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  • pharmacokinetics  (70)
  • evolution  (58)
  • Springer  (128)
  • American Meteorological Society
  • Periodicals Archive Online (PAO)
  • 2010-2014
  • 1995-1999  (128)
  • 1990-1994
  • 1935-1939
  • 1996  (128)
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  • Springer  (128)
  • American Meteorological Society
  • Periodicals Archive Online (PAO)
  • Wiley-Blackwell  (2)
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  • 2010-2014
  • 1995-1999  (128)
  • 1990-1994
  • 1935-1939
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  • 1
    Electronic Resource
    Electronic Resource
    Impaired host odor perception in hybrids between the sibling species Rhagoletis pomonella and R. mendax (1996)
    Springer
    Entomologia experimentalis et applicata 80 (1996), S. 163-165 
    Details
    ISSN: 1570-7458
    Keywords: olfaction ; EAG ; sensory physiology ; antennal sensitivity ; interspecies hybrids ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194749
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  • 2
    Electronic Resource
    Electronic Resource
    Chemosensory basis of feeding and oviposition behaviour in herbivorous insects: a glance at the periphery (1996)
    Springer
    Entomologia experimentalis et applicata 80 (1996), S. 7-13 
    Details
    ISSN: 1570-7458
    Keywords: host-plant selection ; sensory physiology ; neural coding ; deterrents ; peripheral interactions ; receptor sites ; genetics of insects ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Recent advances in our understanding of the relationship between chemosensory and behavioural responses to phytochemicals come from a number of studies on ovipositional and food selection behaviour of flies, butterflies, moths and beetles. Establishing input-output relationships has provided insight into the way in which the activity of chemoreceptors is translated into host-plant selection behaviour. This was achieved for both the qualitative contrast acceptance/rejection and for quantifiable preference hierarchies. By now it is clear that the subtlety of coding the complex phytochemical profiles offered by potential host plants relies on across-fibre patterns or ensemblefiring of taste neurons. Progress along these lines depends on unravelling processing pathways in the central nervous system, still a largely unexplored area in herbivorous insects. Increased interest can be noted for the mechanisms operating during the most peripheral events of chemoreception: the interaction of phytochemical and chemoreceptor, determining the specificity of recognition. Evidence for ‘peripheral integration’ has accumulated. Deterrent receptors have an especially puzzling nature. Although such cells respond to a wide array of structurally diverse secondary plant metabolites, their sensitivity profile differs between closely related species. To what extent membrane-bound receptor molecules are involved and what degree of specificity is conferred by these, is largely unknown. Sensitivity to a certain group or class of compounds is determined by single genes in several cases. This allows for a scenario in which single gene mutations affect stimulus-receptor interactions, which might concurrently affect host-plant selection behaviour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194713
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  • 3
    Electronic Resource
    Electronic Resource
    Insect-plant relations: overview from the symposium (1996)
    Springer
    Entomologia experimentalis et applicata 80 (1996), S. 320-324 
    Details
    ISSN: 1570-7458
    Keywords: multitrophic interactions ; phylogeny ; evolution ; fitness
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194783
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  • 4
    Electronic Resource
    Electronic Resource
    Butterflies and ants: The communicative domain (1996)
    Springer
    Cellular and molecular life sciences 52 (1996), S. 14-24 
    Details
    ISSN: 1420-9071
    Keywords: Lycaenidae ; Formicidae ; symbiosis ; mutualism ; parasitism ; communication ; ecology ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Associations with ants, termed myrmecophily, are widespread in the butterfly family Lycaenidae and range from mere co-existence to more or less specific mutualistic or even parasitic interactions. Secretions of specialized epidermal glands are crucial for mediating the interactions. Transfer of nutrients (carbohydrates, amino acids) from butterfly larvae to ants plays a major role, but manipulative communication with the help of odour signals is also involved. By means of myrmecophily, lycaenid butterflies largely escape ant predation, and certain species gain protection through attendant ants or achieve developmental benefits from ant-attendance. Benefits to the ants range from minimal to substantial food rewards. While most lycaenid species maintain facultative relationships with a variety of ant genera, highly specific and obligatory associations have convergently evolved in a number of butterfly lineages. As a corollary, communication systems are largely unspecific in the former, but may be highly specialized in the latter. The sophisticated communication between obligate myrmecophiles and their host ants is tightly connected with the evolutionary rise of specialized life-cycles and thus is a source of augmenting diversity within the butterflies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01922410
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  • 5
    Electronic Resource
    Electronic Resource
    The accessory gland proteins in maleDrosophila: structural, reproductive, and evolutionary aspects (1996)
    Springer
    Cellular and molecular life sciences 52 (1996), S. 503-510 
    Details
    ISSN: 1420-9071
    Keywords: Drosophila ; accessory gland ; reproduction ; sexual behavior ; sperm displacement ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Recent results from biochemical and molecular genetic studies of the accessory gland proteins in maleDrosophila are reviewed. The most prominent feature is the species-specific variability. However, the analysis of the sex peptide inD. melanogaster shows that there is a strong homology in the molecular structure to the closely related sibling species, and that divergence increases with increasing phylogenetic distance. For this reason the sex peptide, after being transferred to the female genital tract during copulation, reduces receptivity and increases oviposition only in virgin females belonging to the same species group and subgroup. Even though studies were hitherto limited to a small number of the secretory components, it is evident that the accessory gland proteins play a key role in reproductive success of the fruit fly by changing female sexual behavior, supporting sperm transfer, storage and displacement. Thus, genes encoding the accessory gland proteins are apparently under strong evolutionary selection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01969718
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  • 6
    Electronic Resource
    Electronic Resource
    Dominance hierarchies and the evolution of human reasoning (1996)
    Springer
    Minds and machines 6 (1996), S. 463-480 
    Details
    ISSN: 1572-8641
    Keywords: Human reasoning ; evolution ; deontic reasoning ; transitive reasoning ; non-human primates ; neocortical ratio ; dominance hierarchy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Philosophy
    Notes: Abstract Research from ethology and evolutionary biology indicates the following about the evolution of reasoning capacity. First, solving problems of social competition and cooperation have direct impact on survival rates and reproductive success. Second, the social structure that evolved from this pressure is the dominance hierarchy. Third, primates that live in large groups with complex dominance hierarchies also show greater neocortical development, and concomitantly greater cognitive capacity. These facts suggest that the necessity of reasoning effectively about dominance hierarchies left an indelible mark on primate reasoning architectures, including that of humans. In order to survive in a dominance hierarchy, an individual must be capable of (a) making rank discriminations, (b) recognizing what is forbidden and what is permitted based one's rank, and (c) deciding whether to engage in or refriin from activities that will allow one to move up in rank. The first problem is closely tied to the capacity for transitive reasoning, while the second and third are intimately related to the capacity for deontic reasoning. I argue that the human capacity for these types of reasoning have evolutionary roots that reach deeper into our ancestral past than the emergence of the hominid line, and the operation of these evolutionarily primitive reasoning systems can be seen in the development of human reasoning and domain-specific effects in adult reasoning.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00389654
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  • 7
    Electronic Resource
    Electronic Resource
    Integrating neuroscience, psychology, and evolutionary biology through a teleological conception of function (1996)
    Springer
    Minds and machines 6 (1996), S. 481-505 
    Details
    ISSN: 1572-8641
    Keywords: Neuroscience ; evolutionary psychology ; interfield theory ; evolution ; teleology ; function ; functionalism ; brain mapping ; language processing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Philosophy
    Notes: Abstract The idea of integrating evolutionary biology and psychology has great promise, but one that will be compromised if psychological functions are conceived too abstractly and neuroscience is not allowed to play a contructive role. We argue that the proper integration of neuroscience, psychology, and evolutionary biology requires a telelogical as opposed to a merely componential analysis of function. A teleological analysis is required in neuroscience itself; we point to traditional and curent research methods in neuroscience, which make critical use of distinctly teleological functional considerations in brain cartography. Only by invoking teleological criteria can researchers distinguish the fruitful ways of identifying brain components from the myriad of possible ways. One likely reason for reluctance to turn to neuroscience is fear of reduction, but we argue that, in the context of a teleological perspective on function, this concern is misplaced. Adducing such theoretical considerations as top-down and bottom-up constraints on neuroscientific and psychological models, as well as existing cases of productive, multidisciplinary cooperation, we argue that integration of neuroscience into psychology and evolutionary biology is likely to be mutually beneficial. We also show how it can be accommodated methodologically within the framework of an interfield theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00389655
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  • 8
    Electronic Resource
    Electronic Resource
    Conventions and institutions in coordination problems (1996)
    Springer
    De economist 144 (1996), S. 397-428 
    Details
    ISSN: 1572-9982
    Keywords: conventions ; institutions ; game theory ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Economics
    Notes: Summary This survey article starts with a game-theory interpretation of coordination problems that occur in an economy. Three types of games are discussed in which the degree of coordination versus conflict varies. It is shown that game-theoretic techniques for equilibrium selection or securing the highest pay-off outcome do not always suffice, which raises the need for exogenous information. Norms, such as conventions and institutions, may provide this information. The emergence and persistence of norms as well as the relationship between the type of game and the type of norm are discussed. After a discussion on conventions and rationality, some notions from Institutional Economics are introduced, in which institutions are explained as a way to deal with limited and costly information. Some applications are given in the last section.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01682834
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  • 9
    Electronic Resource
    Electronic Resource
    Castes in humivorous and litter-dwelling neotropical nasute termites (Isoptera, Termitidae) (1996)
    Springer
    Insectes sociaux 43 (1996), S. 375-389 
    Details
    ISSN: 1420-9098
    Keywords: Nasutitermitinae ; Subulitermes ; Coatitermes ; Velocitermes ; evolution ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The developmental pathways of the neuter castes were studied in three species of Nasutitermitinae from central Panama. The humivorousSubulitermes denisae andCoatitermes clevelandi display several primitive traits: absence of sex dimorphism, representation of both sexes among workers and soldiers, and occurrence of successive worker instars. The litter-dwellingVelocitermes barrocoloradensis has a more complex caste system: female larvae are larger than males and give rise to the large workers, which constitute the bulk of the work force; male larvae proceed to soldiers through a small worker or a special larval instar. The resulting soldier caste is polymorphic. These results support previously formulated hypotheses regarding a link between humivorous diet and reduced polymorphism on the one hand, and between forest-floor foraging and large continuous size variation among soldiers on the other. Whereas the caste systems ofSubulitermes andCoatitermes probably represent a primitive condition,Velocitermes shares derived traits withNasutitermes and the other fully nasute genera previously studied. I therefore hypothesize that ancestors with these advanced features may have spread from the neotropics and be at the origin of most nasute genera, including humivorous taxa, present in other regions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01258410
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  • 10
    Electronic Resource
    Electronic Resource
    Sequence comparisons of the internal transcribed spacer region of ribosomal genes support close relationships between parasitic ants and their respective host species (Hymenoptera: Formicidae) (1996)
    Springer
    Insectes sociaux 43 (1996), S. 53-67 
    Details
    ISSN: 1420-9098
    Keywords: Formicidae ; Leptothoracini ; Tetramoriini ; internal transcribed spacer ; social parasitism ; evolution ; phylogenetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary A fragment of the internal transcribed spacer (ITS-1) adjacent to the 5.8S rRNA gene of 20 myrmicine ant species was sequenced. Sequence comparisons were carried out between 11 species of the tribe Leptothoracini, five species of the tribe Tetramoriini, three species of the tribe Solenopsidini and one species of the tribe Myrmicini. Additionally, the formicine antCamponotus ligniperda (tribe Camponotini) was analyzed as an outgroup species. Among all investigated species, the fragment had a variable length of ≈ 230–380 bp with only a few conserved sequence elements. The sequences of this fragment were perfectly identical within four palearctic populations ofLeptothorax acervorum indicating that intraspecific variation is rather low. Within the species of Tetramoriini (includingAnergates atratulus) 94.1% of sequence positions were identical, 95.6% within the species of theLeptothorax s.str.-group and 64.6% within the species of theMyrafant-group. Phylogenetic analysis reveals that the social parasitesHarpagoxenus sublaevis, Doronomyrmex goesswaldi, D. kutteri andD. pacis, Chalepoxenus muellerianus as well asStrongylognathus alpinus andTeleutomyrmex schneideri are most closely related to the groups of their respective host species, which generally confirms the taxonomical classifications of the subfamily Myrmicinae based on morphological criteria. The taxonomical positions of the speciesA. atratulus has as yet been uncertain, however, sequence comparison of the ITS-1 fragment leads to the conclusion thatA. atratulus rather belongs to the tribe Tetramoriini than to the Solenopsidini.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01253956
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  • 11
    Electronic Resource
    Electronic Resource
    Sex pheromones and attractants in the Eucosmini and Grapholitini (Lepidoptera, Tortricidae) (1996)
