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  • phylogeny  (44)
  • pharmacokinetics
  • Springer  (82)
  • MDPI Publishing
  • PANGAEA
  • 1995-1999  (82)
  • 1975-1979
  • 1998  (82)
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  • Springer  (82)
  • MDPI Publishing
  • PANGAEA
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  • 1995-1999  (82)
  • 1975-1979
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  • 1
    Electronic Resource
    Electronic Resource
    Ein Archaeotrogon (Aves: Archaeotrogonidae) aus dem Mittel-Eozän der Grube Messel (Hessen, Deutschland)? (1998)
    Springer
    Journal of ornithology 139 (1998), S. 121-129 
    Details
    ISSN: 1439-0361
    Keywords: fossil birds ; Hassiavis laticauda n. gen. n. sp. ; Archaeotrogonidae Mourer-Chauviré 1980 ; feather preservation ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Ein Vogel aus dem Mittel-Eozän der Grube Messel (Hessen, Deutschland) wird als neue Gattung und Art der Archaeotrogonidae Mourer-Chauviré 1980 beschrieben (incertae sedis). Die Exemplare aus Messel wären die ersten artikulierten Skelette dieser Familie.Hassiavis laticauda n. gen. n. sp. unterscheidet sich vor allem im Bau des Coracoids von der GattungArchaeotrogon Milne-Edwards 1892. Besonders bemerkenswert ist die ausgezeichnete Erhaltung der Flügel- und Schwanzbefiederung einiger Exemplare. Einige Schwanzfedern des Holotypus zeigen eine Querbänderung, welche möglicherweise auf die ursprüngliche Pigmentierung dieser Federn zurückzuführen ist. Die phylogenetische Stellung der Archaeotrogonidae wird diskutiert. Zur Zeit sind keine Synapomorphien bekannt, welche diese Familie mit einer der bestehenden Ordnungen verbinden.
    Notes: Summary A bird from the Middle Eocene of the Grube Messel (Hessen, Deutschland) is described as a new genus and species of the Archaeotrogonidae Mourer-Chauviré 1980 (incertae sedis). The specimens from Messel would be the first articulated skeletons of this family.Hassiavis laticauda n. gen. n. sp. is distinguished from the genusArchaeotrogon Milne-Edwards 1892 in the morphology of the coracoid. The excellent preservation of the wing feathers and those of the tail in several of the specimens is exceptional. Some tail feathers of the holotype are barred, which might be traced back to the original pigmentation of these feathers. The phylogenetic position of the Archaeotrogonidae is discussed. At present no synapomorphies are known, which could set up a closer relationship between this family and one of the existing orders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01651221
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  • 2
    Electronic Resource
    Electronic Resource
    Evolutionary distances and identification of Candida species in clinical isolates by Randomly Amplified Polymorphic DNA (RAPD) (1998)
    Springer
    Mycopathologia 142 (1998), S. 57-66 
    Details
    ISSN: 1573-0832
    Keywords: Candida ; identification ; PCR ; phylogeny ; RAPD
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Fast and reliable identification of different species of the genus Candida is important to define adequate therapeutic decisions, because the different species have highly variable susceptibilities to antifungal drugs; azoles and amphothericin B. Accurate statistical records on case history and epidemiological studies also depend on effective identification. To address this problem we established a RAPD method that enabled direct identification of five very common species of Candida. Initially, reference band patterns were established for C. albicans, C. tropicalis, C. parapsilosis, C. glabrata and C. krusei. One of the primers, M2, showed remarkably conserved intra-specific patterns of approximately 10 bands each, ranging in size from 2.0 to 0.1 kb. These patterns were significantly different and species-specific. Few bands were conserved between different species of Candida, which was assumed to be consistent with their phylogenetic relatedness. In addition, band patterns were constant and reproducible and DNA isolated from single colonies yielded sufficient DNA for identification. The reference band patterns were then used, in blind experiments, to identify species of Candida in 50 randomly chosen samples, including clinical isolates and ATCC strains. RAPD results were 100% consistent with results obtained by conventional diagnostic methods and were achieved in one day instead of several days taken by conventional methods. Because ideal identification methods should be consistent with phylogeny and taxonomy we tested whether RAPD could be used to calculate genetic distances. Comparison of RAPD phylogenetic trees with 18S rRNA trees showed significant differences in tree topologies which indicated that RAPD data