gregarious behaviour, caterpillars spin silk tents within they will feed until pupation. Distribution of tents in the field, their effect in microenvironmental larval growth conditions and the consequences for adult body mass and survival of larvae were studied. There was a significant trend for tents to be placed with a southward orientation. Within-plant tent orientation was related to the sun-shade pattern experienced, which was the main effect determining thermal differences between the inside and the outside of the tent. These differences appeared to affect larval growth and survival, with higher survival of larvae and heavier adults emerging from tents oriented to the south-east and east, respectively.
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  • 11
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    Entomologia experimentalis et applicata 76 (1995), S. 121-131 
    ISSN: 1570-7458
    Keywords: Aphis gossypii ; life history ; cucumber ; temperature ; partial resistance ; biological control ; Aphidius colemani
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Life table data forAphis gossypii Glover (Homoptera: Aphididae), an important pest in glasshouse cucumber crops, were studied at 20, 25 and 30°C on two cucumber cultivars (Cucumis sativus L.) in controlled climate cabinets. The development time on the cucumber cv. ‘Sporu’ ranged from 4.8 days at 20°C to 3.2 days at 30°C. Immature mortality was approximately 20% and did not differ between temperatures. Most mortality occurred during the first instar. Reproduction periods did not differ among temperatures, but at 25 and 30°C more nymphs were produced (65.9 and 69.8 nymphs/♀, respectively) than at 20°C (59,9 nymphs/♀) because of a higher daily reproduction. Intrinsic rate of increase was greatest at 25°C (r m =0.556 day−1). At 20 and 30°C the intrinsic rate of increase was 0.426 and 0.510, respectively. On cv. ‘Aramon’, the development time ofA. gossypii was approximately 20% longer at all temperatures. Immature mortality did not differ between the two cultivars. The intrinsic rate of increase on cv. ‘Aramon’ was 15% smaller than on cv. ‘Sporu’. The use of cucumber cultivars partially resistant to aphids is discussed in relation to biological control of cotton aphid in glasshouses. Development time and immature mortality on leaves of the middle and upper leaf layer of glasshouse grown cucumber plants (cv. ‘Aramon’) were comparable to development in the controlled climate cabinets. On the lower leaves immature mortality was much higher (approximately 82%) than on leaves of the middle (24.0%) and upper leaf layer (24.5%). Reproduction was less on the lower leaf layer (45.9, 70.5 and 70.1 nymphs/♀ on leaves of the lower, middle and upper leaf layer, respectively). Aphids, successfully parasitized byAphidius colemani Viereck (Hymenoptera: Braconidae) only reproduced when they were parasitized after the third instar. Fecundity was 0.1 to 0.9 and 10.5 to 13.3 nymphs/♀ for aphids parasitized in the fourth instar or as adults, respectively. Reproduction of aphids that were stung but survived the attack was lower than for aphids not stung. Average longevity of these aphids was equal to the longevity of aphids not stung byA. colemani.
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  • 12
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    Entomologia experimentalis et applicata 88 (1998), S. 97-99 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Curculionidae ; Anthonomus pomorum ; temperature ; diapause ; flight behavior
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 13
    ISSN: 1572-8099
    Keywords: point of fire origin ; fire ; temperature ; plaster ; concrete ; thermal ; damage ; biotite ; magnetization ; susceptibility ; N-rays ; P-rays ; X-rays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Architecture, Civil Engineering, Surveying
    Notes: Abstract Magnetic susceptibility (MS) measurements were taken to determine fire exposure patterns on noncombustible structural members and compartment boundaries. These measurements led on-site fire investigators to the cause of combustion and the point of fire origin. Thermal damage to walls and to ceilings was estimated quantitatively by measuring MS and two-valent Fe ion concentration in building materials such as concrete and plaster. It was shown that these effects are preconditioned by thermochemical transformations in the mineral biotite, which is present as a component of common building materials. For the first time, the effect of a substantial and irreversible increase in biotite magnetization exposed to powerful flows of N- and P-rays was found. It is hoped that the presence of this “magnetic trace” of radiation in building materials will allow investigators to use the magnetometric method at nuclear power plant catastrophes such as that in Chernobyl. It was also shown that the influence of N- and P-rays on biotite's magnetic properties greatly differs from the thermal influence on biotite.
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  • 14
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    Entomologia experimentalis et applicata 93 (1999), S. 149-155 
    ISSN: 1570-7458
    Keywords: Megalurothrips sjostedti ; temperature ; photoperiod ; development ; pre-oviposition ; oviposition ; diapause
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Megalurothrips sjostedti is an economic pest of cowpea in tropical Africa. There are no reports of the effect of temperature on the development of the pest and no diapause has been detected. The developmental rate and reproduction of M. sjostedti was studied under six constant temperatures (14, 17, 20, 23, 26 and 29 °C ) and a photoperiod of L12:D12 in the laboratory. Total developmental time ranged from 33.1 days at 14 °C to 19.2 days at 26 °C. At 29 °C, all larvae died during hatching. Egg, larval and pupal stages required 94.3, 97.1 and 105.3 deg-days (DD) above a threshold of 8.2, 9.1 and 10.4 °C, respectively, to complete development. Total developmental cycle was completed at 163.9 DD above a threshold of 12.6 °C. Adult longevity was lowest (11.1 days) at 29 °C and highest (28.7 days) at 14 °C. At constant temperatures, the highest pre-oviposition period was observed at 29 °C under a photoperiod of L16:D8. Egg production also ceased at this temperature/photoperiod combination. Total fecundity was highest at 26 °C under L10:D14. At cyclical temperatures, pre-oviposition period was longest (12.4 days) at 20/29 °C under L16:D8. Total fecundity was highest (168.4 eggs) at 14/26 °C under L10:D14, and lowest (8.2 eggs) at 20/29 °C under L16:D8. The significance of these findings in the management of M. sjostedti is discussed.
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  • 15
    ISSN: 1570-7458
    Keywords: Amblyseius cucumeris ; Frankliniella occidentalis ; rate of predation ; temperature ; vapor pressure deficit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The influence of temperature and vapor pressure deficit (VPD) on the rate of predation by the predatory mite, Amblyseius cucumeris (Oudemans) on Frankliniella occidentalis (Pergande) was determined under controlled laboratory conditions. The survival of first instars of F. occidentalis was initially determined by themselves. Then the number of first instars that were killed by a single female adult of A. cucumeris was determined for the same density of thrips. The differences in the mortality between the two experiments were used to calculate the rate of predation by A. cucumeris under a range of temperature and VPD regimes. Rate of predation was expressed as the number of thrips killed per h to account for the different time periods that the trials lasted. A quadratic model was fitted to the data. At a constant temperature, the rate of predation decreased with increasing VPD for VPDs 〈-1.24 to 1.44 kPa. Above these VPDs, the rate of predation started to increase again. At a constant VPD, the rate of predation decreased slightly at the lower temperatures and increased at the higher temperatures. The rate of change was dependent upon the VPD. By using the quadratic model, the rate of predation can be predicted for the range of hygrothermal conditions that would be encountered in the greenhouse. The optimal condition for maximum rate of predation by A. cucumeris on first instars of F. occidentalis in the greenhouse is a VPD 〈- 0.75 kPa at the recommended production temperatures and VPDs (17 to 25°C and 〈- 1.5 kPa).
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  • 16
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    Entomologia experimentalis et applicata 89 (1998), S. 207-214 
    ISSN: 1570-7458
    Keywords: Bombus terrestris ; bumblebees ; diapause ; survival ; preoviposition period ; weight ; temperature ; diapause duration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Diapause survival and post-diapause performance (i.e., if a queen starts to lay eggs) of in total 2210 bumblebee queens (Bombus terrestris) were measured under different diapause regimes: 5 temperatures (−5, 0, 5, 10 and 15 °C) in combination with 5 durations of exposure (1, 2, 4, 6 and 8 months). The results show that weight at the start of diapause determines to a large extent whether a queen will be able to survive diapause. Queens with a wet weight below 0.6 g prior to diapause did not survive, but for those queens exceeding this threshold a higher pre- diapause weight did not increase their post-diapause performance. There was no effect of temperature on diapause survival; 76% of the variance in survival could be explained by the duration of the treatment. Neither temperature nor duration of exposure had an effect on post-diapause performance. The preoviposition period of the queens that laid eggs was also determined. The preoviposition period was affected by both temperature and duration of exposure: the preoviposition period decreased with decreasing temperature but also with increasing duration of the treatment.