    Springer
    Chemoecology 7 (1996), S. 13-23 
    Details
    ISSN: 1423-0445
    Keywords: sex pheromone ; synergist ; antagonist ; mate recognition ; reproductive isolation ; chemotaxonomoy ; phylogeny ; evolution ; Lepidoptera ; Tortricidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The geometric isomers (E,E)-, (E,Z)-, (Z,E)-, and (Z,Z)-8,10-dodecadien-1-yl acetate were identified as sex pheromone components or sex attractants in the tribes Eucosmini and Grapholitini of the tortricid subfamily Olethreutinae. Species belonging to the more ancestral Tortricinae were not attracted. Each one isomer was behaviourally active in males ofCydia andGrapholita (Grapholitini), either as main pheromone compound, attraction synergist or attraction inhibitor. Their reciprocal attractive/antagonistic activity in a number of species enables specific communication with these four compounds.Pammene, as well as otherGrapholita andCydia responded to the monoenic 8- or 10-dodecen-1-yl acetates. Of the tribes Olethreutini and Eucosmini,Hedya, Epiblema, Eucosma, andNotocelia trimaculana were also attracted to 8,10-dodecadien-1-yl acetates, but several otherNotocelia to 10,12-tetradecadien-1-yl acetates. The female sex pheromones ofC. fagiglandana, C. pyrivora, C. splendana, Epiblema foenella andNotocelia roborana were identified. (E,E)- and (E,Z)-8,10-dodecadien-1-yl acetate are producedvia a commonE9 desaturation pathway inC. splendana. CallingC. nigricana andC. fagiglandana females are attracted to wingfanning males.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01240633
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  • 12
    Electronic Resource
    Electronic Resource
    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050037
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  • 13
    Electronic Resource
    Electronic Resource
    Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 279-284 
    Details
    ISSN: 1432-1041
    Keywords: Antiallergic drug ; FK613 ; pharmacokinetics ; histamine skin-test ; drug formulation ; urinary excretion ; safety
    Source: Springer Online Journal Archives 1860-2000
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226328
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  • 14
    Electronic Resource
    Electronic Resource
    Multiple dose pharmacokinetics of tiludronate in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 175-181 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050181
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  • 15
    Electronic Resource
    Electronic Resource
    Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 189-193 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050183
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  • 16
    Electronic Resource
    Electronic Resource
    Haemodynamic effects and pharmacokinetics of oral d-and l-nebivolol in hypertensive patients (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 259-264 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050194
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  • 17
    Electronic Resource
    Electronic Resource
    Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 277-281 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050198
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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
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    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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    URL: http://dx.doi.org/10.1007/BF00203783
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    Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 411-415 
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    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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    URL: http://dx.doi.org/10.1007/BF00203788
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    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
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    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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    URL: http://dx.doi.org/10.1007/BF00226330
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  • 21
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    Rectal pharmacokinetics of budesonide (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 293-298 
    Details
    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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    URL: http://dx.doi.org/10.1007/BF00226330
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    Increase in magnesium plasma level after orally administered trimagnesium dicitrate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 317-323 
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    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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    URL: http://dx.doi.org/10.1007/BF00226334
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    Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 47-55 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050068
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    A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy, normotensive volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 57-62 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050069
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    Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 203-208 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050093
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    Effect of food on the bioavailability of oxybutynin from a controlled release tablet (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 221-223 
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    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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    URL: http://dx.doi.org/10.1007/s002280050096
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    Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 167-169 
    Details
    ISSN: 1432-1041
    Keywords: Key words Idebenone; mitochondrial encephalomyopathy ; young patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (Cmax = 452.2 ng ⋅ ml−1, tmax = 2.3 h, AUC = 26 μg ⋅ ml−1 ⋅ h, t1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml−1) and Day 5 (70.6 ng ⋅ ml−1), and mean t1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics.
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    Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 161-166 
    Details
    ISSN: 1432-1041
    Keywords: Key words Amisulpride; ethanol vector ; performance ; memory ; cognitive function ; interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D2- and D3-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible interaction with alcohol on human performance, amisulpride was studied for this potential. Methods: In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride 50 mg and 200 mg, without and with ethanol (0.8 g ⋅kg−1) taken 30 min later. Objective performance tests and self-ratings were done at baseline and 1.5, 3.5 and 6.5 h after drug intake. Memory (immediate and delayed recall) was tested 2 h after dosing. Breath ethanol and the plasma concentrations of amisulpride and prolactin were measured. Three-way ANOVA + Newman-Keul tests were used for statistical analyses; interactions were confirmed by factorial contrast ANOVA. Results: Mean blood ethanol was 0.94, 0.62 and 0.26 g ⋅l−1 at the three test times. It produced significant impairment in all performance tests (symbol digit substitution, simulated driving, body sway, flicker fusion, tapping, nystagmus), reduced both immediate and delayed recall in memory tests, and caused subjective clumsiness, muzziness and mental slowness, mainly between 1.5 to 4.5 h after dosing. Amisulpride, 50 and 200 mg elevated plasma prolactin but had minimal or no effect on performance, attention and memory. The decreases in immediate free recall after the 50 mg dose and in delayed free recall after the 200 mg dose were slight. Amisulpride neither modified blood ethanol concentrations nor enhanced the detrimental effect of ethanol on skilled and cognitive performance; it slightly antagonised ethanol in the digit copying test. Ethanol did not modify the effect of amisulpride on plasma prolactin, and the plasma concentrations of amisulpride were little changed by ethanol. Conclusions: Amisulpride in single oral doses of 50 and 200 mg did not interact significantly with the effects of high, moderate or low concentrations of ethanol on human skilled and cognitive performance. The drugs did interact pharmacokinetically.
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    URL: http://dx.doi.org/10.1007/s002280050178
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    Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 171-173 
    Details
    ISSN: 1432-1041
    Keywords: Key words Mefloquine; mefloquine enantiomers ; carboxylic acid metabolite ; blood concentrations ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. Setting: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. Volunteers: Ten healthy adult Caucasian volunteers. Methods: Drug concentrations were determined by high-performance liquid chromatography (HPLC). Results: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (−)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. Conclusion: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.
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    Pharmacokinetics of dexamethasone in premature neonates (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 477-483 
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    ISSN: 1432-1041
    Keywords: Dexamethasone ; Premature neonates ; pharmacokinetics ; bronchopulmonary dysplasia ; infant ; newborn
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min−1·kg−1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min−1·kg−1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg−1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.
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    Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone – a novel antiarrhythmic agent (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 315-319 
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    ISSN: 1432-1041
    Keywords: Key words Diprafenone; antiarrhythmics ; bioavailability ; human ; foods ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The present study was done to investigate the effect of food on the bioavailability of diprafenone. Methods: The most important pharmacokinetic parameters (Cmax, t1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart. The serum concentrations of diprafenone and its hydroxy-metabolite were determined up to 24 hours after administration by a sensitive, specific HPLC method. Fifteen healthy, male volunteers were enrolled in the trial. Their mean height, weight and age were 183 cm, 80 kg and 22 years, respectively. Fourteen volunteers were found to be rapid hydroxylators and one was a slow hydroxylator of debrisoquine. Only data from the rapid hydroxylators were used in the statistical analysis. Results: Food increased the oral bioavailability of diprafenone by approximately 50%. This effect was similar in rapid and in slow hydroxylators. The only slow hydroxylator in this trial had an AUC0–last ratio (with food/fasting) of 1.54. These findings suggest that diprafenone should be administered in a constant temporal relationship to food.
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    URL: http://dx.doi.org/10.1007/s002280050115
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    Evaluation of plasma and urinary salbutamol levels in COPD (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 91-93 
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    ISSN: 1432-1041
    Keywords: Key words Salbutamol; nebulised ; pharmacokinetics ; COPD ; overnight urinary salbutamol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To evaluate the use of trough plasma salbutamol and overnight urinary salbutamol excretion in the assessment of nebulised salbutamol delivery in patients with chronic obstructive pulmonary disease (COPD). Methods: Twenty in-patients with COPD receiving nebulised salbutamol, age 69.7 years, FEV1 38.1% predicted, were studied on two consecutive days, receiving four 2.5 mg doses of nebulised salbutamol on day 1 and four 5 mg doses of nebulised salbutamol on day 2, the first dose at 8.00 h the last dose at 22.00 h. Salbutamol delivery was assessed after the last dose by trough plasma salbutamol 8.00 h and overnight urinary excretion of salbutamol (22.00–8.00 h). Results: Levels of urinary salbutamol were detectable in all 20 patients at both doses, whereas for plasma salbutamol detectable levels were only found in 16/20 cases at the 2.5 mg dose and in all cases at the 5 mg dose. For overnight urinary salbutamol (μg⋅10 h−1  n = 20) the results were 141 for 2.5 mg and 249 for 5 mg. The dose ratio for urinary salbutamol between 2.5 mg and 5 mg doses was 1.83. Results for plasma salbutamol (ng/ml, n = 16) were 1.58 at 2.5 mg and 2.43 at 5 mg: dose ratio (geometric mean) 1.49. Conclusion: Overnight urinary salbutamol provides a simple and effective measure of nebulised salbutamol delivery in patients with COPD, which would be suitable for studying nebuliser performance and compliance.
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    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: Key words Nalbuphine ; Neonate; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng ⋅ ml−1 in mother plasma samples and from 3.0 to 46.6 ng ⋅ ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
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    Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: Nalbuphine ; Neonate ; therapeutic drug monitoring ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng·ml−1 in mother plasma samples and from 3.0 to 46.6 ng·ml−1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.
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    Pharmacokinetics of quinine in patients with chronic renal failure (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 497-501 
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    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (tmax 4.5 vs 1.6 h, Cmax 6.17 vs 3.45 μg·ml−1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min−1·kg−1, whereas Vz/f remained unchanged (1.82 vs 2.78 1·kg−1). This resulted in the increased values of AUC and prolongation of the t1/2z and MRT in the patients (AUC 181.5 vs 61.8 μg·min−1·ml−1, t1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.
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    Stereoselective pharmacokinetics of mefloquine in young children (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 241-244 
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    ISSN: 1432-1041
    Keywords: Key words Mefloquine ; Children; enantiomer ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: the stereospecificity of mefloquine pharmacokinetics in children has been investigated. Patients: Twelve children aged 6 to 24 months were treated for uncomplicated falciparum malaria with a single oral dose of 25 mg⋅kg−1 racemic mefloquine in combination with sulfadoxine and pyrimethamine. Methods: concentrations of mefloquine enantiomers were determined using a coupled achiral-chiral chromatographic system. Pharmacokinetic parameters were calculated using model-independent analysis. Results: Maximum plasma concentrations, areas under the curve and apparent plasma elimination half-lives were higher for the (−) enantiomer than its antipode. In contrast, the apparent volume of distribution (V/f) and total clearance (Cl/f) values were higher for the (+) enantiomer. Conclusion: the stereoselectivity of mefloquine pharmacokinetics is similar to that observed in adults.
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    A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 335-337 
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    ISSN: 1432-1041
    Keywords: Key words Cyclosporine ; Ursodiol; ursodeoxycholic acid ; absorption ; pharmacokinetics ; liver transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml–1, Cmax was 832 vs 871 ng⋅ml–1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.