could not accurately measure the relative distances between different species. Also, computer simulations of RAPD random patterns were used to test whether the observed degree of RAPD band pattern similarities could occur at random. These simulations suggested that the level of inter-specific band pattern similarities observed in our data could be obtained at random, while intra-specific pattern similarities could not. RAPD would be helpful to discriminate between isolates but not to quantitate the differences. We suggest that the inaccurate estimate of genetic distances from RAPD is a general limitation of the technique and not a specific problem of our identification method. Because of the repetitive character of the target sequences, genetic distances calculated from RAPD could be affected by paralogy, namely, recombination and duplication events not parallel with speciation events.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006998325716
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  • 3
    Electronic Resource
    Electronic Resource
    Mitochondrial DNA analysis of Sporothrix schenckii in North and South America (1998)
    Springer
    Mycopathologia 142 (1998), S. 115-118 
    Details
    ISSN: 1573-0832
    Keywords: epidemiology ; mitochondrial DNA ; phylogeny ; restriction fragment length polymorphism (RFLP) ; Sporothrix schenckii
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Mitochondrial DNA (mtDNA) types based on restriction fragment length polymorphism (RFLP) patterns with HaeIII were investigated in clinical isolates of Sporothrix schenckii in North and South America. In addition to 14 mtDNA types (Types 1–14) so far reported, six new mtDNA types, Types 15–20 were found in this study. Type 3 was divided into two subtypes, Subtype 3A and Subtype 3B based on RFLP with Msp1. Type 14 was also divided into three subtypes, Subtype 14A, Subtype 14B and Subtype 14C based on RFLP with Hha1. Nineteen isolates in the United States consisted of 1 isolate of Type 1, 12 of Type 2, 2 of Type 4, 3 of Type 14 (1 of Subtype 14B and 2 of Subtype 14C) and 1 of Type 15. Twenty nine isolates in Venezuela consisted of 13 of Type 3 (Subtype 3B), 6 of Type 4, 1 of Type 18, 3 of Type 19 and 6 of Type 20. Thirteen isolates in Argentina consisted of 2 of Type 3 (Subtype 3A), 4 of Type 4, 4 of Type 16 and 3 of Type 17. One isolate in Brazil was Type 3 (Subtype 3A). Based on the phylogeny of 20 mtDNA types (Types 1–20) constructed by estimating sequence divergences of mtDNA, mtDNA types were clustered into two groups: Group A (Types 1–3, Type 11 and Types 14–19) and Group B (Types 4–10, Types 12–13 and Type 20). These results suggest that S. schenckiiisolates in North and South America mainly belong to Group A.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006952702947
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  • 4
    Electronic Resource
    Electronic Resource
    Cleavase Fragment Length Polymorphism (CFLP): A Methodology to Further Exploit Polymorphisms from PCR Products of Plastid DNA (ptDNA) in Phaseolus (1998)
    Springer
    Plant molecular biology reporter 16 (1998), S. 271-282 
    Details
    ISSN: 1572-9818
    Keywords: CFLP ; Cleavase I ; Phaseolus ; phylogeny ; ptDNA intergenic regions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The CFLP methodology was applied for Cleavase I site detection within ptDNA intergenic regions (atpB-rbcL and rps14-psaB) at both interspecific and intraspecific levels in the genus Phaseolus. Optimal Cleavase I reaction temperature was 55 °C and the semi-dry electrophoretic transfer was more efficient than the original capillary one. Cleavase reactions yield a high number of fragments as compared to PCR-RFLP and allowed differentiation within and between landraces and wild forms of the Lima bean (Phaseolus lunatus L.) originating from Andean and Mesoamerican regions of Latin America. From sequencing data and using stemloop program (GCG, Madison), congruent numbers of hairpins/fragments were identified within the sequences, highlighting the robustness of the Cleavase I. Our results pointed out the ubiquity of short conserved motifs amongst a geographically localized group of species. In the vicinity of these motifs, synapomorphic-like substitutions were frequently observed. A phylogenetic tree based on these sequences is congruent with the CFLP pattern as well as with the widely accepted phylogeny of the genus. The usefulness of this new tool as alternative and/or complementary to PCR-RFLP technology on ptDNA is suggested and discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007500914695
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  • 5
    Electronic Resource
    Electronic Resource