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  • 17
    ISSN: 1570-7458
    Keywords: cowpea ; Vigna unguiculata ; pod sucking bugs ; age-specific life tables ; temperature ; insect development ; cohort statistics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Age-specific life tables of two important pests of cowpea, Vigna unguiculata (L.) Walp., the pod sucking bugs Clavigralla tomentosicollis Stål and C. shadabi Dolling (Heteroptera: Coreidae), were obtained from observations carried out at different temperatures. A biophysical model was found satisfactory to describe the temperature-response of developmental and mortality rates of egg and nymphal stages, with a peak developmental rate around 34°C in both species. The variability in development times was small and the experimental data did not permit any conclusion with regard to the Erlang probability density function. Survival of eggs and nymphs remained high between 20° and 30°C for both species. At temperatures above 34°C, C. tomentosicollis survivorship and fecundity was higher than that of C. shadabi, which in turn laid more eggs at temperatures between 20° and 30°C. Maximum fecundity is estimated to be at 29°C for C. tomentosicollis (99 eggs/female) and 26°C for C. shadabi (261 eggs/female). At 30°C, the intrinsic rate of increase reached a maximum in both species, 0.152 per day for C. tomentosicollis and 0.145 per day for C. shadabi, and remained high for C. tomentosicollis until 36°C. C. tomentosicollis performed significantly better on pigeonpea, Cajanus cajan Millsp., than on cowpea at higher temperatures.
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  • 18
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    Entomologia experimentalis et applicata 90 (1999), S. 25-35 
    ISSN: 1570-7458
    Keywords: Aphis gossypii ; development ; survival ; fecundity ; intrinsic rate of increase ; life table ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Life table parameters of Aphis gossypii Glover (Homoptera: Aphididae) on Gossypium hirsutum L. were determined at six temperatures (10, 15, 20, 25, 30, and 35 ± 0.5 °C) in the laboratory. Relationships of life table parameters with temperature were described with mathematical equations. Development was fastest at 30 °C, with a pre-larviposition period of 4.6 d. Survival to adult was greatest at 25 °C (81%). Fecundity was highest at 25 °C, with a total fecundity of 28.3 nymphs per female and a mean reproductive rate of 3.1 nymphs per female per day. Threshold temperatures for development in the first through fourth instar and the adult were 8.2, 8.0, 7.2, 6.2 and 7.9 °C, respectively. The durations of these stages, expressed as temperature sums above these thresholds, were 24.2, 23.7, 23.0, 25.5 and 168.8 degree-days (D°), respectively. A. gossypii achieved its maximum net reproductive number (24.4 nymphs per female) and greatest intrinsic rate of increase (0.386 d−1) at 25 °C. The high relative rate of population increase at 25 °C results in a daily population increase of 47% and a doubling time of only 1.8 d, illustrating the tremendous growth capacity of A. gossypii populations under favourable conditions. Compared to literature sources, our source of A. gossypii, fed on cotton, showed a comparatively great heat tolerance.
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  • 19
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    Entomologia experimentalis et applicata 82 (1997), S. 159-166 
    ISSN: 1570-7458
    Keywords: Diaeretiella rapae ; reproduction ; life-tables ; temperature ; Diuraphis noxia ; biological control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Diaeretiella rapae (M'Intosh), a polyphagous and cosmopolitan parasite of aphids, was imported from China to the USA for biological control of Diuraphis noxia (Mordwilko), a pest of small grains. We studied several aspects of its biology on D. noxia hosts in the laboratory at 3 constant temperatures, 10.0, 21.1, and 26.7 °C. Females lived significantly longer than males at all 3 temperatures, and longevity was greatest at 10 °C, followed by 21.1 and 26.7 °C. Fecundity (= number of mummies) did not differ significantly among the 3 temperatures studied. The ovarian egg-load was 129.1 ± 9.3, and was significantly affected by the size of adult females. A pre-oviposition period ± 0.26 days) was detected at 10 °C, but not at the other temperatures. Pre-imaginal survivorship was similar among temperatures, while R o and T c decreased with temperature, and r m increased with temperature. The offspring sex ratio (proportion females) was lowest at 26.7 °C, and similar between 10.0 and 21.1 °C. In addition, the offspring sex ratio significantly declined with the age of the female parent. The suitability of D. rapae for colonization against D. noxia in North America is discussed in relation to its responses to temperature and the climate of its home range.
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  • 20
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    Entomologia experimentalis et applicata 82 (1997), S. 319-333 
    ISSN: 1570-7458
    Keywords: chlorogenic acid ; light availability ; Lycopersicon esculentum ; Manduca sexta ; protein ; rutin ; temperature ; tomatine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We examined how light availability influenced the defensive chemistry of tomato (Lycopersicon esculentum: Solanaceae). Tomato plants were grown either in full sunlight or under shade cloth rated at 73%. Leaves from plants grown in full sunlight were tougher, had higher concentrations of allelochemicals (chlorogenic acid, rutin and tomatine), and had less protein than leaves from plants grown in shade. We determined how these differences in host plant quality due to light availability affected the behavior and growth of a Solanaceae specialist, Manduca sexta. Both in the greenhouse and in the field, caterpillars on shade-grown plants grew heavier in a shorter amount of time than those on plants that had previously been grown in full sunlight. In contrast, the effects of previous light availability to plants on caterpillar behavior appeared to be minor. To further investigate how light availability to plants influenced herbivore growth, we examined the effects of leaf-powder diets made from tomato leaves of different ages (new, intermediate, or mature) grown in full sunlight or shade on caterpillar performance. Caterpillars fed diets made from plants grown in shade consumed less but grew faster than larvae fed diets made from tomato plants grown in full sunlight. Caterpillars fed diets made from new leaves grew larger in less time than caterpillars fed diets made from intermediate aged leaves. Caterpillars did not survive on the mature leaf powder diets. There were plant-light treatment by larval thermal regime interactions. For example, at 26:15 °C , plant-light treatment had no effect on stadium duration, but at 21:10 °C, stadium duration was prolonged with the full sunlight-new leaf diet compared with the shaded-new leaf diet. In a second diet experiment, we examined the interactive effects of protein and some tomato allelochemicals (rutin, chlorogenic acid and tomatine) on the performance of caterpillars. There were food quality by thermal regime interactions. For instance, at 26:15 °C , neither protein nor allelochemical concentration influenced stadium duration, whereas at 21:10 °C, stadium duration was prolonged with the low protein-high allelochemical diet, which simulated full sunlight leaves. In sum, light availability to plants affected defensive chemistry and protein concentration. The difference in food quality was great enough to influence the growth of a specialist insect herbivore, but the effects were temperature-dependent.
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  • 21
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    Entomologia experimentalis et applicata 75 (1995), S. 127-134 
    ISSN: 1570-7458
    Keywords: bruchid ; diapause ; photoperiod ; temperature ; multivoltinism
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    Topics: Biology
    Notes: Abstract A wild bean weevil,Kytorhinus sharpianus Bridwell (Coleoptera: Bruchidae), has a multivoltine life cycle and enters a hibernal larval diapause at the fourth instar under a short daylength (Shimada & Ishihara, 1991). Here, we investigated their diapause incidence under different photoperiods at 24°C and 27°C. The critical photoperiods for diapause induction were 14.5 h at 24°C and 14 h at 27°C. The stages susceptible to diapause-inducing stimuli were estimated by transferring larvae of various instars from long days to short days and vice versa. Then we investigated the incidence of larval diapause. The sensitive stage was estimated to be from the third to early fourth instar. Though larval diapause, which was induced under a short daylength, was terminated only by increasing the daylength, the termination was more synchronized by an exposure to a low temperature followed by increasing temperature, irrespective of photoperiod.
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  • 22
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    Entomologia experimentalis et applicata 84 (1997), S. 255-265 
    ISSN: 1570-7458
    Keywords: Delia radicum ; postdiapause development ; temperature ; Diptera ; Anthomyiidae
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    Topics: Biology
    Notes: Abstract Canadian populations of D. radicum differ in their response to temperature during postdiapause development. Populations that are primarily of the early-emerging type ( $$\left( { \leqslant 256DD_{04} } \right)$$ ) (St-Jean, Quebec; London, Ontario) have high values for the parameters describing this response: % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaamOuamaaBa% aaleaacaWGTbaabeaakiabg2da9aaa!38F2!$$R_m = $$ 12.7–13.3; $$T_m = $$ 28.0–31.8 °C ; Tσ = 10.3–14.2 ( $$R_m $$ , the maximum developmental rate at the temperature, $$T_m $$ [ °C ] where the developmental rate is highest, and Tσ , the parameter which gives the shape of the truncated normal curve fitted to the data), a low degree-day requirement for emergence (160–232 $$DD_{04} $$ ), and may lack a developmental delay at temperatures above ca. 21 °C . Populations of the late-emerging type (Kildare, Prince Edward Island) have low parameter values ( $$ R_m = 2.5$$ , $$T_m = 19.3$$ °C ; Tσ = 6.4), high degree-day requirements (530 $$DD_{04} $$ ), and a developmental delay at high temperatures. The parameters for the early-emergers in the population from Winnipeg, Manitoba (74% early) were intermediate ( $$R_m = 9.1$$ , $$T_m = 27.1$$ °C , Tσ = 10.7, $$ DD_{04} = 246 $$ ), but resembled the early rather than the late type. This population varied from 31 to 90% early type over a 10-year period and the rate of postdiapause development at 20 °C was directly related to the percentage early. In the year with the most rapid development (90% early), development was significantly slower than in the populations from other locations with predominantly early populations, and the year with the slowest development (31% early) showed significantly faster development than that from Kildare, Prince Edward Island (100% late). Therefore the parameters for early and late types of development will not be accurate for use in mixed populations, and the parameters in mixed populations will change among years. Populations of D. radicum in North America and Europe (67 locations by years) varied from 0–100% early. At Winnipeg, the percentage early was directly related to the annual temperature accumulation ( $$DD_{05} $$ ) during the growing season. The calculation of developmental parameters for the early-emergers of mixed populations provides a more accurate basis for estimating the times of first emergence and the first peak of emergence than parameters based on the whole population. Since postdiapause developmental rates vary both among and annually within locations, developmental models should be designed to include such variations.