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    Absolute bioavailability of fluoride from disodium monofluorophosphate and enteric-coated sodium fluoride tablets (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 321-326 
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    ISSN: 1432-1041
    Keywords: Key words Sodium fluoride ; Disodium monofluorophosphate; absolute bioavailability ; pharmacokinetics ; elderly population
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The absolute bioavailability and other pharmacokinetic parameters of two fluoride formulations were investigated in 13 healthy volunteers, aged 61–70 years. Methods: The following formulations were administered, under fasting conditions, in a single-dose three-way cross-over design: tablets of 76 mg disodium monofluoro phosphate (MFP, equivalent to 10.0 mg F− ion), enteric-coated (e.c.) tablets of 25 mg sodium fluoride (NaFor, equivalent of 11.3 mg F− ion), and an isoosmotic aqueous injection solution (4 ml) of 22.1 mg sodium fluoride (NaFiv, equivalent of 10.0 mg F− ion). There was a wash-out period of at least one week between each administration. Blood was sampled before and during a 24-hour period after administration. For F− excretion urine was sampled 48 hours before (baseline) and over the 48 hours after the adminstration. Results: The mean t1/2 values of the three formulations were 8.3, 8.7 and 8.3 h for MFP, NaFor and NaFiv respectively, and were not significant different. Mean Cmax after MFP was significantly higher than after NaFor [344 vs 142 μg⋅l−1]. Mean tmax for MFP was shorter than for NaFor [1.1 vs 4.6 h]. MFP had significantly higher bioavailability [102.8%] than NaFor [64.2%]. Conclusion: The MFP formulation showed higher bioavailability with smaller variation than the NaFor formulation. MFP is preferable, therefore, for fluoride therapy in clinical practice, and changing from NaFor to MFP will require adjustment of the dose.
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    Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 491-495 
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    ISSN: 1432-1041
    Keywords: Key words Aprotinin ; Arginine vasopressin; bioavailability ; dDAVP ; enzyme inhibitor ; gastrointestinal tract ; healthy volunteer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19–34 years, followed for 8 h after each drug administration. Methods: For i.v. administration the subjects received 4 μg dDAVP. For intestinal administration 500 μg dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml⋅min−1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. Results: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml⋅min⋅kg−1. The mean bioavailability after duodenal administration of dDAVP + aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor.
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    Bioavailability of estradiol from a new matrix and a conventional reservoir-type transdermal therapeutic system (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 327-330 
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    ISSN: 1432-1041
    Keywords: Key words Hormone replacement therapy; estradiol ; pharmacokinetics ; bioequivalence ; postmenopausal volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 μg per day of 17β-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. Results: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
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    Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 331-334 
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    ISSN: 1432-1041
    Keywords: Key words Zopiclone ; Itraconazole; drug interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. Methods: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. Results: Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng ⋅ ml−1. The t1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml−1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Conclusion: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.
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    Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam (1996)
    Springer
    European journal of clinical pharmacology 51 (1996), S. 335-338 
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    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Sauna; metabolism ; pharmacokinetics ; heat ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg−1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration. Results: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. Conclusions: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.
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    The ecology and evolution of bacteriocins (1996)
    Springer
    Journal of industrial microbiology and biotechnology 17 (1996), S. 151-158 
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    ISSN: 1476-5535
    Keywords: bacteriocins ; colicins ; evolution ; ecology ; Escherichia coli
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract In this review we focus on the ecological and evolutionary forces that determine the frequency and diversity of colicins inEscherichia coli. To begin, we describe that this killing phenotype is ubiquitous inE. coli, with as many as 50% of the isolates from a population producing colicin toxins, and that each population sampled has its own unique distribution of the more than 20 known colicin types. Next, we explore the dynamics of colicinogeny, which exhibits a typical form of frequency dependence, where the likelihood of successful colicin invasion into a population increases as the initial density of colicinogenic cells increases. We then incorporate thoughts on the evolution of chromosomal resistance to colicins and describe how resistance might influence the dynamics of colicinogen invasion and maintenance and the resulting colicin diversity. The final section deals with a genetic and phylogenetic characterization of colicins and a discussion of the evolutionary mechanisms responsible for generating colicin diversity. In this final section we provide details of the different molecular mechanisms known to play a role in generating colicin diversity, including the two most dominant forces in colincin evolution: recombination and positive, deversifying, selection.
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    Olefinic acetates, Δ-9,11–14: OAc and Δ-7,9–12: OAc used as sex pheromone components in three geometrid moths,Idaea aversata, I. straminata, andI. biselata (Geometridae, Lepidoptera) (1996)
    Springer
    Journal of chemical ecology 22 (1996), S. 1505-1526 
    Details
    ISSN: 1573-1561
    Keywords: Sex pheromone ; Idaea aversata ; Idaea straminata ; Idaea biselata ; (Z,Z)-9,11-tetradecadienyl acetate ; (Z,Z)-7,9-dodecadienyl acetate ; (Z,E)-7,9-dodecadienyl acetate ; Lepidoptera ; Geometridae ; electroantennography ; single cell recording ; biosynthesis ; phylogeny ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Pheromone compounds so far identified from most geometrid moths consist of all-Z diene, triene, or tetraene hydrocarbons with chain lengths of C17 to C21, and their monoepoxide derivatives biosynthesized from linoleic and linolenic acids. The present study reports the occurrence of olefinic acetates as sex pheromones in three species of Geometridae. (Z,Z)-9,11-tetradecadienyl acetate and (Z,Z)-7,9-dodecadienyl acetate found in female gland extracts ofIdaea aversata elicited significant responses from conspecific male antennae in gas chromatography with electroantennographic detection (GCEAD). In extracts ofI. straminata, (Z,Z)-7,9-dodecadienyl acetate, (E,Z)-7,9-dodecadienyl acetate, and (Z,Z)-7,9-dodecadienyl acetate were found, and the synthetic compounds elicited strong responses from conspecific male antennae. In the third species,I. biselata, only (Z,Z)-7,9-dodecadienyl acetate was found in the female extracts, and this compound elicited a strong EAD response from the conspecific male antenna. The identities of the pheromone components inI. aversata andI. straminata were further confirmed according to their characteristic ions after GC-MS analyses. Single sensillum recordings fromI. aversata showed two types of pheromone-detecting sensilla present on the male antenna. One type contained two receptor neurons, one of which was specifically tuned to (Z,Z)-9,11-tetradecadienyl acetate, the other to (Z,E)-9,11-tetradecadienyl acetate. A second type contained one neuron responding to (Z,Z)-7,9-dodecadienyl acetate. The two types were clearly different also with respect to external morphology, the former being considerably longer and having a larger base diameter. Also inI. straminata two physiological types of sensilla could be distinguished. One type contained two neurons, one of which responded to (Z,Z)-7,9-dodecadienyl acetate, the other to (Z,E)-9,11-tetradecadienyl acetate. The second type contained one neuron, responding to (Z,Z)-7,9-dodecadienyl acetate. No correlation between external morphology and physiological response of the investigated sensilla was observed inI. straminata. In field tests, a two-component blend containing (Z,Z)-9,11-tetradecadienyl acetate and (Z,Z)-7,9-dodecadienyl acetate in a ratio of 10:1 was attractive to males ofI. aversata. This two-component blend was also attractive to males ofI. straminata, but in a ratio of 1:1. High numbers of maleI. biselata were caught in traps baited with (Z,Z)-7,9-dodecadienyl acetate alone. The incorporation of deuterium labels into pheromone components after topical application of deuterium-labeled palmitic acid confirmed that the pheromone components ofI. aversata could be synthesized from this precursor, as has been previously observed for acetate pheromone components of many other moth species. Our results suggest that an evolutionary reversal back to the production of palmitic acid-derived pheromone components has occurred within the geometrid subfamily Sterrhinae.
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    Interspecies relationships among ADP-ribosylation factors (ARFs): Evidence of evolutionary pressure to maintain individual identities (1996)
    Springer
    Molecular and cellular biochemistry 159 (1996), S. 15-23 
    Details
    ISSN: 1573-4919
    Keywords: guanine nucleotide-binding proteins ; evolution ; phylogeny ; structure-function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract ADP-ribosylation factors (ARFs) are ∼20-kDa guanine nucleotide-binding proteins that are allosteric activators of the NAD:arginine ADP-ribosyltransferase activity of cholera toxin and appear to play a role in intracellular vesicular trafficking. Although the physiological roles of these proteins have not been defined, it has been presumed that each has a specific intracellular function. To obtain genetic evidence that each ARF is under evolutionary pressure to maintain its structure, and presumably function, rat ARF cDNA clones were isolated and their nucleotide and deduced amino acid sequences were compared to those of other mammalian ARFs. Deduced amino acid sequences for rat ARFs 1, 2, 3, 5 and 6 were identical to those of the known cognate human and bovine ARFs; rat ARF4 was 96% identical to human ARF4. Nucleotide sequences of both the untranslated as well as the coding regions were highly conserved. These results indicate that the ARF proteins are, as a family, extraordinarily well conserved across mammalian species. The unusually high degree of conservation of the untranslated regions is consistent with these regions having important regulatory roles and that individual ARFs contain structurally unique elements required for specific functions.
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    Chemotaxis of the unicellular green algaDunaliella salina and the ciliatedTetrahymena pyriformis—effects of glycine, lysine, and alanine, and their oligopeptides (1996)
    Springer
    Bioscience reports 16 (1996), S. 467-476 
    Details
    ISSN: 1573-4935
    Keywords: Chemotaxis ; evolution ; oligopeptides ; Tetrahymena ; Dunaliella
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Chemotactic properties of amino acids (L-alanine, glycine and L-lysine) and their oligopeptides (10−6M) and binding sites to these ligands were investigated in two unicellular models, the heterotrophicTetrahymena pyriformis and the auxotrophicDunaliella salina. Chemotaxis ofDunaliella induced by simple amino acids and their derivatives demonstrated that binding sites (receptors) for food molecules are not only present in the membrane but are also able to induce their basic physiological response. InTetrahymena, substances with special molecular structure and properties (polar, hydrophilic character of the signal peptide chain)-5-L-Lys, 5-Glywere required for chemoattraction, other peptides tested, lacking the required structure, were repellent. Divergences in chemotaxis and binding assays of both species suggest that trends of functional and binding parameters do not run parallel at this level of evolution.
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    Molecular characterization of transketolase (EC 2.2.1.1) active in the Calvin cycle of spinach chloroplasts (1996)
    Springer
    Plant molecular biology 32 (1996), S. 475-484 
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    ISSN: 1573-5028
    Keywords: carbon fixation ; chloroplasts ; evolution ; isoenzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A cDNA encoding the Calvin cycle enzyme transketolase (TKL; EC 2.2.1.1) was isolated from Sorghum bicolor via subtractive differential hybridization, and used to isolate several full-length cDNA clones for this enzyme from spinach. Functional identity of the encoded mature subunit was shown by an 8.6-fold increase of TKL activity upon induction of Escherichia coli cells that overexpress the spinach TKL subunit under the control of the bacteriophage T7 promoter. Chloroplast localization of the cloned enzyme is shown by processing of the in vitro synthesized precursor upon uptake by isolated chloroplasts. Southern blot-analysis suggests that TKL is encoded by a single gene in the spinach genome. TKL proteins of both higher-plant chloroplasts and the cytosol of non-photosynthetic eukaryotes are found to be unexpectedly similar to eubacterial homologues, suggesting a possible eubacterial origin of these nuclear genes. Chloroplast TKL is the last of the demonstrably chloroplast-localized Calvin cycle enzymes to have been cloned and thus completes the isolation of gene probes for all enzymes of the pathway in higher plants.
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    Phylogenetic relationship among all living species of the genusBubalus based on DNA sequences of the cytochromeb gene (1996)
    Springer
    Biochemical genetics 34 (1996), S. 443-452 
    Details
    ISSN: 1573-4927
    Keywords: Bubalus ; tamaraw ; anoa ; cytochromeb ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The cytochromeb genes of all living species ofBubalus, including the river type and the swamp type of domestic buffaloes (Bubalus bubalis), were sequenced to clarify their phylogenetic relationships. These sequences were compared together with the African buffalo (Syncerus caffer) and banteng (Bos javanicus) sequences as an outgroup. Phylogenetic trees ofBubalus species based on the DNA sequences of the cytochromeb gene demonstrated that the tamaraw (Bubalus mindorensis), endemic to the Philippines, could be classified into the subgenusBubalus, not the subgenusAnoa. The divergence time between the lowland anoa (B. depressicornis) and the mountain anoa (B. quarlesi) was estimated at approximately 2.0 million years (Myr), which is almost the same as the coalescence time for theBubalus sequences. This large genetic distance supports the idea that the lowland anoa and the mountain anoa are different species. An unexpectedly large genetic distance between the river and the swamp type of domestic buffaloes suggests a divergence time of about 1.7 Myr, while the swamp type was noticed to have the closest relationship with the tamaraw (1.5 Myr). This result implies that the two types of domestic buffaloes have differentiated at the full species level.