    Phylogenetic analysis and predicted secondary structures of the rDNA internal transcribed spacers of the powdery mildew fungi (Erysiphaceae) (1998)
    Springer
    Mycoscience 39 (1998), S. 441-453 
    Details
    ISSN: 1618-2545
    Keywords: Erysiphaceae ; internal transcribed spacer ; phylogeny ; powdery mildew ; secondary structure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The nucleotide sequences of the internal transcribed spacer (ITS) regions of the ribosomal DNA including the 5.8S rRNA gene and the 5′ end of the 28S rRNA gene have been determined for 19 species in 10 genera of the powdery mildew fungi in order to analyze their phylogenetic relationship. These fungi were divided into two large groups based on the nucleotide length of the ITS regions, and this grouping was in line with that based on the morphological characters of the anamorphic stage rather than the teleomorphic stage. Although the variable ITS sequences were often ambiguously aligned, conserved sites were also found. Thus, a neighbor-joining tree was constructed using the nucleotide sequence data of the conserved sites of the ITS regions, the 5.8S rRNA gene, and the 5′ end of the 28S rRNA gene. The phylogenetic tree displayed the presence of four groups in the powdery mildews, which were distinguished by their morphology and/or host ranges. In the ITS2 region, the presence of a common secondary structure having four hairpin domains was suggested, in spite of the highly variable nucleotide sequences of this region. The predicted secondary structure was supported by the compensatory mutations as well as compensatory conserved sequences and high G+C content in the predicted stem regions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02460905
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  • 6
    Electronic Resource
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    Molecular phylogenetic study of the basidiomycetous anamorphic yeast genusTrichosporon and related taxa based on small subunit ribosomal DNA sequences (1998)
    Springer
    Mycoscience 39 (1998), S. 7-13 
    Details
    ISSN: 1618-2545
    Keywords: phylogeny ; SSU rDNA ; Trichosporon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Small subunit ribosomal DNA sequences of all species of the basidiomycetous anamorphic yeast genusTrichosporon were determined, and phylogenetic trees were constructed by the neighbor-joining and maximum likelihood methods. The sequence data showed that, with the exception ofT. pullulans, the genus is monophyletic, although its members have two different major ubiquinones, Q9 and Q10. The genus can be divided phylogenetically into three major clusters. Species with Q10 as the major ubiquinone constitute a single cluster, while those with Q9 form two clusters.Trichosporon pullulans was phylogenetically distinct from other taxa of the genus. It is located in a cluster containingCystofilobasidium capitatum, Mrakía frigida, Xanthophyllomyces dendrorhous and three species ofUdeniomyces. This result sugests thatT. pullulans does not belong to the genusTrichosporon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02461572
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  • 7
    Electronic Resource
    Electronic Resource
    Morphometric and phylogenetic analysis of theDaviesia ulicifolia complex (Fabaceae, Mirbelieae) (1998)
    Springer
    Plant systematics and evolution 209 (1998), S. 93-122 
    Details
    ISSN: 1615-6110
    Keywords: Fabaceae ; Mirbelieae ; Daviesia ulicifolia ; Phenetics ; ordination ; phylogeny ; morphometric characters ; gap coding ; paraphyly ; species problem ; Flora of Australia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Daviesia ulicifolia is a widespread species that exhibits complex variation throughout its range. Using ordination and cluster analysis of morphometric characters we resolved ten terminal taxa for phylogenetic analysis. A data set including these and five closely related species was coded for a combination of morphometric and qualitative characters and analysed using parsimony. This revealed thatD. ulicifolia is paraphyletic by inclusion ofD. acicularis, D. arenaria andD. microcarpa. One terminal cluster is more similar to an outgroup species (D. arthropoda) than toD. ulicifolia and should be treated as a new species. Given recent theoretical and empirical studies showing paraphyly to be both expected and observed at species level, we propose that all existing species in this group continue to be recognised taxonomically. We suggest subdividingD. ulicifolia into several subspecies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00991527
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  • 8
    Electronic Resource
    Electronic Resource