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  • 23
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    Entomologia experimentalis et applicata 79 (1996), S. 9-17 
    ISSN: 1570-7458
    Keywords: Anthonomus pomorum ; temperature ; diel cycle ; Coleoptera ; Curculionidae
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    Topics: Biology
    Notes: Abstract Individual pairs of overwintered adult apple blossom weevils, Anthonomus pomorum (L.), confined with apple twigs under different ambient temperatures in the laboratory and on apple trees in the field, were observed through day and night for their spring activities. Flight behavior in relation to ambient temperature was also investigated under laboratory conditions using flight stands. Both sexes displayed predominantly nocturnal behavior patterns in both the laboratory and the field. Feeding, crawling, and mating activities increased following sunset in the field or onset of scotophase in the laboratory while resting occurred most frequently during daylight hours. Results of the laboratory experiments showed that temperature affected significantly the activity patterns. The diel pattern of activities became less distinctive at higher temperatures (above 15°C), and total activities in crawling, feeding, and mating were suppressed significantly at lower temperatures (below 5°C). Over 97% of the test weevils initiated take-off response from flight stands at 20°C within the 30 min trial period; however, flight initiation rarely occurred at temperatures 12°C or below. Overall, results of the laboratory and field experiments indicate that A. pomorum is a remarkably cold-adapted insect with ability to crawl, feed, and mate at a few degrees above freezing, a physiological attribute necessary for the exploitation of early stages of apple bud development in the cold early spring.
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  • 24
    ISSN: 1570-7458
    Keywords: seasonal trapping ; light traps ; pheromone traps ; trapping periodicity ; temperature ; reproductive state ; eastern hemlock looper
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    Topics: Biology
    Notes: Abstract The seasonal flight activity of both sexes of the eastern hemlock looper, Lambdina fiscellaria fiscellaria Guenée (Lepidoptera: Geometridae) was studied during two consecutive years in Quebec and Newfoundland, using light (L), pheromone (P) and combined light and pheromone (LP) traps. Moth density significantly affected the performance of the different traps, with P traps being more effective at low than high density. However, P trap catches decreased just prior to the onset of female captures, probably as a result of competition between traps and virgin calling females. Nearly all females caught in L and LP traps were already mated and even the first females caught had laid at least half of their egg complement. In Quebec under warm nights, the pattern of male activity occurred at different times, with peak P catches being later in the scotophase than those of L traps, but overall similar numbers of males were caught in both traps. In contrast, under cool nights, males were caught early in the night in both P and L traps, suggesting a strong competition effect between traps, although more males were caught in P than L traps overall. In Newfoundland, the pattern of male captures in L and P traps was similar at both high and low temperatures, so competition between trap types would always be high. Under these conditions P traps were more effective than L traps. Irrespective of the region, year or temperature, significantly more males were captured in LP, with the effect of L and P being additive. In both regions, females responded similarly to L and LP traps with peak activity occurring early in the night. Captures of females were lower than those of males under cool temperatures, suggesting that the temperature threshold for flight is higher for females. The use of L and P traps simultaneously and/or in combination is discussed in relation to integrated pest management programs and ecological considerations.
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  • 25
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    Entomologia experimentalis et applicata 80 (1996), S. 461-468 
    ISSN: 1570-7458
    Keywords: Trichogramma minutum ; Choristoneura fumiferana ; Ephestia kuehniella ; biological control ; inundative release ; weather ; host acceptance ; realized fecundity ; temperature
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    Topics: Biology
    Notes: Abstract The effects of weather conditions and two parasitoid quality attributes, realized fecundity and host acceptance, were assessed on the field efficacy of mass-released Trichogramma minutum. Temperature was the most important single variable, explaining up to 75% of the variation in field parasitism. There were significant positive relationships between both the sum of the maximum temperatures and the number of degree-hours above a 15 °C threshold, accumulated in the three days following the release, and parasitism in the field. There was a significant negative relationship between the mean relative humidity and the odds of parasitism in the field. Quality parameters based on parasitoid biology were not effective for predicting field efficacy if poor weather conditions persisted after a release. If weather conditions were ‘good’ (i.e. accumulated maximum temperatures above 62 °C, in the 3 days following the release), then parameters such as release rate and fecundity in the lab were useful predictors of field performance. There was no relationship between host acceptance measured in the lab and field parasitism. Given the importance of field temperatures for field performance, selection for cold tolerance of T. minutum would be desirable.
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  • 26
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    Entomologia experimentalis et applicata 93 (1999), S. 297-302 
    ISSN: 1570-7458
    Keywords: smaller fruit tortrix ; Grapholita lobarzewskii ; phenology ; post-diapause development ; temperature ; thermal threshold ; thermal constant ; forecasting ; modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The smaller fruit tortrix, Grapholita lobarzewskii Nowicki, has become a major pest in the recent past in apple orchards north of the Alps. Nevertheless little is known about the biology and the behaviour of this species. The effect of temperature on post-diapause development and survival was studied under controlled conditions in order to establish a basis for the forecasting of adult emergence. Survival was found to be highest at 17 °C and lowest at 11.8 °C. The sex ratio did not differ significantly from 1:1. Based on a linear relationship between temperature and developmental rates, thermal thresholds of 9.6 °C and 9.8 °C were determined for females and males respectively. The thermal constants, i.e., the mean developmental times in physiological time units, were found to be 342 day-degrees for females and 317 day-degrees for males, suggesting a slight protandry. Based on the mean and the variance of the developmental times, a simple temperature-driven phenology model was built using a time-varying distributed delay. The model was validated by visually comparing the predictions with independent observations on adult emergence, and by calculating the temporal deviations of the predictions. In 4 out of 5 years the mean error was less than 3 days. The model was therefore found to give reliable forecasts of the emergence of G. lobarzewskii and can be used to determine the optimal time for the exposure of pheromone traps, the application of pheromone dispensers for mating disruption, and for the timing of insecticide applications.
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  • 27
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    Journal of polymers and the environment 7 (1999), S. 101-108 
    ISSN: 1572-8900
    Keywords: Polylactic acid ; temperature ; respirometers ; soil degradation
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    Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract A respirometric system was used to analyze the biodegradation of high molecular weight (120,000 to 200,000 g mol−1) polylactic acid (PLA) plastic films in soil under laboratory conditions. The respirometric system consisted of air-conditioning pretraps, a soil reactor, and a carbon dioxide (CO2) posttrap. A 200-g homogeneous soil mixture of all-purpose potting soil : manure soil : sand [1 : 1 : 1 (w/w)] and 1.5 g of PLA plastic films in 1 × 1-cm2 squares was added to each bottle. The respirometers were placed in a 28, 40, or 55°C water bath for 182 days. Treatments (three replicates) included native corn starch (positive control), polyethylene (Glad Cling Wrap; negative control), and three PLA films: Ca-I (Cargill Dow Polymers LLC, monolayer), GII (Cargill Dow Polymers LLC, Generation II), and Ch-I (Chronopol; monolayer). The degree of polymer mineralization was indicated by the cumulative CO2 liberated from each respirometer. The initial average mineralization rate and total percentage mineralized of the PLA plastic films at 28, 40, and 55°C was 24.3, 41.5, and 76.9 mg/day with a 27, 45, and 70% carbon loss, respectively. No decrease in soil pH was observed after 182 days of mineralization. Hence, increase in soil temperature drastically enhanced the biodegradation of PLA plastic films in soil under laboratory conditions (P 〈 0.0001).