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    URL: http://dx.doi.org/10.1007/BF00570125
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    Characterization of a maize ribosomal P2 protein cDNA and phylogenetic analysis of the P1/P2 family of ribosomal proteins (1996)
    Springer
    Plant molecular biology 30 (1996), S. 655-658 
    Details
    ISSN: 1573-5028
    Keywords: cDNA ; evolution ; p2 protein ; ribosome ; Zea mays
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The nucleotide sequence of a full-length ribosomal P2 protein cDNA from maize was determined and used for a sequence comparison with the P2 and P1 proteins from other organisms. The integration of these data into a phylogenetic tree shows that the P proteins separated into the subspecies P1 and P2 before the eukaryotic kingdoms including plants developed from their ancestor.
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    URL: http://dx.doi.org/10.1007/BF00049340
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    RNA editing in plant mitochondria and chloroplasts (1996)
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    Plant molecular biology 32 (1996), S. 343-365 
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    ISSN: 1573-5028
    Keywords: RNA editing ; tRNA editing ; chloroplast ; mitochondrion ; post-transcriptional modification ; initiation codon ; stop codon ; deamination ; evolution ; guide RNA ; transgenic plants ; plastid transformation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract In the mitochondria and chloroplasts of higher plants there is an RNA editing activity responsible for specific C-to-U conversions and for a few U-to-C conversions leading to RNA sequences different from the corresponding DNA sequences. RNA editing is a post-transcriptional process which essentially affects the transcripts of protein coding genes, but has also been found to modify non-coding transcribed regions, structural RNAs and intron sequences. RNA editing is essential for correct gene expression: proteins translated from edited transcripts are different from the ones deduced from the genes sequences and usually present higher similarity to the corresponding non-plant homologues. Initiation and stop codons can also be created by RNA editing. RNA editing has also been shown to be required for the stabilization of the secondary structure of introns and tRNAs. The biochemistry of RNA editing in plant organelles is still largely unknown. In mitochondria, recent experiments indicate that RNA editing may be a deamination process. A plastid transformation technique showed to be a powerful tool for the study of RNA editing. The biochemistry as well as the evolutionary features of RNA editing in both organelles are compared in order to identify common as well as organelle-specific components.
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    URL: http://dx.doi.org/10.1007/BF00039390
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    Higher-plant chloroplast and cytosolic fructose-1,6-bisphophosphatase isoenzymes: origins via duplication rather than prokaryote-eukaryote divergence (1996)
    Springer
    Plant molecular biology 32 (1996), S. 485-491 
    Details
    ISSN: 1573-5028
    Keywords: Calvin cycle ; sedoheptulose-1,7-bisphosphatase ; isoenzymes ; endosymbiosis ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Full-size cDNAs encoding the precursors of chloroplast fructose-1,6-bisphosphatase (FBP), sedoheptulose-1,7-bisphosphatase (SBP), and the small subunit of Rubisco (RbcS) from spinach were cloned. These cDNAs complete the set of homologous probes for all nuclear-encoded enzymes of the Calvin cycle from spinach (Spinacia oleracea L.). FBP enzymes not only of higher plants but also of non-photosynthetic eukaryotes are found to be unexpectedly similar to eubacterial homologues, suggesting a eubacterial origin of these eukaryotic nuclear genes. Chloroplast and cytosolic FBP isoenzymes of higher plants arose through a gene duplication event which occurred early in eukaryotic evolution. Both FBP and SBP of higher plant chloroplasts have acquired substrate specificity, i.e. have undergone functional specialization since their divergence from bifunctional FBP/SBP enzymes of free-living eubacteria.
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    URL: http://dx.doi.org/10.1007/BF00019100
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    A model for the evolution of the plastid sec apparatus inferred from secY gene phylogeny (1996)
    Springer
    Plant molecular biology 32 (1996), S. 685-692 
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    ISSN: 1573-5028
    Keywords: evolution ; protein transport ; sec apparatus ; secA ; secY ; thylakoid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Plastids possess a bacteria-like sec apparatus that is involved in protein import into the thylakoid lumen. We have analyzed one of the genes essential for this process, secY. A secY gene from the unicellular red alga Cyanidium caldarium was found to be transcriptionally active, demonstrating for the first time that secY is functional in a plastid. Unlike the situation seen in bacteria the C. caldarium gene is transcribed monocistronically, despite the fact that it is part of a large ribosomal gene cluster that resembles bacterial spc operons. A molecular phylogeny is presented for 8 plastid-encoded secY genes, four of which have not been published yet. In this analysis plastid secY genes fall into two classes. One of these, comprising of genes from multicellular red algae and Cryptophyta, clusters in a neighbour-joining tree with a cyanobacterial counterpart. Separated from the aforesaid are secY genes from Chromophyta, Glaucocystophyta and a unicellular red alga. All plastid and cyanobacterial sequences are located on the same branch, separated from bacterial homologues. We postulate that the two classes of secY genes are paralogous, i.e. their gene products are involved in different protein translocation processes. Based on this assumption a model for the evolution of the plastid sec apparatus is presented.
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    URL: http://dx.doi.org/10.1007/BF00020209
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    Gene-specific universal mammalian sequence-tagged sites: Application to the canine genome (1996)
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    Biochemical genetics 34 (1996), S. 321-341 
    Details
    ISSN: 1573-4927
    Keywords: genome mapping ; evolution ; homology ; polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We are developing a genetic map of the dog based partly upon markers contained within known genes. In order to facilitate the development of these markers, we have used polymerase chain reaction (PCR) primers designed to conserved regions of genes that have been sequenced in at least two species. We have refined the method for designing primers to maximize the number that produce successful amplifications across as many mammalian species as possible. We report the development of primer sets for 11 loci in detail:CFTR, COL10A1, CSFIR, CYP1A1, DCN1, FES, GHR, GLB1, PKLR, PVALB, andRB1. We also report an additional 75 primer sets in the appendices. The PCR products were sequenced to show that the primers amplify the expected canine genes. These primer sets thus define a class of gene-specific sequence-tagged sites (STSs). There are a number of uses for these STSs, including the rapid development of various linkage tools and the rapid testing of genomic and cDNA libraries for the presence of their corresponding genes. Six of the eleven gene targets reported in detail have been proposed to serve as “anchored reference loci” for the development of mammalian genetic maps [O'Brien, S. J.,et al., Nat. Genet. 3:103, 1993]. The primer sets should cover a significant portion of the canine genome for the development of a linkage map. In order to determine how useful these primer sets would be for the other genome projects, we tested the 11 primer sets on the DNA from species representing five mammalian orders. Eighty-four percent of the gene-species combinations amplified successfully. We have named these primer sets “universal mammalian sequence-tagged sites” because they should be useful for many mammalian genome projects.
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    URL: http://dx.doi.org/10.1007/BF00553904
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    Gene-specific universal mammalian sequence-tagged sites: Application to the canine genome (1996)
    Springer
    Biochemical genetics 34 (1996), S. 321-341 
    Details
    ISSN: 1573-4927
    Keywords: genome mapping ; evolution ; homology ; polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We are developing a genetic map of the dog based partly upon markers contained within known genes. In order to facilitate the development of these markers, we have used polymerase chain reaction (PCR) primers designed to conserved regions of genes that have been sequenced in at least two species. We have refined the method for designing primers to maximize the number that produce successful amplifications across as many mammalian species as possible. We report the development of primer sets for 11 loci in detail:CFTR, COL10A1, CSFIR, CYP1A1, DCN1, FES, GHR, GLB1, PKLR, PVALB, andRB1. We also report an additional 75 primer sets in the appendices. The PCR products were sequenced to show that the primers amplify the expected canine genes. These primer sets thus define a class of gene-specific sequence-tagged sites (STSs). There are a number of uses for these STSs, including the rapid development of various linkage tools and the rapid testing of genomic and cDNA libraries for the presence of their corresponding genes. Six of the eleven gene targets reported in detail have been proposed to serve as “anchored reference loci” for the development of mammalian genetic maps [O'Brien, S. J.,et al., Nat. Genet. 3:103, 1993]. The primer sets should cover a significant portion of the canine genome for the development of a linkage map. In order to determine how useful these primer sets would be for the other genome projects, we tested the 11 primer sets on the DNA from species representing five mammalian orders. Eighty-four percent of the gene-species combinations amplified successfully. We have named these primer sets “universal mammalian sequence-tagged sites” because they should be useful for many mammalian genome projects.
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    URL: http://dx.doi.org/10.1007/BF02399951
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    Elongation factor 1α genes of the red alga Porphyra purpurea include a novel, developmentally specialized variant (1996)
    Springer
    Plant molecular biology 31 (1996), S. 77-85 
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    ISSN: 1573-5028
    Keywords: developmental regulation ; elongation factor ; evolution ; gene expression ; rhodophyte, sporophyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The life cycle of the red alga Porphyra purpurea alternates between two morphologically distinct phases: a shell-boring, filamentous sporophyte and a free-living, foliose gametophyte. From a subtracted cDNA library enriched for sporophyte-specific sequences, we isolated a cDNA encoding an unusual elongation factor 1α (EF-1α) that is expressed only in the sporophyte. A second EF-1α gene that is expressed equally in the sporophyte and the gametophyte was isolated from a genomic library. These are the only EF-1α genes detectable in P. purpurea. The constitutively expressed gene encodes and EF-1α very similar to those of most eukaryotes. However, the sporophyte-specific EF-1α is one of the most divergent yet described, with nine insertions or deletions ranging in size from 1 to 26 amino acids. This is the first report of a developmental stage-specific EF-1α outside of the animal kingdom and suggests a fundamental role for EF-1α in the developmental process.
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    Regulation, unique gene organization, and unusual primary structure of carbon fixation genes from a marine phycoerythrin-containing cyanobacterium (1996)
    Springer
    Plant molecular biology 32 (1996), S. 1103-1115 
    Details
    ISSN: 1573-5028
    Keywords: carboxysomes ; evolution ; ribulose 1,5-bisphosphate carboxylase/oxygenase ; Synechococcus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Marine phycoerythrin-containing cyanobacteria are major contributors to the overall productivity of the oceans. The present study indicates that the structural genes of the carbon assimilatory system are unusually arranged and possess a unique primary structure compared to previously studied cyanobacteria. Southern blot analyses of Synechococcus sp. strain WH7803 chromosomal DNA digests, using the ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) large subunit gene from Synechococcus sp. strain PCC6301 as a heterologous probe, revealed the presence of a 6.4 kb HindIII fragment that was detectable at only low stringency. Three complete open reading frames (ORFs) were detected within this fragment. Two of these ORFs potentially encode the Synechococcus sp. strain WH7803 rbcL and rbcS genes. The third ORF, situated immediately upstream from rbcL, potentially encodes a homologue of the ccmK gene from Synechococcus sp. strain PCC7942. The deduced amino acid sequences of each of these ORFs are more similar to homologues among the β/γ purple bacteria than to existing cyanobacterial homologues and phylogenetic analysis of the Rubisco large and small subunit sequences confirmed an unexpected relationship to sequences from among the β/γ purple bacteria. This is the first instance in which the possibility has been considered that an operon encoding three genes involved in carbon fixation may have been laterally transferred from a purple bacterium. Analysis of mRNA extracted from cells grown under diel conditions indicated that rbcL, rbcS and ccmK were regulated at the transcriptional level; specifically rubisco transcripts were highest during the midday period, decreased at later times during the light period and eventually reached a level where they were all but undetectable during the dark period. Primer extension analysis indicated that the ccmK, rbcL and rbcS genes were co-transcribed.
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    Molecular characterization of a phosphoenolpyruvate carboxylase in the gymnosperm Picea abies (Norway spruce) (1996)
    Springer
    Plant molecular biology 32 (1996), S. 923-936 
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    ISSN: 1573-5028
    Keywords: PEPC ; C3 metabolism ; gene expression ; evolution ; gymnosperm ; Picea abies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Phosphoenolpyruvate carboxylase (PEPC) genes and cDNA sequences have so far been isolated from a broad range of angiosperm but not from gymnosperm species. We constructed a cDNA library from seedlings of Norway spruce (Picea abies) and identified cDNAs coding for PEPC. A full-length PEPC cDNA was sequenced. It consists of 3522 nucleotides and has an open reading frame (ORF) that encodes a polypeptide (963 amino acids) with a molecular mass of 109 551. The deduced amino acid sequence revealed a higher similarity to the C3-form PEPC of angiosperm species (86–88%) than to the CAM and C4 forms (76–84%). The putative motif (Lys/Arg-X-X-Ser) for serine kinase, which is conserved in all angiosperm PEPCs analysed so far, is also present in this gymnosperm sequence. Southern blot analysis of spruce genomic DNA under low-stringency conditions using the PEPC cDNA as a hybridization probe showed a complex hybridization pattern, indicating the presence of additional PEPC-related sequences in the genome of the spruce. In contrast, the probe hybridized to only a few bands under high-stringency conditions. Whereas this PEPC gene is highly expressed in roots of seedlings, a low-level expression can be detected in cotyledons and adult needles. A molecular phyiogeny of plant PEPC including the spruce PEPC sequence revealed that the spruce PEPC sequence is clustered with monocot and dicot C3-form PEPCs including the only dicot C4 form characterized so far.
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    Genetic and morphological divergence in theAndrocymbium gramineum complex (Colchicaceae) (1996)
    Springer
    Plant systematics and evolution 201 (1996), S. 149-162 
    Details
    ISSN: 1615-6110
    Keywords: Colchicaceae ; Androcymbium ; Allozymes ; morphology ; endemism ; evolution ; conservation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Narrow endemism is a poor predictor of genetic potential in the six taxa that conform theAndrocymbium gramineum complex, as shown by the unexpectedly high values of variability associated with ten allozymic loci and 13 biometrical variables. Although both levels are shown not to be correlated, variability is always concentrated within populations. This result, together with environmental, reproductive and historical data strongly suggests differentiation in local isolates, where changes can be quickly assimilated by stochastic processes. A key implication for conservation is that sampling within the largest population will save effort while neglecting only very low frequency alleles.
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    Luzula sect.Luzula (Juncaceae) in Spain (1996)
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    Plant systematics and evolution 200 (1996), S. 1-11 
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    ISSN: 1615-6110
    Keywords: Juncaceae ; Luzula sect.Luzula ; Taxonomy ; karyotypes ; evolution ; Flora of Spain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A survey ofLuzula sect.Luzula (Juncaceae) with data on karyology, morphology and distribution in the Iberian Peninsula is provided. Names published from the region are evaluated.L. campestris subsp.campestris, L. c. subsp.nevadensis, L. sudetica, L. ×heddae, L. congesta, L. ×danica, L. alpina, L. multiflora, andL. multiflora s. l. are discussed. A diploid taxon with agmatoploid karyotype, morphologically close toL. multiflora andL. alpina, has been revealed and is described asL. multiflora subsp.monticola. L. campestris subsp.iberica has been relegated to the synonymy of subsp.campestris, L. c. subsp.carpetana was found to belong toL. multiflora s. l.
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    Species boundaries, phylogenetic relationships, and ecological differentiation inAnthriscus (Apiaceae) (1996)
    Springer
    Plant systematics and evolution 199 (1996), S. 17-32 
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    ISSN: 1615-6110
    Keywords: Apiaceae ; Umbelliferae ; Anthriscus ; Taxonomy ; phylogeny ; evolution ; ecological radiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Species boundaries and phylogenetic relationships of 17 taxa ofAnthriscus (Apiaceae), with special emphasis on the critical sect.Cacosciadium, were explored using morphological data with principal component analysis, phenetics, and phylogenetics. The analyses did not provide satisfactory resolution of taxa from sect.Cacosciadium and only four species were retained. The total number of species was reduced to nine. Sect.Cacosciadium is distinguished by only two synapomorphies while sects.Anthriscus andCaroides are better supported. Present geographic and ecological variation suggests that the radiation ofAnthriscus occurred through divergence of peripheral isolated populations adapting to different habitats: high montane meadows and screes, shady climax forests, and seasonally dry habitats at lower altitudes. The adaptive significance of particular morphological traits is discussed.
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    Enzyme analysis of genetic variation and relationships in diploid and polyploid taxa ofGalium (Rubiaceae) (1996)
    Springer
    Plant systematics and evolution 202 (1996), S. 121-135 
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    ISSN: 1615-6110
    Keywords: Rubiaceae ; Galium ; Allozyme variation ; systematics ; ploidy level ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Allozyme variation at 11 loci (with 37 alleles) was studied electrophoretically in seven outbreeding, closely related diploid and tetraploid taxa, seven from sect.Leptogalium and two from sect.Leiogalium. Whereas the sections are clearly distinct by several different alleles, aggregates, species and subspecies differ only in the frequency or presence/absence of common alleles. The resulting dendrogram suggests phylogenetic relationships and is supported by other multidisciplinary evidence. Tetraploids have originated independently in several groups, and there is evidence for tetrasomic inheritance and thus for autopolyploidy in spite of normal meiotic bivalent pairing and partly suspected hybrid origin. Tetraploids differ from related diploids only little in number of alleles and expected heterozygosity within populations, but clearly exhibit higher numbers of genotypes. This often corresponds to their greater morphological variability, increased adaptive flexibility, and better colonizing capacity compared to related diploids.
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    Cytological variation and evolution withinPelargonium sectionHoarea (Geraniaceae) (1996)
    Springer
    Plant systematics and evolution 203 (1996), S. 111-142 
    Details
    ISSN: 1615-6110
    Keywords: Pelargonium ; sect.Hoarea ; Chromosomes ; B chromosomes ; Robertsonian translocation ; centric fusion ; evolution ; systematics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Chromosome numbers of 65 species of sect.Hoarea have been determined. These show three basic chromosome numbers, x = 11, 10 and 9. Only a few species are tetraploid. In five species both diploid and tetraploid cytotypes are reported. Several cases of deviations in chromosome numbers and cytological abnormalities were found, most of these being related to the presence of B chromosomes that occur in eight species. Evidence is presented to suggest that the basic chromosome numbers of x = 10 and x = 9 are derived from x = 11 by centric fusion. Although variation in basic chromosome number withinPelargonium has been the subject of detailed study, this is the first time that evidence has been found for a mechanism of change in basic number, that of centric fusion by Robertsonian translocation. For the species of sect.Hoarea with x = 9, where the evidence for Robertsonian translocation is greatest, this process has probably taken place quite recently. In contrast to results from other sections of the genusPelargonium, the three different basic numbers of sect.Hoarea do not contradict its delimitation as a natural taxon.
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    Can biology make ethics objective? (1996)
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    Biology and philosophy 11 (1996), S. 21-31 
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    ISSN: 1572-8404
    Keywords: Morality ; evolution ; justification ; objectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract A familiar position regarding the evolution of ethics is that biology can explain the origin of morals but that in doing so it removes the possibility of their having objective justification. This position is set fourth in detail in the writings of Michael Ruse (1986, 1987, 1989, 1990a, 1990b) but it is also taken by many others, notably, Jeffrie Murphy (1982), Andrew Oldenquist (1990), and Allan Gibbard (1990), I argue the contrary view that biology provides a justification of the existence of morals which is objective in the sense of being independent of people's moral views and their particular desires and preferences. Ironically, my argument builds on the very premises which are supposed to undermine the objectivity of morals. But my argument stops short of claiming that biology can give us a basis for justifying some particular system of morals. Drawing on an analogy with social contract theory, I offer a general reason why this more ambitious project cannot be expected to succeed if the argument is pursued along the same lines. Finally, I give reasons why the possibility of objective justification for a particular morality cannot be ruled out in general on evolutionary grounds.
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    Natural selection and self-organization (1996)
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    Biology and philosophy 11 (1996), S. 33-65 
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    ISSN: 1572-8404
    Keywords: Background assumptions ; Darwinism ; evolution ; Newtonian dynamics ; nonequilibrium thermodynamics ; nonlinear dynamics ; probability revolution ; selection ; self-organization ; systems dynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract The Darwinian concept of natural selection was conceived within a set of Newtonian background assumptions about systems dynamics. Mendelian genetics at first did not sit well with the gradualist assumptions of the Darwinian theory. Eventually, however, Mendelism and Darwinism were fused by reformulating natural selection in statistical terms. This reflected a shift to a more probabilistic set of background assumptions based upon Boltzmannian systems dynamics. Recent developments in molecular genetics and paleontology have put pressure on Darwinism once again. Current work on self-organizing systems may provide a stimulus not only for increased problem solving within the Darwinian tradition, especially with respect to origins of life, developmental genetics, phylogenetic pattern, and energy-flow ecology, but for deeper understanding of the very phenomenon of natural selection itself. Since self-organizational phenomena depend deeply on stochastic processes, self-organizational systems dynamics advance the probability revolution. In our view, natural selection is an emergent phenomenon of physical and chemical selection. These developments suggest that natural selection may be grounded in physical law more deeply than is allowed by advocates of the autonomy of biology, while still making it possible to deny, with autonomists, that evolutionary explanations can be modeled in terms of a deductive relationship between laws and cases. We explore the relationship between, chance, self-organization, and selection as sources of order in biological systems in order to make these points.
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    Explanatory pluralism in evolutionary biology (1996)
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    Biology and philosophy 11 (1996), S. 193-214 
    Details
    ISSN: 1572-8404
    Keywords: Adaptationism ; avatars ; competition ; explanation ; evolution ; macroevolution ; optimality ; reductionism ; species selection ; species sorting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract The ontological dependence of one domain on another is compatible with the explanatory autonomy of the less basic domain. That autonomy results from the fact that the relationship between two domains can be very complex. In this paper I distinguish two different types of complexity, two ways the relationship between domains can fail to be transparent, both of which are relevant to evolutionary biology. Sometimes high level explanations preserve a certain type of causal or counterfactual information which would be lost at the lower level; I argue that this is central to the proper understanding of the adaptationist program. Sometimes high level kinds are multiply realised by lower level kinds: I argue that this is central to the understanding of macroevolution.
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    The individuality of the species: A Darwinian theory? — from Buffon to Ghiselin, and back to Darwin (1996)
    Springer
    Biology and philosophy 11 (1996), S. 215-244 
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    ISSN: 1572-8404
    Keywords: Classes ; classification ; evolution ; Buffon ; Darwin ; Ghiselin ; individuality ; ordering ; concept of species
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract Since the 1970s, there has been a tremendous amount of literature on Ghiselin's proposal that “species are individuals”. After recalling the origins and stakes of this thesis in contemporary evolutionary theory, I show that it can also be found in the writings of the French naturalist Buffon in the 18th Century. Although Buffon did not have the conception that one species could be derived from another, there is an interesting similarity between the modern argument and that of Buffon regarding the “individuality of species’. The analogy is strong enough to force us to recognize that genuine evolutionary (or Darwinian) questions might be of secondary importance in the discussion. In consequence, the third section of the paper proposes an alternative schema for the “logical structure” of the Darwinian concept of species. Darwin distinguished the problem of the designation of a concrete species, and the problem of its signification of species within his theory of descent? The resulting notion of species involves a logical structure based on the fusion of the logical operations of classification and ordering. The difficulty — and interest — is that this interpretation of species does not entail any precise operational definition of species; it can only tell us what the ultimate signification of classification is within the theory of descent with modification through natural selection.
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    The extended replicator (1996)
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    Biology and philosophy 11 (1996), S. 377-403 
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    ISSN: 1572-8404
    Keywords: development ; developmental systems ; gene ; genetic information ; evolution ; information ; inheritance ; interactor ; Lamarck ; Meme ; replicator ; selection ; unit of selection ; vehicle ; Weismann
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract This paper evaluates and criticises the developmental systems conception of evolution and develops instead an extension of the “gene's eye” conception of evolution. We argue (i) Dawkin's attempt to segregate developmental and evolutionary issues about genes is unsatisfactory. On plausible views of development it is arbitrary to single out genes as the units of selection. (ii) The genotype does not carry information about the phenotype in any way that distinguishes the role of the genes in development from that other factors. (iii) There is no simple and general causal criterion which distinguishes the role of genes in development and evolution. (iv) There is, however, an important sense in which genes but not every other developmental factor represent the phenotype. (v) The idea that genes represent features of the phenotype forces us to recognise that genes are not the only, or almost the only, replicators. Many mechanisms of replication are involved in both development and evolution. (vi) A conception of evolutionary history which recognises both genetic and non-genetic replicators, lineages of replicators and interactors has advantages over both the radical rejection of the replicator/interactor distinction and the conservative restriction of replication to genetic replication.