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  • 28
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    Journal of applied electrochemistry 27 (1997), S. 1328-1332 
    ISSN: 1572-8838
    Keywords: metal hydride ; capacity ; temperature ; performance ; enthalpy
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    Topics: Chemistry and Pharmacology , Electrical Engineering, Measurement and Control Technology
    Notes: Abstract The effect of temperature on the performance of a LaNi4.76Sn0.24 metal hydride electrode was investigated in the temperature range of 0 to 50°C. The electrode showed a maximum discharge capacity at 25°C. The total resistance increases with a decrease of temperature from 50°C to 0°C. The apparent activation enthalpies at different states of charge were determined by evaluating the polarization resistance at different temperatures. It was found that the apparent activation enthalpy is an indicator of the relative reaction rate of the charge-transfer reaction and hydrogen absorption.
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  • 29
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    Journal of polymers and the environment 7 (1999), S. 83-92 
    ISSN: 1572-8900
    Keywords: Polylactic acid ; temperature ; relative humidity ; degradation
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    Topics: Chemistry and Pharmacology , Energy, Environment Protection, Nuclear Power Engineering , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Three high molecular weight (120,000 to 200,000 g mol−1) polylactic acid (PLA) plastic films from Chronopol (Ch-I) and Cargill Dow Polymers (GII and Ca-I) were analyzed for their degradation under various temperature and relative humidity (RH) conditions. Two sets of plastic films, each containing 11 samples, were randomly hung in a temperature/humidity-controlled chamber by means of plastic-coated paper clips. The tested conditions were 28, 40, and 55°C at 50 and 100% RH, respectively, and 55°C at 10% RH. The three tested PLA films started to lose their tensile properties when their weight-average molecular weight (M w) was in the range of 50,000 to 75,000 g mol−1. The average degradation rate of Ch-I, GII, and Ca-I was 28,931, 27,361, and 63,025 M w/week, respectively. Hence, GII had a faster degradation rate than Ch-I and Ca-I under all tested conditions. The degradation rate of PLA plastics was enhanced by the increase in temperature and relative humidity. This trend was observed in all three PLA plastics (Ca-I, GII, and Ch-I). Of the three tested films, Ch-I was the first to lose its mechanical properties, whereas Ca-I demonstrated the slowest loss, with mechanical properties under all tested conditions.
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    Journal of applied electrochemistry 29 (1999), S. 81-85 
    ISSN: 1572-8838
    Keywords: cupric oxide ; powder ; current density ; temperature ; sodium sulfate
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    Topics: Chemistry and Pharmacology , Electrical Engineering, Measurement and Control Technology
    Notes: Abstract Electrosynthesis of cupric oxide powder was carried out on a laboratory scale in an electrochemical cell under various experimental conditions. The electrolysis was appraised in terms of the particle size of the cupric oxide product and the anodic dissolution of the copper electrode. Using a previously determined pH value of 7.50, the other optimum electrolysis operating conditions established were a current density of 4000Am−2, temperature of 353K, and Na2SO4 concentration of 0.5m. The optimum values of current efficiency, cell voltage and specific energy consumption for the electrochemical synthesis of cupric oxide powder were determined.
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    Journal of applied electrochemistry 29 (1999), S. 525-528 
    ISSN: 1572-8838
    Keywords: brine ; chlor-alkali cells ; solubility ; sulfate ions ; temperature
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    Topics: Chemistry and Pharmacology , Electrical Engineering, Measurement and Control Technology
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  • 32
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    Journal of solution chemistry 24 (1995), S. 153-170 
    ISSN: 1572-8927
    Keywords: Densities ; excess volume ; pressure ; temperature ; ethylbenzene ; octanol ; nonanol ; dodecanol ; order creation
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The excess volume V E of binary mixtures of octanol, nonanol and dodecanol in ethylbenzene have been calculated from the densities measured with a vibrating tube densimeter at temperatures from 50 to 100 °C and at pressures from 0.1 to 7.5 MPa. The values of V E are positive for all the three mixtures in the complete temperature, pressure and mole fraction ranges studied. The maxima in V E is observed at 0.4 mole fraction of alkanol. The results are discussed in terms of specific interactions present in the binary mixtures. The second order thermodynamic quantities (∂V E /∂T)p,(∂V E /∂P)T and (∂V E /∂P)T which have been derived from the effect of temperature and pressure on V E , indicate an overall net creation of order in the binary mixtures of ethylbenzene with higher homologues of alkanols.
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  • 33
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    Journal of solution chemistry 24 (1995), S. 753-769 
    ISSN: 1572-8927
    Keywords: Conductivity ; sodium trifluoromethanesulfonate ; ion association ; temperature ; pressure
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The electrical conductances of dilute (0.001 to 0.1 mol-kg−1) aqueous sodium trifluoromethanesulfonate (NaCF3SO3) solutions have been measured from 0 to 450°C and pressures to 250 MPa. The limiting molar conductance $$\Lambda _0 $$ increases with increasing temperature from 0 to 300°C and decreasing density from 0.8 to 0.3 g-cm−3. Above 300°C, $$\Lambda _0 $$ is nearly temperature independent, but increases linearly with decreasing density. The logarithm of the molal association constant of NaCF3SO3 calculated at temperatures from 372 to 450°C is represented as a function of temperature (Kelvin) and density of water (g-cm−3) by $$\log K_m = 0.888 - 330.4/T - (12.83 - 5349/T)\log \rho _w $$ The relative strengths of NaCF3SO3 and NaCl are similar within the accuracy of the current measurements over the limited range of temperature and pressure that could be investigated here.
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  • 34
    ISSN: 1572-8773
    Keywords: cadmium ; copper ; iron ; photoperiod ; temperature ; zinc
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The importance of photoperiod and ambient temperature on the accumulation of cadmium in the liver and kidneys of bank voles was determined in the present study. Males and females, aged 1 month, were given 3.0 μg Cd ml−1 drinking water and divided into four groups according to photoperiod (16 h light/8 h dark and 8 h light/16 h dark) and ambient temperature (20 or 5°C); liver and kidneys were removed for cadmium as well as copper, iron and zinc analyses at the end of 6 weeks. Bank voles exposed to 5°C in both photoperiods consumed approximately 30% less water containing cadmium than those kept at 20°C. However, the total accumulation of cadmium in the liver and kidneys of males and females exposed to the low temperatures was 4.3–4.8 and 2.2–3.3 times less than that in animals maintained at room temperature in the long and short photoperiod, respectively. Simultaneously, the low temperature brought about an increase in the copper concentrations in the liver (12–43%) and kidneys (47–78%), giving rise to an inverse correlation between the cadmium accumulation and the tissue copper concentration. In contrast to cadmium and copper, the concentrations of iron and zinc were affected primarily by photoperiod. These findings indicate that ambient temperature is an important determinant of cadmium retention in the bank vole. It appears that low temperature decreases tissue cadmium accumulation not only by reducing cadmium intake but also through changes in copper metabolism.
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  • 35
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    Journal of solution chemistry 27 (1998), S. 373-393 
    ISSN: 1572-8927
    Keywords: Iodide ; voltammetry ; diffusion coefficients ; temperature ; Stokes–Einstein equation ; solvation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The oxidation wave of iodide in 0.075 mol-L−1 H2SO4 was analyzed at 25, 40, 55, 70, and 85°C. The reversibility of the I2/I− system was checked using logarithmic transforms, half-wave potentials, and by studying I −1 = f(ω−1/2). The limiting currents obtained enabled us to determine the diffusion coefficient of I− using Newman's equation. These experimental results were compared with Nernst's limiting values. The Stokes–Einstein equation is not verified. Hydration numbers for I− at different temperatures were established. An empirical equation is proposed to predict the evolution of diffusion coefficients in a sulfuric acid medium with temperature.
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  • 36
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    Journal of solution chemistry 25 (1996), S. 711-729 
    ISSN: 1572-8927
    Keywords: Conductivity ; aqueous ; sodium hydroxide ; ion association ; temperature ; pressure
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The limiting molar conductances Λ0 and ion association constants of dilute aqueous NaOH solutions (〈0.01 mol-kg−1) were determined by electrical conductance measurements at temperatures from 100 to 600°C and pressures up to 300 MPa. The limiting molar conductances of NaOH(aq) were found to increase with increasing temperature up to 300°C and with decreasing water density ρw. At temperatures ≥400°C, and densities between 0.6 to 0.8 g-cm−3, Λ0 is nearly temperature-independent but increases linearly with decreasing density, and then decreases at densities 〈0.6 g-cm−3. This phenomenon is largely due to the breakdown of the hydrogen-bonded, structure of water. The molal association constants K Am for NaOH( aq ) increase with increasing temperature and decreasing density. The logarithm of the molal association constant can be represented as a function of temperature (Kelvin) and the logarithm of the density of water by $$\begin{gathered} log K_{Am} = 2.477 - 951.53/T - (9.307 \hfill \\ - 3482.8/T)log \rho _{w } (25 - 600^\circ C) \hfill \\ \end{gathered} $$ which includes selected data taken from the literature, or by $$\begin{gathered} log K_{Am} = 1.648 - 370.31/T - (13.215 \hfill \\ - 6300.5/T)log \rho _{w } (400 - 600^\circ C) \hfill \\ \end{gathered} $$ which is based solely on results from the present study over this temperature range (and to 300 MPa) where the measurements are most precise.