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    Changing conceptions of species (1996)
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    Biology and philosophy 11 (1996), S. 405-420 
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    ISSN: 1572-8404
    Keywords: species ; evolution ; natural selection ; gradualism ; punctuated equilibria ; variation ; Lamarck ; Darwin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract Species are thought by many to be important units of evolution. In this paper, I argue against that view. My argument is based on an examination of the role of species in the synthetic theory of evolution. I argue that if one adopts a gradualist view of evolution, one cannot make sense of the claim that species are “units” in the minimal sense needed to claim that they are units of evolution, namely, that they exist as discrete entities over time. My second argument is directed against an appeal to Eldredge and Gould's theory of punctuated equilibria to support the claim that species are units of evolution. If one adopts their view, it may be possible to identify discrete temporal entities that can plausibly be termed ‘species’, but there is no reason to claim that those entities are “units of evolution”. Thus, on two plausible interpretations of the role of natural selection in the process of evolution, species are of no special importance. I then consider some of the reasons why species have been thought to be important evolutionary units by many contemporary evolutionary biologists. Finally, I discuss briefly the implications of this conclusion for evolutionary biology.
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    Naturalism, evidence and creationism: The case of Phillip Johnson (1996)
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    Biology and philosophy 11 (1996), S. 543-559 
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    ISSN: 1572-8404
    Keywords: Creationism ; evidence ; evolution ; naturalism ; Phillip Johnson ; scientific methodology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract Phillip Johnson claims that Creationism is a better explanation of the existence and characteristics of biological species than is evolutionary theory. He argues that the only reason biologists do not recognize that Creationist's negative arguments against Darwinism have proven this is that they are wedded to a biased ideological philosophy —Naturalism — which dogmatically denies the possibility of an intervening creative god. However, Johnson fails to distinguish Ontological Naturalism from Methodological Naturalism. Science makes use of the latter and I show how it is not dogmatic but follows from sound requirements for empirical evidential testing. Furthermore, Johnson has no serious alternative type of positive evidence to offer for Creationism, and purely negative argumentation, despite his attempt to legitimate it, will not suffice.
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    Some Nonhuman Animals Can Have Pains in a Morally Relevant Sense (1996)
    Springer
    Biology and philosophy 12 (1996), S. 51-71 
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    ISSN: 1572-8404
    Keywords: philosophy of mind ; ethics ; animal pain ; Peter Carruthers ; consciousness ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract In a series of works, Peter Carruthers has argued for the denial of the title proposition. Here, I defend that proposition by offering direct support drawn from relevant sciences and by undercutting Carruthers‘ argument. In doing the latter, I distinguish an intrinsic theory of consciousness from Carruthers‘ relational theory of consciousness. This relational theory has two readings, one of which makes essential appeal to evolutionary theory. I argue that neither reading offers a successful view.
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    URL: http://dx.doi.org/10.1023/A:1017933132500
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    Clinical and pharmacokinetic phase I trial of oral dimethylaminoetoposide (NK611) administered for 21 days every 35 days (1996)
    Springer
    Investigational new drugs 14 (1996), S. 379-386 
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    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were évaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2α ranged from 0.47 to 1.54 h and t1/2β from 2.0–11.6 h. Mean values for C max and AUC were 1.47 ± 0.331 μg/ml and 13.67±3.81 μg/ml·h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day.
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    Interspecies Scaling of Bosentan, A New Endothelin Receptor Antagonist and Integration of in Vitro Data into Allometric Scaling (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 97-101 
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    ISSN: 1573-904X
    Keywords: allometric scaling ; interspecies scaling ; pharmacokinetics ; clearance ; in vitro models ; bosentan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans. Methods. One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling. Results. The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight). Conclusions. This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.
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    Percutaneous Absorption of Ketoprofen from Different Anatomical Sites in Man (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 168-172 
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    ISSN: 1573-904X
    Keywords: ketoprofen ; nonsteroidal anti-inflammatory agent ; topical application ; percutaneous absorption ; regional variation ; pharmacokinetics ; urinary excretion ; enantiomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. Methods. The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. Results. The relative bioavailabilities of ketoprofen gel were 0.90 ± 0.50, 1.08 ± 0.63, and 0.74 ± 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen Cmax for gel applied to the back and arm were similar (p 〉 0.05) but Cmax was lower when applied to the knee (p 〈 0.05). The time to Cmax ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. Conclusions. The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.
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    Pharmacokinetics of eltanolone following bolus injection and constant rate infusion (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 535-549 
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    ISSN: 1573-8744
    Keywords: eltanolone ; pregnanolone ; Kabi 2213 ; context sensitive time ; anaesthesia ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis, the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80 (0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of 35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5). The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained after bolus injection were very much similar to the parameters obtained after infusion with the exception of t1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration, is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70–80 min following an infusion of 10 hr.
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    Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 313-325 
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    ISSN: 1573-8744
    Keywords: etoposide ; etoposide phosphate ; bioequivalence ; pharmacokinetics ; pharmacodynamics ; humans ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m2 per day etoposide equivalent dose infused iv over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, Cmax, and AUC0-∞, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.
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    In vivo relationships between the cerebral pharmacokinetics and pharmacodynamics of thiopentone in sheep after short-term administration (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 1-18 
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    ISSN: 1573-8744
    Keywords: thiopentone ; pharmacokinetics ; pharmacodynamics ; brain ; cerebral blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The cerebral kinetics and dynamics of thiopentone after infusions of 250, 500, and 750 mg over 2 min were examined in chronically instrumented sheep (6, 6, and 5 sheep per dose, respectively). The cerebral kinetics were studied by rapid sampling of arterial and dorsal sagittal sinus blood (afferent and efferent blood for the brain, respectively) for 40 min, and could be described by a single flow-limited compartment when arterial concentrations and cerebral blood flow were used as forcing input functions. The half-lives of equilibration between blood and the brain were estimated to be 0.67 (SEM=0.07), 0.57 (0.03) and 0.74 (0.05) min for the 250-, 500- and 750-mg doses, respectively, showing that the cerebral concentrations of thiopentone rapidly equilibrate with the afferent blood concentration. Simultaneous pharmacodynamic measurements included cerebral blood flow via a Doppler flowmeter on the sagittal sinus, and an index of the depth of anesthesia based on an algesimetry method. Thiopentone transiently reduced cerebral blood flow to 82 (SEM=3), 80% (7), and 74% (10) of baseline for the 250−, 500−, and 750-mg doses, respectively, and failure to account for drug-induced changes in cerebral bloof flow in the model overestimated the apparent volume of the brain by 12% for the 500-mg dose. For the 500-mg dose, the changes in cerebral blood flow could be accounted for by an effect compartment with a half-life of 0.82 min for arterial blood, and 0.00 min for sagittal sinus blood, showing the effluent brain concentrations were in equilibrium with this drug effect. The time course of the depth of anesthesia for the 250-mg dose could be accounted for by an effect compartment with a half-life of 1.33 min for arterial blood, and 0.41 min for sagittal sinus blood. Thus, the rate of equilibration between blood and brain could not account for all of this delay. It is concluded that after short-term administration thiopentone equilibrated rapidly with the brain, and that this is consistent with the observation that the magnitude of its clinically relevant effects closely follow the time course of the arterial blood concentrations.
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    Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 551-568 
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    ISSN: 1573-8744
    Keywords: azosemide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various segments of GI tract
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Azosemide, 5, 10, 20, and 30 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of azosemide in rats (n=7–12). The absorption of azosemide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of azosemide after oral administration were also investigated. After intravenous (iv) dose, the pharmacokinetic parameters of azosemide such ast 1/2, MRT, VSS, CL, CLR, and CLNR were found to be dose-dependent in the dose ranges studied. The percentages of the iv dose excreted in 8-hr urine as azosemide, MI (a metabolite of azosemide), glucuronide of azosemide, and glucuronide of MI—expressed in terms of azosemide—were also dose-dependent in the dose ranges studied. The data above suggest saturable metabolism of azosemide in rats. The measurements taken after the iv administrations such as the 8 hr urine output, the total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight, and diuretic, natriuretic, kaluretic, and chloruretic efficiencies were also shown to be dose-dependent. However, the total amount of potassium excreted in 8-hr urine per 100 g body weight was dose-independent. Similar dose-dependency was also observed following oral administration. Azosemide was absorbed from all regions of GI tract studied and approximately 93.5, 79.1, 86.1, and 71.5% of the doses (5, 10, 20, and 30 mg/kg, respectively) were absorbed between 1 and 24 hr after oral administration. The appearance of multiple peaks after oral administration is suspected to be due mainly to the gastric emptying pattern. The percentages of azosemide absorbed from the GI tract as unchanged azosemide for up to 24 hr after oral doses of 5, 10, 20, and 30 mg/kg were significantly different with doses (decreased with increasing doses), suggesting that the problem of azosemide precipitating in acidic gastric juices or dissolution may have at least partially influenced the absorption of azosemide after oral administration.
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    A conspectus of the Cladocera of the subterranean waters of the world (1996)
    Springer
    Hydrobiologia 325 (1996), S. 1-30 
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    ISSN: 1573-5117
    Keywords: subterranean Cladocera ; history ; ecology ; adaptation ; evolution ; biogeography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A synthesis of current knowledge of the Cladocera living in non-surface waters is provided. For all 94 species and subspecies recorded (Dec. 1994) we give information on their ranges, ecological characteristics, and a review of literature data. We also give a historic survey of the development of concepts, identify categories among groundwater-dwelling species, and discuss their adaptations and the evolutionary lines present. Of the estimated total of c. 450 non-marine Cladocera of the world, c. 20% may occur in underground aquatic habitats, but true groundwater forms (stygobionts or stygobites) are relatively few, possibly not more than 10 species (c. 2.5% of the total). This number may increase, as attention is given to subterranean habitats outside Europe.
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    Types of diapause in Crustacea: definitions, distribution, evolution (1996)
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    Hydrobiologia 320 (1996), S. 15-26 
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    ISSN: 1573-5117
    Keywords: Crustacea ; diapause ; photoperiod responses ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Definitions of diapause and of the three types of diapause (embryonal, larval and imaginal) as they apply to the Crustacea are given and the distribution of the types among different orders of crustaceans is discussed. A special role of diapause as a way to escape competition among ecologically similar species is noted and the significance of photoperiod responses as a pace-maker of the biorhythmical function of diapause for a wide range of species is demonstrated. A common unspecific regression for the description of oxygen consumption with duration of diapause in crustaceans of different sizes, different orders and different types of diapause is suggested. A special significance of embryonal diapause for the adaptation of palaeo-, meso- and neolimnic species of crustaceans that migrated from the sea into inland waterbodies is postulated.
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    Leeches (Oligochaeta?: Euhirudinea), their phylogeny and the evolution of life-history strategies (1996)
    Springer
    Hydrobiologia 334 (1996), S. 277-285 
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    ISSN: 1573-5117
    Keywords: leech ; oligochaete ; parasite ; evolution ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Powerful tests of adaptational hypotheses can be made in the context of well-supported cladograms by investigating the most parsimonious transformation of intrinsic or extrinsic factors to explain their distribution across taxa in a cladogram. Such tests are used here to discover patterns of life-history evolution in leeches; in particular in relation to exploitation of terrestrial and aquatic habitats, parental care and resource utilization. Moreover, the relationships among leeches, acanthobdellids and branchiobdellids is reaffirmed as is their collective placement within the oligochaetes.
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    Diapause, a potent force in the evolution of freshwater crustaceans (1996)
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    Hydrobiologia 320 (1996), S. 1-14 
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    ISSN: 1573-5117
    Keywords: diapause ; freshwater Crustacea ; antiquity ; diversity ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract After a brief historical review of the discovery of diapause in freshwater crustaceans, its dramatic nature in certain cyclopoid copepods, in which diapausing individuals may occur at densities of 〉 106 per m2, is used to illustrate the enormous ecological significance of the phenomenon. Some of the problems presented by dispause in cyclopoid copepods are noted, including the different behaviour in different lakes of what appears to be a single species. Different physiological cues or different genetic endowments are clearly involved. The wider incidence of diapause in freshwater copepods and ostracods is noted. Among freshwater crustaceans it it the Branchiopoda that have universally adopted diapause, always at the egg stage. Even such an ancient order as the Anostraca, perhaps the most primitive of all crustaceans, produces elaborately constructed resting eggs that are capable of cryptobiosis, can remain viable in a dry state for long periods, and can tolerate extreme conditions. The nature of branchiopod resting eggs is briefly reviewed. Of these, only those of the Anomopoda are protected by containers derived from the parental carapace. These are mechanically complex in the most advanced species but, as shown by fossils, are extremely ancient structures. Factors initiating the onset and termination of diapause in branchiopods are briefly noted, and the process of hatching of resting eggs is outlined.