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    Archive of applied mechanics 68 (1998), S. 128-136 
    ISSN: 1432-0681
    Keywords: Key words frictional heating ; temperature ; contact pressure ; punch indentation ; thermoelasticity
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    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Summary An axisymmetric contact problem with frictional heating is considered in which a parabolic annular punch is pressed into a plane surface and rotates about its axis of symmetry at constant speed. The problem is formulated in terms of one governing equation with unknown pressure. This equation is solved numerically. The change of the geometry of the contact region and pressure has been investigated.
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    Archive of applied mechanics 67 (1997), S. 331-338 
    ISSN: 1432-0681
    Keywords: Key words frictional heating ; wear ; contact pressure ; temperature ; brake system
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    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Summary A transient contact problem with frictional heating and wear for two nonuniform sliding half-spaces is considered. One of the two half-spaces is assumed to be slightly curved to give a Hertzian initial pressure distribution: the other is a rigid nonconductor. Under the assumption that the contact pressure distribution could be described by Hertz formulas during all the process of interaction, the problem is formulated in terms of one integral equation of Volterra type with unknown radius of contact area. A numerical solution of this equation is obtained using a piecewise-constant presentation of an unknown function. The influence of operating parameters on the contact temperature and the radius of the contact area is studied.
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  • 39
    ISSN: 1573-0417
    Keywords: diatoms ; temperature ; climatic change ; paleoclimate proxies ; canonical correspondence analysis ; weighted-averaging ; Yukon ; Northwest Territories
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract We identified, enumerated, and interpreted the diatom assemblages preserved in the surface sediments of 59 lakes located between Whitehorse in the Yukon and Tuktoyaktuk in the Northwest Territories (Canada). The lakes are distributed along a latitudinal gradient that includes several ecoclimatic zones. It also spans large gradients in limnological variables. Thus, the study lakes are ideal for environmental calibration of modern diatom assemblages. Canonical correspondence analysis, with forward selection and Monte Carlo permutation tests, showed that maximum lake depth and summer surface-water temperature were the two environmental variables that accounted for most of the variance in the diatom data. The concentrations of sodium and calcium were also important explanatory variables. Using weighted-averaging regression and calibration techniques, we developed a predictive statistical model to infer lake surface-water temperature, and we evaluated the feasibility of using diatoms as paleoclimate proxies. This model may be used to derive paleotemperature inferences from fossil diatom assemblages at appropriate sites in the western Canadian Arctic.
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  • 40
    ISSN: 1573-0417
    Keywords: diatoms ; temperature ; sediment traps ; seasonal succession ; resuspension ; Lake Holzmaar
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract The seasonal sedimentation pattern of diatom valves in Lake Holzmaar was investigated during 1995 by deploying sediment traps at three different lake depths. According to the sedimentation pattern, the major reproduction zone of diatoms was restricted to the upper 6 m of the water body. The population growth started late in April and blooms of Cyclotella cf. comensis Grun., which dominates the plankton diatoms, and Fragilaria crotonensis Kitton were collected in traps during June and September, and July, respectively. During summer, the seasonal sedimentation pattern of each taxon, as collected in the upper traps, was reflected in the concentrations in the lowest trap. However, in May and from September onwards, the community composition in the lowest trap and augmented trapping rates suggest both sediment focusing and resuspension of bottom sediments. The temperature signals as recorded by δ18O values of diatom valves should, therefore, reflect integrated temperatures between 0 and 6 m depth. However, temperatures during summer and autumn are expected to be accentuated in the sedimentary record since the isotopic signal is weighted by both the number and the weight-mass of the valves. During summer, the transfer of these signals by the sedimenting diatoms retains the information pattern recorded, while in spring and autumn/winter additional influxes caused by resuspension may somewhat alter those temperature informations. The proxy signals finally stored in the sediments, may, therefore, not precisely represent the successive temperatures currently recorded during 1995 within mid-lake.
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  • 41
    ISSN: 1573-0417
    Keywords: palaeolimnology ; acidification ; diatoms ; chrysophytes ; pigments ; chironomids ; temperature ; Alps ; Italy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Geosciences
    Notes: Abstract A palaeoecological study of an oligotrophic alpine lake, Paione Superiore (Italy), provided a record of historical changes in water quality. Historical trends in lake acidification were reconstructed by means of calibration and regression equations from diatoms, chrysophycean scales and pigment ratios. The historical pH was inferred by using two different diatom calibration data sets, one specific to the alpine region. These pH trends, together with the record of sedimentary carbonaceous particles and chironomid remains, indicate a recent acidification of this low alkalinity lake. Concentration of total organic matter, organic carbon, nitrogen, biogenic silica (BSiO2), chlorophyll derivatives (CD), fucoxanthin, diatom cell concentration and number of chironomid head capsules increased during the last 2–3 decades. When expressed as accumulation rates, most of these parameters tended to decrease from the past century to c. 1950, then all except P increased to the present day. A marked increase in sedimentary nitrogen may be related to atmospheric pollution and to the general increases in output of N in Europe. High C/N ratios indicate a prevailing allochthonous source of organic matter. Finally, the increase in measured air temperature from the mid-1800's appeared to be related to lake water pH before industrialization: cold periods generally led to lower pH and vice-versa. The more recent phenomenon of anthropogenic acidification has apparently decoupled this climatic-water chemistry relationship.
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  • 42
    ISSN: 1573-0832
    Keywords: Anthracnose ; guava ; Colletotrichum glososporioides ; temperature ; free moisture ; inoculum density
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The influence of environmental factors (temperature and humidity), inoculum density on infection by Colletotrichum glososporioides and development of anthracnose lesions were determined on uninjured, sand-injured and punctured fruits. The optical temperature for severe infection was 30 °C, whereas the disease incidence was less at 20 and 35 °C. Inoculated guavas that received 1–60 h of continuous free moisture developed lesions, but the disease was minimal (0–7%) after 1–6 h free moisture. Infection rates of uninjured, sand-injured and punctured fruits receiving 60 h of free moisture were 34, 70 and 100%, respectively. Disease incidence increased as inoculum density increased from 101 to 106 conidia/ml. In field conditions, the development of anthracnose lesions was greater on punctured guavas than on uninjured or sand-injured ones, in both rainy and winter seasons. In general, the number of lesions was highest in sand-injured fruits, followed by punctured and uninjured fruits. In rainy season the number of lesions on injured and uninjured fruits was greater than similarly treated guavas in winter.
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  • 43
    ISSN: 1573-0832
    Keywords: Antagonism ; biocontrol ; ginger ; postharvest rot ; Sclerotium rolfsii ; Trichoderma ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Sclerotium rolfsii is a destructive soil-borne and postharvest plant pathogen. Use of the antagonistic fungus Trichoderma sp. has been earlier reported by us to successfully control this pathogen under postharvest conditions. In the present paper we report on the effects of temperature on the growth and biocontrol potential of Trichoderma sp. on S. rolfsii. Experimental results indicated that S. rolfsii and Trichoderma sp. have different temperature optima for growth: 30–35 °C for the pathogen and 25–30 °C for the antagonist. In dual culture, Trichoderma overgrew S. rolfsii at 25 °C and 30 °C, but at 35 °C and 37 °C, S. rolfsii overgrew the colony of Trichoderma. Trichoderma produced higher concentration of fungitoxic metabolites in broth culture at higher temperatures. In bioassays using ginger slices and whole rhizomes, it has been demonstrated that Trichoderma is not very effective in suppressing S. rolfsii at temperatures above 30 °C. In light of these results, possible mechanisms of biocontrol of S. rolfsii as a postharvest pathogen has been discussed. Storage temperature has been suggested as a critical factor in biocontrol of S. rolfsii.