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    Larval development of Octomeris sulcata Nilsson-Cantell (Cirripedia: Thoracica: Chthamalidae) from Japan and Korea (1996)
    Springer
    Hydrobiologia 325 (1996), S. 65-76 
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    ISSN: 1573-5117
    Keywords: Larval development ; chthamalid barnacle ; Octomeris sulcata ; food preference ; evolution ; gnathobase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Embryos obtained from gravid adults of the chthamalid barnacle Octomeris sulcata Nilsson-Cantell from Japan and Korea were cultured through six naupliar stages to the cyprid and juvenile barnacle stage in laboratory conditions, fed either the diatom Skeletonema costatum (Grev.) Cleve or the dinoflagellate Prorocentrum minimum (Pavillard) Schiller. The nauplii were planktotrophic and, depending on diet, reached the cyprid stage 9 or 17 days after hatching in individual cultures at 22 °C with 24 h illumination. The survival rate was higher and the duration of the naupliar stages was shorter when fed P. minimum rather than S. costatum. This is probably due to the presence of feathered setae on the antennae. Feathered or plumose setae in nauplii of different cirripede taxa are apparently linked to the type of phytoplankton in the seas when these taxa first evolved. The larval stages of O. sulcata are described, and morphological differences between larvae reared from Japanese andKorean adults are compared. The polygonal cephalic shield and unilobed labrum, a pair of posterior shield spines after naupliar stage IV, feathered setae and a hispid seta on the coxa of the antenna, a cuspidate seta on the mandible, and the gnathobase of the antenna are important in distinguishing the nauplii of this species from other species, including Chthamalidae.
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    Comparative fluorescencein situ hybridization mapping of primate chromosomes withAlu polymerase chain reaction generated probes from human/rodent somatic cell hybrids (1996)
    Springer
    Chromosome research 4 (1996), S. 38-42 
    Details
    ISSN: 1573-6849
    Keywords: chromosome ; evolution ; FISH ; intrachromosomal rearrangements ; phylogeny ; subregional chromosome painting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We have usedAlu polymerase chain reaction generated probes from rearranged human/rodent somatic cell hybrids for fluorescencein situ hybridization and comparative mapping of some intrachromosomal changes in the karyotypes of great apes (Pan troglodytes, P. paniscus, Gorilla gorilla Pongo pygmaeus), a gibbon (Hylobates lar), and an Old World monkey (Macaca fuscata). Probes containing chromosomes 2 and 18 fragments confirmed inversions already suggested by the banding pattern of great ape homologues. However, a chromosome 3 fragment showed complex rearrangements in the gibbon and macaque karyotype which were previously not well defined from banding. ‘Subchromosomal painting’ will allow the identification of intrachromosomal changes on the basis of DNA homology and provides a powerful method to study karyological and genomic evolution.
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    URL: http://dx.doi.org/10.1007/BF02254943
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    Multiple selection responses in house mice bidirectionally selected for thermoregulatory nest-building behavior: Crosses of replicate lines (1996)
    Springer
    Behavior genetics 26 (1996), S. 439-446 
    Details
    ISSN: 1573-3297
    Keywords: Heterosis ; nest-building behavior ; Mus domesticus ; selection ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Psychology
    Notes: Abstract Replicate high-selected, control, and low-selected lines were crossed at generation 46 of bidirectional selection for thermoregulatory nest-building behavior. Previous analysis of the lines at their limits had revealed multiple responses to uniform selection, where each of the four selected lines responded differently to reverse selection (Laffan, 1989). The reciprocal F1 crosses showed significant heterosis for nest-building behavior compared to the contemporaneous generations of the parental lines. This pattern of heterosis in all three crosses is consistent with the finding that nest-building behavior in each of the four replicate lines had a different genetic basis, in spite of the phenotypic similarity between the two replicate lines in the high and low direction of nesting. This heterosis effect and the larger number of young weaned in all three crosses compared to their respective contemporaneous generation of the parental lines also support earlier findings that larger nests are closely related to fitness.
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    URL: http://dx.doi.org/10.1007/BF02359488
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    Multiple solutions, illegal parameter values, local minima of the sum of squares, and anomalous parameter estimates in least-squares fitting of the two-compartment pharmacokinetic model with absorption (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 79-101 
    Details
    ISSN: 1573-8744
    Keywords: two-compartment model ; parameter estimation ; least squares ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract When the two-compartment model with absorption is fitted to data by nonlinear least squares, in general six different outcomes can be obtained, arising from permutation of the three exponential rate constants. The existence of multiple solutions in this sense is analogous to the flip-flop phenomenon in the one-compartment model. It is possible for parameter estimates to be inconsistent with the underlying physical model. Methods for recognizing such illegal estimates are described. Other common difficulties are that estimated values for two of the rate constants are almost identical with very large standard deviations, or that the parameter estimation algorithm converges poorly. Such unwanted outcomes usually signal a local (false) minimum of the sum of squares. They can be recognized from the ratio of largest to smallest singular value of the Jacobian matrix, and are, in principle, avoidable by starting the estimation algorithm with different initial values. There also exists a class of data sets for which all outcomes of fitting the usual equations are anomalous. A better fit to these data sets (smaller sum of squares) is obtained if two of the relevant rate constants are allowed to take complex conjugate values. Such data sets have usually been described as having “equal rate constants.” A special form of the model equation is available for parameter estimation in this case. Precautions relating to its use are discussed.
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    URL: http://dx.doi.org/10.1007/BF02353511
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    Genetic variation and phenotypic plasticity in a trophically polymorphic population of pumpkinseed sunfish (Lepomis gibbosus) (1996)
    Springer
    Evolutionary ecology 10 (1996), S. 631-652 
    Details
    ISSN: 1573-8477
    Keywords: common environment ; reciprocal transplant ; genetic differentiation ; phenotypic plasticity ; trophic polymorphism ; evolution ; specialization ; fish
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Adaptive variation can exist at a variety of scales in biological systems, including among species, among local populations of a single species and among individuals within a single population. Trophic or resource polymorphisms in fishes are a good example of the lowest level of this hierarchy. In lakes without bluegill sunfish (Lepomis macrochirus), pumpkinseed sunfish (Lepomis gibbosus) can be trophically polymorphic, including a planktivorous limnetic form found in the pelagic habitat, in addition to the usual benthic form found in the littoral zone. In this paper we examine the degree to which morphological differences between the two forms are caused by genetic differences versus phenotypic plasticity. Adults from pelagic and littoral sites in Paradox Lake, NY, were bred separately and their progeny were raised in cages both in the open water and shallow water habitats of an artificial pond. The experimental design permitted two tests of genetic differences between the breeding stocks (in open and shallow water cages, respectively) and two tests of phenotypic plasticity (in the limnetic and benthic offspring, respectively). Limnetic progeny were more fusiform than benthic progeny raised in the same habitat. In addition, progeny of both stocks displayed limnetic-type characteristics when raised in the open water and benthic-type characteristics in the shallow water. Thus, genetic differences and phenotypic plasticity both contributed to the trophic polymorphism. Phenotypic plasticity and genetic differentiation accounted for 53 and 14%, respectively, of the variation in morphology. This study addresses the nature of subtle phenotypic differences among individuals from a single population that is embedded within a complex community, a condition that is likely to be the norm for most natural populations, as opposed to very large differences that have evolved in relatively few populations that reside in species-poor environments.
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    URL: http://dx.doi.org/10.1007/BF01237711
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    Fluconazole Distribution to the Brain: A Crossover Study in Freely-moving Rats Using In Vivo Microdialysis (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1570-1575 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; fluconazole ; pharmacokinetics ; brain distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to determine if the microdialysis sampling technique is feasible to study the central nervous system distributional kinetics of a novel triazole antifungal agent, fluconazole, in an awake, freely-moving rat model, and to determine fluconazole distribution to the extracellular fluid (ECF) of the brain. Methods. The relative recovery of the microdialysis probes (CMA-12) was determined in vitro and in vivo by retrodialysis using UK-54,373, a fluorinated analog of fluconazole. Sprague-Dawley rats received 10 mg/kg and 20 mg/kg fluconazole IV bolus doses in a crossover design, and brain extracellular fluid fluconazole concentrations were monitored using microdialysis and on-line HPLC analysis. The plasma fluconazole concentration vs. time data were determined using sequential blood sampling and HPLC analysis. Results. There was no statistical difference between relative probe recoveries for both fluconazole and UK-54,373, either in vitro or in vivo, and probe recoveries did not change during the course of the in vivo crossover experiment. Fluconazole rapidly distributes into in the brain ECF and the average brain distribution coefficient (brain/plasma AUC ratio) was 0.60 ± 0.18 and was independent of dose. Plasma pharmacokinetic parameters were linear in the dose range studied. Conclusions. Fluconazole rapidly reaches a distributional equilibrium between brain extracellular fluid and plasma, and the distribution to the brain is substantial and not dependent on dose over a two-fold range. Furthermore, the results indicate that microdialysis utilizing UK-54,373 as the in vivo retrodialysis probe calibrator is a feasible method to study the transport of fluconazole into the central nervous system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016048100712
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    Species Difference in the Disposition of Liposomes Among Mice, Rats, and Rabbits: Allometric Relationship and Species Dependent Hepatic Uptake Mechanism (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1049-1054 
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    ISSN: 1573-904X
    Keywords: liposome ; species difference ; pharmacokinetics ; drug delivery system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The species difference in the pharmacokinetics of liposomes was investigated in mice, rats and rabbits. Methods. Liposomes were intravenously injected at doses of 1, 10 and 100 (nmol/g body weight), and the time courses of liposomes in blood, liver and spleen were measured. Pharmacokinetic parameters were regressed as a function of body weight (BW) and dose of liposomes (D). The uptake mechanism of liposomes was also examined with the isolated perfused liver between rats and mice. Results. Mean residence time increased with the increase of BW and D of liposomes. This increase of mean residence time resulted from the decreased total body clearance, which was principally explained by the species difference in the hepatic uptake clearance (CLh) of liposomes. The parameter CLh was regressed well by a multiple regression as a function of BW and D. In this analysis, an exponent for BW was around 0.5, which clearly indicates that smaller animals have higher uptake clearance per unit BW. Immunohistochemical analysis revealed that there was no significant difference in the density of Kupffer cells among these species. This suggest that the species difference in CLh resulted not from the density of Kupffer cells but from the uptake ability of Kupffer cells amoung species. In the isolated perfused liver, the hepatic uptake of liposomes was mainly explained by opsonin dependent uptake in rats, while opsonin independent uptake in mice. Conclusions. These quantitative and qualitative information on the species difference of liposome disposition will provide an useful information for constructing a drug delivery system using liposomes.
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    URL: http://dx.doi.org/10.1023/A:1016058724452
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    Bioequivalence of a Highly Variable Drug: An Experience with Nadolol (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1109-1115 
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    ISSN: 1573-904X
    Keywords: nadolol ; pharmacokinetics ; bioequivalence ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC∞, and Cmax in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC∞. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.
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    URL: http://dx.doi.org/10.1023/A:1016031313065
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    Comparison of Pharmacokinetic Parameters of a Polypeptide, the Bowman-Birk Protease Inhibitor (BBI), and Its Palmitic Acid Conjugate (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1373-1377 
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    ISSN: 1573-904X
    Keywords: pharmacokinetics ; polypeptide ; BBI ; palmitic acid ; conjugation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The alteration of the pharmacokinetic parameters of the poly-peptide BBI through conjugation with palmitic acid was examined. Methods. 125I-BBI or l25I-Pal-BBI was administered iv to 6 week old CF-1 mice at a dose of 3mg/kg. The mice were sacrificed at 5, 10, 20, 60, 120, 240, 360, and 480 min and the total radioactivity was determined for blood and each organ. The blood was analyzed on a Sephadex G-50 size-exclusion column to determine the amount of intact polypeptide present in the blood. From the amount of intact polypeptide at each time point, the pharmacokinetic parameters were determined. Results. By conjugating three palmitic acids to each BBI molecule, the area under the curve (AUC) and mean residence time (MRT) increase by a factor of 10.8 and 2.8, respectively. There was also a difference in the organ distribution between the two treatments; while 125I-BBI was rapidly cleared from the kidneys, l25I-Pal-BBI was predominantly to the liver. Subsequent studies suggested that the binding of the conjugate to non-albumin serum proteins was most likely the cause of the altered pharmacokinetics. Conclusions. The residence time in the blood and the lipophilicity of BBI were increased upon conjugation with palmitic acid through a reversible disulfide linkage. Pharmacokinetic studies showed an increase in the AUC and a decrease in kidney clearance in palmitic acid conjugates, indicating a potential increase of the therapeutic efficacy of the polypeptide drug.