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  • 44
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    Mycopathologia 136 (1996), S. 109-114 
    ISSN: 1573-0832
    Keywords: Fungi ; post-harvest rot ; relative humidity ; temperature ; Vitex doniana
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The fungi associated with rot of Vitex doniana fruits (blackplum) were isolated and identified. Aspergillus niger, Botryodiplodia theobromae, Candida spp. Penicillium chrysogenum, Rhizopus stolonifer, Fusarium pallidoroseum F. oxysporum and Mucor mucedo were the primary rot causing fungi in contrast to Cladosporium herbarum and Mucor circinelloides which were just present as secondary colonizers. The rot fungi penetrated mainly through wounds and bruises on the surface of fruits. Mature green fruits were less susceptible to infection than half ripe and fully ripened red fruits. Optimum rot by pathogenic isolates occurred at 25–30 °C and relative humidity 72.5–100%. The results of investigation of influence of storage temperatures and relative humidity on the quality of uninoculated healthy fruits are presented and discussed.
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  • 45
    ISSN: 1573-0832
    Keywords: interspecific interactions ; ochratoxin ; Aspergillus ochraceus ; spoilage fungi ; water relations ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The effect of water availability (water activity,aw; 0.995–0.90) and temperature (18–30 °) on in vitro interactions between an ochratoxin producing strain of Aspergillus ochraceus and six other spoilage fungi was assessed in dual culture experiments on a maize meal-based agar medium. Inprimary resource capture of nutrient substrate, A. ochraceus was dominant against many of the interacting species, being able to overgrow and replace A. candidus, and sometimes A. flavus and the Eurotium spp. regardless of aw or temperature. However, with freely available water (0.995 aw) A. alternata and A. niger were dominant, with mutual antagonism between A. ochraceus and A. flavus at 25–30 °C. In the driest conditions tested (0.90 aw) there was also mutual antagonism between A. ochraceus and the two Eurotium spp. Overall, under allconditions tested the Index of Dominance for A. ochraceus was much higher than for other competing species combined suggesting that A. ochraceus wasa good competitive colonist able to replace a numberof other species. However, the growth rate ofA. ochraceus was modified and decreased by the interaction with competitors. Interaction between A. ochraceus and species such as A. alternata (18°C/0.995) and Eurotium spp. (0.995–0.95 and 25–30 °C) resulted in a significant stimulation of ochratoxin production. Theresults are discussed in relation to the effect that environmental factors have on the possible competitiveness of A. ochraceus in the maizegrain ecosystem and the role of ochratoxin in nicheexclusion of competitors.
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  • 46
    ISSN: 1573-0867
    Keywords: heavily fertilized soils ; P supplying capacity ; P uptake ; residual P ; soil test methods ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Nine heavily fertilized soils were collected from southern and central Norway. A greenhouse experiment in the phytotron was conducted to evaluate the P supplying capacities of these soils at different temperatures (9, 12 and 18 °C). The crops were grown in succession and the sequence was oat, rye grass (cut twice), oat, rape and oat. Effect of temperature on dry matter (DM) yield and P uptake was more marked up to the fourth crop but the effect varied among crops. The DM yields of oat and rape increased with increasing temperature but the opposite was the case with rye grass. The yield differences among soils at 12 °C were highly significant (p 〈 0.01) in contrast to 9 and 18 °C. The amount of P taken up by plants in these soils was highest at 18. °C. The P supplying capacity was highest in the soils with higher content of organic P. Generally, the soils of very fine and coarse texture classes failed to supply enough P to crops to avoid P deficiency in the successive crops. Soil P test (P-NH4-lactate) values in most of the soils increased with increasing temperatures. The highest temperature effect was seen in the Særheim sand soil. Soil P test extractants P-AL, Bray-1 and Colwell-P were used to determine P in the soil after each harvest and the soil P test values were compared with P uptake by crops. Only the P-AL extractant was significantly correlated to cumulative P removal (CPR) by plants in most of the soils. Regression equation was calculated for each soil. The value of removed P per harvest (RPH) varied from 10.33 to 20.87 mg P kg−1 soil. Phosphorus drawdown slope was determined for each soil and the number of consecutive harvests necessary to reduce the P-AL value to a normal level (110 mg P kg−1 soil) was calculated. The drawdown slope varied widely (1.257–2.801) and this reflected the P buffer capacity and the number of crops required to lower the soil test P value to a normal level. The highest drawdown slope was found in the soils with higher P supplying capacities. The Bray-1 extractant was significantly correlated in the soils with higher buffer capacity but the Colwell-P method did not show significant correlation in any of the soils.
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  • 47
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    Nutrient cycling in agroecosystems 46 (1996), S. 179-187 
    ISSN: 1573-0867
    Keywords: electrical conductivity ; leaching ; nitrogen ; pH ; phosphorus ; potassium ; release pattern ; slow-release fertilizers ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract We studied the effect of temperature on the release of N, P, and K from slow-release fertilizers (SRF). The study was conducted in micro-lysimeters filled with moist peat medium. Increasing the temperature from 4 to 12°C slightly increased N release from three different slow-release N (SRN) carriers with different particle sizes and coating thicknesses. At 21°C the rate of release was significantly different than the other two temperatures. Urea formaldehyde (UF), sulphur coated urea (SCU) and coated calcium nitrate (CCN), incubated in sphagnum moss peat, released between 3 and 20% of the applied N in six weeks. For eight synthetic and organic NPK carriers, the release pattern was similar to UF and SCU. However, the leaching losses of N from the NPK fertilizers were up to twenty times more than for the SRN products. Except for Osmocote® and Duna, which released 30–40% of the applied N as mineral-N within six weeks, all other slow-release and slowly mineralized NPK carriers acted like readily water-soluble compound NPK. Temperature did not affect the nutrient release from NPK fertilizers.
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  • 48
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    Nutrient cycling in agroecosystems 42 (1995), S. 159-163 
    ISSN: 1573-0867
    Keywords: nitrous oxide ; tropical soils ; agriculture ; N availability ; temperature ; soil water content
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract N2O emission rates seem to be higher from soils in warm climates than from soils in temperate climates. Warm and moist conditions promote microbial processes that generate N2O. Clearance of tropical forests enhances N2O formation, but emission measurements from other agricultural operations in the tropics are few. Limiting fertilizer application to recommended rates applied at appropriate times and avoiding fallow land wherever practical serves to limit N2O emissions. More specific advice for agriculture in warm climates requires further studies.
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  • 49
    ISSN: 1573-0832
    Keywords: Entomopathogenic hyphomycete ; Paecilomyces fumosoroseus ; inoculum persistence ; solar radiation ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The detrimental effect of solar radiation on the survival of conidia of the entomopathogenic fungusPaecilomyces fumoroseus was studied by monitoring germinability and ability to form colonies (CFU) of conidia irradiated at two temperatures, 25 and 35 °C, harmless to shaded conidia. There was no apparent effect when spores were exposed to a high level of artificial radiation (0.66 W m−2 UVB). However, at a lower level of irradiance (0.33 W m−2), effects of radiation occurred more quickly at 35 °C than at 25 °C. Under natural solar radiation, the rate of decrease in germinability or viability was doubled at 35 °C as compared to 25 °C, indicating an interaction between temperature and radiation effects under natural conditions. This interaction was not detected in indoor experiments, indicating that the spectral distribution of UV radiation has to be taken in account as well as its irradiance when studying its effects.
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  • 50
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    Surveys in geophysics 17 (1996), S. 289-306 
    ISSN: 1573-0956
    Keywords: Effective properties ; pore fluids ; cracked rock ; permeability ; stress ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Abstract Fluids saturating cracked rocks within the crust can vary widely in composition and physical properties, which depend greatly on pressure and temperature. External non-hydrostatic stress applied to a cracked medium may result in a significant change of crack volume (and hence, for the undrained regime, pore-fluid pressure) due to the processes of crack closure (opening), and thus lead to a drastic change of the overall physical parameters of a rock. The purpose of the study is to estimate theoretically, using the effective-medium theory, the macroscopic seismic and transport parameters (such as permeability) of cracked rocks (granites) saturated with hydrocarbon gases, oils, brines and water. Variations of crack geometry and fluid parameters in the closed system (at constant fluid mass) under uniaxial compression are considered as well. The results show that composition of a saturating fluid as well as fluid temperature greatly influence the effective permeability and shear velocities of a rock mass, while thermal conductivity is not so sensitive to variations of fluid parameters.