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    URL: http://dx.doi.org/10.1023/A:1016078118033
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    Disposition Characteristics of Plasmid DNA in the Single-pass Rat Liver Perfusion System (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 599-603 
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    ISSN: 1573-904X
    Keywords: plasmid DNA ; liver perfusion ; pharmacokinetics ; gene therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To define the hepatic uptake mechanism of a plasmid DNA, we quantitated the uptake of pCAT (plasmid DNA encoding chloramphenicol acetyltransferase reporter gene fused to simian virus 40 promoter), a model plasmid, after a single pass through the perfused rat liver using albumin- and erythrocyte-free Krebs-Ringer bicarbonate buffer (pH 7.4). Methods. [32P]pCAT was introduced momentarily into this system from the portal vein as a bolus input or constant infusion mode, and the outflow patterns and hepatic uptake were evaluated using statistical moment analysis. Results. The venous outflow samples had electrophoretic bands similar to that of the standard pCAT, suggesting that the plasmid is fairly stable in the perfusate during liver perfusion. In bolus experiments, pCAT was largely taken up by the liver and the uptake was decreased with increase in injected dose. Statistical moment analysis against outflow patterns demonstrated that the apparent volume of distribution of pCAT was greater than that of human serum albumin, indicating a significant reversible interaction with the tissues. The results of collagenase perfusion experiments suggest that the hepatic accumulation of pCAT occurred preferentially in the nonparenchymal cells (NPC). The amount of total recovery in the liver decreased substantially by preceding administration of polyinosinic acid, dextran sulfate, succinylated bovine serum albumin, but not by polycytidylic acid. This suggests that pC AT is taken up by the liver via scavenger receptors for polyanions on the NPC. In constant infusion experiments, the presence of 2,4-dinitrophenol and NH4C1 caused a significant increase in the outflow concentration of [32P]pCAT and decrease by half in the total hepatic recovery than that of plasmid DNA administered alone, suggesting that plasmid DNA may undergo internalization by the NPC. Conclusions. The liver plays an important role in the elimination of plasmid DNA and a successful delivery system will be required to avoid its recognition by the scavenger receptors on the liver NPC.
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    URL: http://dx.doi.org/10.1023/A:1016058407671
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    Interspecies Pharmacokinetics of a Novel Hematoregulatory Peptide (SK&F 107647) in Rats, Dogs, and Oncologic Patients (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 794-797 
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    ISSN: 1573-904X
    Keywords: allometric scaling ; peptide ; pharmacokinetics ; hematology ; infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. Methods. Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 ng/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). Results. In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vdss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a·Wb), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vdss, and T1/2 of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. Conclusions. Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.
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    URL: http://dx.doi.org/10.1023/A:1016020221300
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    Macromolecular Carrier Systems for Targeted Drug Delivery: Pharmacokinetic Considerations on Biodistribution (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 820-831 
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    ISSN: 1573-904X
    Keywords: macromolecular carrier ; pharmacokinetics ; targeting ; protein drugs ; gene medicines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokintic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.
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    URL: http://dx.doi.org/10.1023/A:1016084508097
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    Evaluation of Pharmacokinetic Studies: Is It Useful to Take into Account Concentrations Below the Limit of Quantification? (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 839-845 
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    ISSN: 1573-904X
    Keywords: pharmacokinetics ; precision ; accuracy ; limit of quantification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Based on real data, to evaluate the usefulness of taking into account samples with values below the limit of quantification (LOQ) for the evaluation of pharmacokinetic studies. Methods. To compare for two drugs, after single dose administration the pharmacokinetic parameters obtained by using a poorly sensitive assay (PSA) and a highly sensitive assay (HSA), acting as reference; To evaluate the results of pharmacokinetic studies in the light of different values for the LOQ. Results. Under certain conditions, such as homogeneous population, sufficient subject number, sufficient sampling times and acceptable accuracy (CV 〈 20%) for the concentrations, it is possible to get valuable and more reliable kinetic information by using concentrations obtained with a poor precision (CV 〉 20%). This is especially true for the parameters associated with the terminal phase, such as t1/2β and AUC, but also for parameters depending to a lesser extent on the terminal phase, such as tl/2α and AUCtn. Moreover, the mean concentration time curve is by far best defined by using all the concentrations. Conclusions. In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.
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    URL: http://dx.doi.org/10.1023/A:1016088609005
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    A Fractal Approach to Heterogeneous Drug Distribution: Calcium Pharmacokinetics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 663-670 
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    ISSN: 1573-904X
    Keywords: fractal ; fractal kinetics ; calcium kinetics ; heterogeneity ; drug distribution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To point out the importance of heterogeneity in drug distribution processes and develop a noncompartmental approach for the description of the distribution of drug in the body. Methods. A dichotomous branching network of vessels for the arterial tree connected to a similar venous network was used to describe the heterogeneity of blood flow in the successive generations of the networks. The relevant kinetics of drug distribution in the well perfused and the deep tissues was considered to take place under well stirred (homogeneous) and understirred (heterogeneous) conditions, respectively. Results. A “homogeneous model” with classical kinetics (which is mathematically equivalent with the one-compartment model) was developed for these drugs which are confined to well perfused (“well stirred”) spaces. A “heterogeneous model” was proposed for the drugs reaching understirred spaces using a decreasing with time rate coefficient (fractal kinetics) to model the diffusion of drug under heterogeneous conditions. The analysis of the model equations revealed that the homogeneous model can be considered as a special case of the heterogeneous model. Concentration-time plots of multiexponential type were generated using the heterogeneous model equation. The empirically used power functions of time for the analysis of calcium clearance curves, were found to be similar to the equation adhering to the heterogeneous model. Fittings comparable to multiexponential models were obtained when the heterogeneous model equation with only one adjustable parameter was applied to six sets of long period calcium data. Conclusions. The heterogeneous processes of drug distribution in the body can obey the principles of fractal kinetics. Calcium clearance curves were analysed with the heterogeneous model. The validity of multicompartmental models which are based on the concept of homogeneity to describe drug distribution should be reconsidered.
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    URL: http://dx.doi.org/10.1023/A:1016031129053
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    In Vivo ESR Studies on Pharmacokinetics and Metabolism of Parenteral Lipid Emulsion in Living Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 729-733 
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    ISSN: 1573-904X
    Keywords: in vivo ESR ; spin-label ; lipid emulsion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We applied non-invasive and real-time method with in vivo ESR spectroscopy to determining pharmacokinetics and metabolism of lipid emulsion as a drug carrier in living mice. Methods. A spin-labeled triglyceride (SL-TG) was newly synthesized and lipid emulsion containing SL-TG was prepared. In vivo ESR spectra in mice were observed after intravenous administration of the lipid emulsion. Results. In vivo ESR spectra consisted of three components, coinciding with the in vitro spectra of SL-TG particles, free and immobilized fatty acids. The amount of the components depended on both the observing domain and the period after administration. In the chest, all three components were observed, while SL-TG particle was lacking in the abdomen. The half-life of the lipid particles in the chest was 2 hr. Conclusions. Non-invasive and real-time analysis of drug carriers in living animal is successfully accomplished using an in vivo ESR method.
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    URL: http://dx.doi.org/10.1023/A:1016047532687
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    Intravenous Microdialysis in the Mouse and the Rat: Development and Pharmacokinetic Application of a New Probe (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 12-17 
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    ISSN: 1573-904X
    Keywords: intravenous microdialysis sampling ; flurbiprofen ; pharmacokinetics ; rat ; mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A flexible microdialysis probe was designed for intravenous sampling in small laboratory animals. Methods. Surgical techniques were developed to implant this probe via the femoral vein in the vena cava of the mouse and the rat. The in- and outlet of the probe were exteriorized above the tail of the animal and were directly connected to the microsyringe pump for perfusate delivery and to the injection valve for on-line HPLC analysis of the microdialysate samples. Results. The in vitro recoveries of flurbiprofen and naproxen for these probes were 68.2 ± 6.9% (mean ± S.D., n= 12) and 66.5 ± 7.3%, respectively. The relative loss by in vivo retrodialysis, measured the day after the implantation of the probes, was 66.1 ± 8.8% for flurbiprofen and 60.9 ± 9.9% for naproxen. The pharmacokinetics of unbound flurbiprofen were studied following i.v. bolus administration of flurbiprofen to the mouse (n = 4) and the rat (n = 6) with on-line HPLC analysis of microdialysates every 10 minutes during 6 to 8 hours. Flurbiprofen microdialysate concentrations were converted to unbound concentrations using the in vivo loss of flurbiprofen by retrodialysis carried out just before the start of the pharmacokinetic experiment. The integrity of the probe throughout the experiment was monitored by continuous retrodialysis of naproxen. Conclusions. The developed techniques can be used to carry out routine pharmacokinetic studies in the mouse and the rat as illustrated by our experiments with flurbiprofen, a compound with very high plasma protein binding.
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    Pharmacokinetics and Biodistribution of Oligonucleotide Adsorbed onto Poly(isobutylcyanoacrylate) Nanoparticles After Intravenous Administration in Mice (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 38-43 
    Details
    ISSN: 1573-904X
    Keywords: oligonucleotides ; nanoparticles ; pharmacokinetics ; poly(isobutylcyanoacrylate) ; tissue distribution ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to evaluate the ability of nanoparticles to be used as a targeted delivery system for oligonucleotides. Methods. Pharmacokinetic and tissue distribution were carried out in mice by measuring the radioactivity associated to the model oligothymidylate 33P-pdT16 loaded to poly(isobutylcyanoacryrate) (PIBCA) nanoparticles. In addition, we have used a TLC linear analyzer to measure quantitatively on a polyacrylamide gel electrophoresis, the amount of non degraded pdT16 Results. Organ distribution study has shown that nanoparticles deliver 33P-pdT16 specifically to the liver reducing its distribution in the kidney and in the bone marrow. Nanoparticles could partially protect pdT16 against degradation in the plasma and in the liver 5 min after administration, whereas free oligonucleotide was totally degraded at the same time. Conclusions. Nanoparticles protect oligonucleotides in vivo against degradation and deliver them to the liver.
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    URL: http://dx.doi.org/10.1023/A:1016017014573
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    A Pharmacokinetic Approach for Evaluating Cytokine Binding Macromolecules as Antagonists (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 84-90 
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    ISSN: 1573-904X
    Keywords: antibodies ; soluble receptors ; immunoadhesins, cytokines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Cytokine binding macromolecules such as antibodies and soluble receptors sometimes produce undesirable agonist-like activities instead of the expected antagonist-like effects when the cytokine binding macromolecule extends the half-life of a short-lived cytokine. The purpose of this paper is to identify the pharmacokinetic and physicochemical properties that can cause these agonist-like activities. Methods. A simple pharmacokinetic model was used to determine whether a given cytokine binding macromolecule will function effectively as an antagonist in therapeutic situations in which cytokine is released chronically. Results. The model proposed satisfactorily fits experimental data for soluble interleukin-4 receptor and for an anti-interleukin-4 monoclonal antibody under conditions in which agonist-like and antagonist activity are observed. Conclusions. We show that the unexpected agonist-like activities result only when there is nonlinearity in the cytokine-cytokine receptor interaction and the cytokine binding macromolecule prolongs the half-life of the cytokine.
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    URL: http://dx.doi.org/10.1023/A:1016033418207
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    Liposomal Methylprednisolone in Rats: Dose-Proportionality and Chronic-Dose Pharmacokinetics/Pharmacodynamics (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 141-145 
    Details
    ISSN: 1573-904X
    Keywords: liposomes ; methylprednisolone ; pharmacokinetics ; dose dependence ; multiple doses ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. Methods. Male Lewis rats received 10 mg/kg IV bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. Results. Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistance over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg IV doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). Conclusions. These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016054022750
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