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  • 51
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    Nutrient cycling in agroecosystems 47 (1996), S. 19-28 
    ISSN: 1573-0867
    Keywords: elemental sulphur ; model ; oxidation rate ; particle size distribution ; soil ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Finely-powdered elemental sulphur is a useful source of fertilizer S, being readily oxidizable in soil to plant-available sulphate yet possessing some slow release characteristics. Two mesh sizes were evaluated using four soils from northeast Scotland. Particle size analysis found that the 120 and 300 mesh S samples had specific surface areas of 1300 and 1940 cm2 g−1, respectively, with most of the surface area in particles of 10 – 20 µm diameter. The S oxidation rate was similar in all four soils but was greater for the 300 mesh than for the 120 mesh S: mean values of 51% and 18% were oxidized over 7 weeks at 14 °C, respectively. The time course of oxidation followed a sigmoidal pattern with a pronounced lag which was modelled using the logistic equation. Maximum specific oxidation rates were 11–28 µg S cm−2 day−2 for the 300 mesh S at 14 °C. These were significantly slower at 7 °C and the temperature response was calculated as a Q10 of 4.0. A model of seasonal S oxidation was developed using a cosine function for the annual temperature, the Arrhenius equation to relate S oxidation rate to temperature and a generalization of the logistic equation to describe the time course of S oxidation. Simulations showed that the 300 mesh S would be useful for spring S applications in east Scotland and if applied in autumn could supply S during the autumn and again in the spring. The 120 mesh S would be less effective in autumn but more resistant to winter leaching. The 120 mesh S applied to the warmer soils of southwest England would behave the same as 300 mesh S applied in east Scotland.
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  • 52
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    Experimental and applied acarology 23 (1999), S. 669-679 
    ISSN: 1572-9702
    Keywords: Panonychus ulmi ; dipause eggs ; overwintering ; dipause termination ; temperature ; photoperiod
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract In apple orchards in northern Greece, females of Panonychus ulmi Koch were found to lay diapause eggs from late August to the beginning of October. The course of diapause termination in the field was determined by transferring diapause eggs during winter and early spring from apple orchards with the varieties ‘Starkinson’ and ‘Firiki’ to short days (LD 8:16) (1992–1996), and long days (LD 16:8) (1994–1995), both at 20 °C. Percentages of diapause termination were very low to zero from October to the beginning of January, then progressively increased throughout January and February. Diapause termination in 50% of the eggs occurred in the first half of February in lowland mite populations irrespective of the year and location from which the eggs originated, and about one month earlier in a population originating from an altitude of 300 m. For each sampling date throughout the winter, the mean number of days required for 50% egg hatch at 20 °C (T50%) was similar under either a long (LD 16:8) or a short (LD 8:16) photoperiod. Diapause eggs collected in October 1995 from two orchards and maintained at 0, 5, 10 and 15 °C for various periods were subsequently transferred to 20 °C and LD 8:16, where TP50% was determined. It was shown that temperature, duration of maintenance at the different temperatures and the orchard from which the eggs originated had a significant effect on T50% and therefore on diapause development. Additionally, in our strains diapause intensity was much weaker than in strains from more northern latitudes and was terminated even without any cold exposure. The variation in diapause intensity in different strains of P. ulmi may have an adaptive significance for this widespread species.
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  • 53
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    Journal of statistical physics 85 (1996), S. 471-488 
    ISSN: 1572-9613
    Keywords: Electron-phonon interaction ; temperature ; polaron ; Holstein model ; bifurcation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract It is proved that the polaronic and bipolaronic structures found in the adiabatic Holstein model at large electron-phonon coupling by Aubry, Abramovici, and Raimbault survive under connection of the electrons to a low-temperature heat bath, uniformly in the size of the system. Bounds are computed for one-dimensional nearest neighbor chains, and some sample solutions are continued numerically.
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  • 54
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    Cellular and molecular life sciences 51 (1995), S. 260-266 
    ISSN: 1420-9071
    Keywords: Salmon ; satellite cells ; cell culture ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Temperature is known to affect fish growth, and in Atlantic salmon there is an influence on muscle cellularity. Primary muscle cell culture makes it possible to investigate direct effects of temperature on myogenic cells. Salmon myosatellite cells were cultured for the first time in this study. The cells were cultured at either 5°C or 11°C. Increased temperature led to an increase in differentiation rate and especially hypertrophic growth (Q10=4.0). No nuclear proliferation was evident in the satellite cell population isolated at either temperature. This may be due to the presence of different subpopulations of myogenic cells at different developmental ages or the presence of indirect factors in vivo.
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  • 55
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    Aquatic sciences 57 (1995), S. 325-337 
    ISSN: 1420-9055
    Keywords: Oxygen ; temperature ; patchiness ; microscale
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The presence and extent of small scale vertical structure in dissolved oxygen were investigated in a tropical Australian lake. At a 9 m deep site an extremely high oxygen patch appeared near the bottom boundary. Light levels reaching the bottom boundary during the life of the patch exceeded 10 µEinst m−2 s−1. The patch remained for 1.5 h before gradually reaching ambient oxygen levels. The patch's disappearance coincided with decreasing light levels during the late afternoon. Differences in the extent of oxygen vertical patchiness between deep (16 m) and shallow (9 m) sites were also observed. At the deep site, the distribution of oxygen steps over the water column coincided largely with the distribution of temperature steps. This indicates the dominance of physical processes at that site. At the shallow site, marked vertical patchiness in oxygen was observed with no similar patchiness in temperature. This indicates the prevalence of biological and chemical processes.
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  • 56
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    European journal of clinical pharmacology 49 (1996), S. 387-391 
    ISSN: 1432-1041
    Keywords: Key words Liver function tests; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h⋅l−1, clearance was reduced (5.0 vs. 11.8 l⋅h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P 〈 0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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  • 57
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    European journal of clinical pharmacology 47 (1995), S. 507-511 
    ISSN: 1432-1041
    Keywords: Methotrexate ; Juvenile rheumatoid arthritis ; pharmacokinetics ; age dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5–16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg·kg−1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.
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  • 58
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    European journal of clinical pharmacology 47 (1995), S. 525-530 
    ISSN: 1432-1041
    Keywords: Antipyrine disposition ; Obesity ; pharmacokinetics ; oxidative metabolism ; weight reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t 1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t 1/2 15.5 vs 12.0 h respectively), but its clearance rate (CLo) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg−1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t 1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CLo. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t 1/2 whereas its CLo is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.
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  • 59
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
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  • 60
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    European journal of clinical pharmacology 48 (1995), S. 385-390 
    ISSN: 1432-1041
    Keywords: Furosemide ; Dialysis ; continuous ambulatory peritoneal ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min−1 and this was much lower in the CAPD patients (61.9 ml·min−1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.
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  • 61
    ISSN: 1432-1041
    Keywords: Caffeine ; Cardio-green ; Indocyanine Green ; altitude ; metabolism ; pharmacokinetics ; hypoxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg−1) was administered as an intravenous bolus and caffeine (4 mg · kg−1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1−1 · min−1), and increased clearance (117 vs 86 ml · min−1 · 70 kg−1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1−1 · min−1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min−1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.
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  • 62
    ISSN: 1432-1041
    Keywords: Diltiazem ; sustained-release formulation ; pharmacokinetics ; bioavailability ; bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the “once a day” formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.
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  • 63
    ISSN: 1432-1041
    Keywords: Diabetes ; Human insulin ; Lorazepam ; pharmacokinetics ; glucuronidation ; enterohepatic circulation ; animal insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml·min−1·kg−1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.
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  • 64
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    European journal of clinical pharmacology 48 (1995), S. 273-277 
    ISSN: 1432-1041
    Keywords: Mesalamine ; 5-aminosalicylic acid ; controlled release capsules ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.
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  • 65
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    European journal of clinical pharmacology 49 (1995), S. 127-137 
    ISSN: 1432-1041
    Keywords: Thiopental ; Pharmacokinetic modelling ; pharmacokinetics ; single dose ; multiple dosing ; neurosurgical patients ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg−1, and the steady-state volume of distribution (Vss) was 2.16 1·kg−1. The distribution (t1/2α) and elimination (t1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min−1·kg−1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg·1−1 (mean 16.0 mg·1−1 and median 14.3 mg·1−1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg·1−1 (25.4 mg·1−1, and median 23.3 mg·1−1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg−1. The mean Vss was 2.68 1·kg−1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2β and the mean residence time became longer due to a decrease in clearance. For t1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml·min−1·kg−1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.
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  • 66
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    European journal of clinical pharmacology 49 (1995), S. 139-143 
    ISSN: 1432-1041
    Keywords: Intestinal absorption ; Amoxicillin ; pharmacokinetics ; maximum entropy ; input rate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.
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  • 67
    ISSN: 1432-1041
    Keywords: Antiallergic drug ; FK613 ; pharmacokinetics ; histamine skin-test ; drug formulation ; urinary excretion ; safety
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and 〉89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80–250 ng · ml-1 was recommended to ensure the suppression of histamine-induced wheal by 〉50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.
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  • 68
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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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  • 69
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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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  • 70
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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
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    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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  • 71
    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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  • 72
    ISSN: 1432-1041
    Keywords: Key words Tiludronate; healthy volunteers ; bisphosphonates ; pharmacokinetics ; calcium metabolism ; bone resorption ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. Results and conclusions: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg ⋅ l−1, and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg⋅l−1 for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae 24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1–84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way.
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  • 73
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    European journal of clinical pharmacology 51 (1996), S. 189-193 
    ISSN: 1432-1041
    Keywords: Key words Dihydropyridine ; Amlodipine ; Grapefruit juice; flavonoids ; interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Objective: This study was performed to assess whether coadminstration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine). Methods: Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study. Results: When amlodipine was coadministered with grapefruit juice, Cmax was 115% and AUC(0–72 h) was 116% compared with water, but tmax was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4–8 h after drug administration, coinciding with Cmax, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study. Conclusion: An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR. The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects.
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  • 74
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    European journal of clinical pharmacology 51 (1996), S. 259-264 
    ISSN: 1432-1041
    Keywords: Key words Nebivolol ; Hypertension; d ; l-enantiomers ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nebivolol is a selective β1-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study. Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment. Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml ⋅ 100 ml−1 tissue) as compared to active nebivolol treatment (5.17 ml ⋅ 100 ml−1 tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml ⋅ 100 ml−1 tissue) or on active treatment (5.97 ml ⋅ 100 ml−1 tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units). Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects.
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  • 75
    ISSN: 1432-1041
    Keywords: Key words Pantoprazole; Proton pump inhibitor drug interaction ; oral anticoagulant phenprocoumon ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC0–24h and Cmax of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC0–24h and of Cmax of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC0–24h; 0.95, 0.88–1.03 for Cmax) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated.
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  • 76
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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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  • 77
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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
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    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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  • 78
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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
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    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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  • 79
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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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  • 80
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    European journal of clinical pharmacology 49 (1996), S. 387-391 
    ISSN: 1432-1041
    Keywords: Liver function tests ; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h·l−1, clearance was reduced (5.0 vs. 11.8 l·h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r=0.41, P=0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r=0.94, P〈0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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  • 81
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    European journal of clinical pharmacology 49 (1996), S. 411-415 
    ISSN: 1432-1041
    Keywords: Moxisylyte ; pharmacokinetics ; intracavernous administration ; healthy volunteers ; adverse events ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The concentration-time profiles of specific metabolites of moxisylyte, an α-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). Results: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. Conclusion: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.
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  • 82
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    European journal of clinical pharmacology 47 (1995), S. 543-548 
    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
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  • 83
    ISSN: 1432-1041
    Keywords: Granisetron ; pharmacokinetics ; elderly ; tolerance
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    Topics: Chemistry and Pharmacology , Medicine
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  • 84
    ISSN: 1432-1041
    Keywords: Growth hormone ; Jet-injection ; pharmacokinetics ; pharmacodynamics ; Somatomedin C ; free fatty acids
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) were studied after a single subcutaneous dose given by jet-injection, and have been compared with the results obtained after conventional needle-injection. Twelve healthy male volunteers completed an open label, randomised, two-way crossover study, with a 7-day washout period between the two single sc doses. Pharmacokinetic parameters were derived from rhGH concentrations in blood samples collected regularly over 24 h after dosing on Day 1 of each period. To investigate the pharmacodynamics, additional samples were taken for the analysis of somatomedin C (IGF-I) and free fatty acids (FFA). A higher and earlier Cmax was found after jet-injection (ratio (%) jet-injected/needle-injected 124; 90%-confidence interval 108 – 142). The AUC0−∞ for rhGH were similar (ratio (%) jet-injected/needle-injected 98; 90%-confidence interval 93 – 103). Both treatments were associated with a significant and similar rise in IGF-I. Both administrations of rhGH were associated with identical rhythmical changes in FFA. The study indicates that jet-injected and needle-injected rhGH are bioequivalent with respect to the amount absorbed. The criterion for bioequivalence is not met for the rate of absorption. It is unlikely that the latter finding will influence the pharmacodynamics of rhGH, since bioequipotency was established for the effect on IGF-I generation. Jet-injection was safe in use and was generally well tolerated.
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  • 85
    ISSN: 1432-1041
    Keywords: Losartan ; Cimetidine ; pharmacokinetics ; plasma renin activity
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I·ml−1·h−1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.
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  • 86
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    European journal of clinical pharmacology 48 (1995), S. 501-504 
    ISSN: 1432-1041
    Keywords: Quinidine ; CYP2D6 ; Sparteine oxidation polymorphism ; (3S)-3OH-quinidine ; quinidine-N-oxide ; dihydroquinidine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h−1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h−1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.
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  • 87
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    European journal of clinical pharmacology 49 (1995), S. 221-228 
    ISSN: 1432-1041
    Keywords: Nefazodone ; Geriatric assessment ; Hepatic cirrhosis ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects ≤55 years of age (YNG), 12 elderly subjects ≥65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20–60 ml·min−1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.
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  • 88
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    European journal of clinical pharmacology 49 (1995), S. 229-235 
    ISSN: 1432-1041
    Keywords: Nefazodone ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR≥72 ml·min−1·1.73 m−2, 6 with moderate (MOD) renal impairment, CLCR 31–60 ml·min−1·1.73 m−2 and 9 with severe (SEV) renal impairment, CLCR≤30 ml·min−1·1.73 m−2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.
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  • 89
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    European journal of clinical pharmacology 49 (1996), S. 293-298 
    ISSN: 1432-1041
    Keywords: Key words Budesonide; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol ⋅ l−1 (0.95–8.2), 3.0 nmol ⋅ l−1 (0.64–8.9) and 1.3 nmol ⋅ l−1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax = 1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax = 2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
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  • 90
    ISSN: 1432-1041
    Keywords: Felodipine ; pharmacokinetics ; haemodynamics ; congestive heart failure
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (V SS). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.
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  • 91
    ISSN: 1432-1041
    Keywords: Cholesterol acyltransferase ; Hypocholesterolaemic ; 447C88 ; volunteers ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 447C88 (N-Heptyl-N′-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng·ml−1 (23 nM). It is poorly absorbed but 5 mg·kg−1·day−1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng·ml−1 and 9.0 ng·ml−1·h after 200 mg rising to 5.4 ng·ml−1 and 23.8 ng·ml−1·h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.
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  • 92
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    European journal of clinical pharmacology 49 (1996), S. 293-298 
    ISSN: 1432-1041
    Keywords: Budesonide ; enema ; pharmacokinetics ; healthy subjects ; hepatic bypass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. Cmax was 3.3 nmol·l-1 (0.95–8.2), 3.0 nmol·l-1 (0.64–8.9) and 1.3 nmol·l-1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [tmax=1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [tmax=2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%). The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.
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  • 93
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    European journal of clinical pharmacology 49 (1996), S. 317-323 
    ISSN: 1432-1041
    Keywords: Magnesium ; Plasma level ; pharmacokinetics ; bioavailability ; circadian fluctuation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Magnesium plasma concentrations were measured in healthy probands before and after administration of trimagnesium dicitrate by the oral and intravenous routes. There was a notable circadian fluctuation of the plasma concentration with a peak in the evening hours. After oral administration of 12 and 24 mmol magnesium, a long-lasting, statistically significant increase in plasma magnesium concentration measured as the increase in area under the curve (AUC) between 0 and 12 h, of 3.1% and 4.6%, respectively, was found. After intravenous administration of 4 and 8 mmol magnesium, AUCs increased by 9.5% and 16.1%, respectively. The decline in the plasma magnesium concentration after i.v. administration was compatible with a three-compartment model with a terminal half-time of about 8 h. Although no absolute value of the oral bioavailability of trimagnesium dicitrate could be determined from the data, our results may be important in helping to elucidate the influence of magnesium preparations on the plasma magnesium concentration. By comparing the effects of different preparations, it should be possible to estimate the relative oral bioavailability and the bioequivalence of these preparations.
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  • 94
    ISSN: 1432-1041
    Keywords: Key words Tolcapone ; Elderly; levodopa ; pharmacokinetics ; pharmacodynamics ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. Methods: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. Results: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long half-life of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. Conclusion: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson’s disease.
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  • 95
    ISSN: 1432-1041
    Keywords: Key words Cilazapril ; Caucasians ; Chinese; cilazaprilat ; pharmacokinetics ; pharmacodynamics ; ACE inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract. Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system.
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  • 96
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    Electronic Resource
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    European journal of clinical pharmacology 50 (1996), S. 203-208 
    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Felodipine; dehydrofelodi-pine ; pharmacokinetics ; blood pressure ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, Cmax was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and Cmax (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and Cmax were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and Cmax of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine.
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  • 97
    ISSN: 1432-1041
    Keywords: Key words Oxybutynin; effect of food ; N-desethyl oxybutynin ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The Cmax of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.
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  • 98
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice
    Source: Springer Online Journal Archives 1860-2000
    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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  • 99
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 100
    Electronic Resource
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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
    Source: Springer Online Journal Archives 1860-2000
    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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