    Genetic control of fruit polymorphism in the GenusFedia (Valerianaceae) in the light of dimorphic and trimorphic populations ofF. pallescens (1998)
    Springer
    Plant systematics and evolution 210 (1998), S. 199-210 
    Details
    ISSN: 1615-6110
    Keywords: Valerianaceae ; Valerianeae ; Fedia ; Fruit polymorphism ; seed dispersal ; supergene ; genetic control ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The genusFedia consists of three species (F. cornucopiae, F. graciliflora andF. pallescens) of winter annual herbs, endemic to the western Mediterranean Basin. The deciduous terminal fruits of these taxa are polymorphic in the development of their pericarp and/or calyx, and each population is dimorphic or more rarely trimorphic. The three main fruit types are dispersed in several manners, and are specialized for either epizoochory or myrmecochory. On the basis of our experimental study of dimorphic and trimorphic populations ofF. pallescens subsp.pallescens, a genetic model is presented in order to explain the control of this intrapopulational polymorphism. It is postulated that two diallelic loci are tightly linked on the same chromosome in a functional supergene. One allele of each locus displays a dominance effect in the heterozygous state. Within the four possible homologous allelic segments, only two are present in the dimorphic populations, three in the trimorphic ones, and are otherwise associated in diverse combinations in the remaining taxa of the genus. Similar examples of fruit polymorphism are already documented in the tribeValerianeae, subtribeFediinae. The hypothesis is put forward that this fruit polymorphism is a synapomorphy for the subtribe.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00985668
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  • 9
    Electronic Resource
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    Phylogenetic relationships in thePrimulales inferred fromrbcL sequence data (1998)
    Springer
    Plant systematics and evolution 211 (1998), S. 93-102 
    Details
    ISSN: 1615-6110
    Keywords: Primulales ; Primulaceae ; Myrsinaceae ; Theophrastaceae ; DNA ; rbcL sequences ; phylogeny ; classification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A cladistic analysis of phylogenetic relationships in thePrimulales has been conducted, based on nucleotide sequence data from the chloroplast DNA generbcL. The analysis included 16 taxa representing all three families in the order, and also six genera from other orders, viz.Magnolia (Magnoliaceae),Caltha (Ranunculaceae),Geranium (Geraniaceae),Nicotiana (Solanaceae),Diospyros (Ebenaceae), andManilkara (Sapotaceae). Previous cladistic analyses of morphological data have indicated that theTheophrastaceae are monophyletic, and that theMyrsinaceae are paraphyletic if including the genusMaesa. The results of the present work corroborate this conclusion, but also indicate that thePrimulaceae are paraphyletic.Maesa is part of an unresolved clade that also include theTheophrastaceae and thePrimulaceae, and theMyrsinaceae s. str. The latter is part of a monophyletic group also comprising thePrimulaceae-Lysimachiinae andCyclamen. It is concluded that dramatic changes in family circumscriptions are needed in order for taxonomy to reflect strictly monophyletic groups in thePrimulales.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00984914
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  • 10
    Electronic Resource
    Electronic Resource
    Evaluation of random amplified polymorphic DNA for species identification and phylogenetic analysis inStylosanthes (Fabaceae) (1998)
    Springer
    Plant systematics and evolution 211 (1998), S. 201-216 
    Details
    ISSN: 1615-6110
    Keywords: Fabaceae ; Stylosanthes ; RAPDs ; phylogeny ; systematics ; taxon identification
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Random amplified polymorphic DNA (RAPD) was assessed for its suitability as a tool to be used in the identification of taxa from the genusStylosanthes (Fabaceae, Papilionoideae, Aeschynomeneae). Five random primers were used to ‘fingerprint’ accessions from seven species in the genus, and generated RAPD profiles that were species-specific. Data were used to examine evolutionary relationships between taxa, employing both clustering and ordination techniques, and the results were compared with those from a previous cladistic analysis of chloroplast DNA (cpDNA) restriction fragments. Both multivariate approaches indicated relationships that were generally similar to those obtained by RFLP analysis of cpDNA. However, while cluster analysis grouped together all accessions within species, ordination placed certain accessions ofS. humilis, S. macrocephala andS. capitata into separate groups. Experiments to test the assumed homology of comigrating RAPDs estimated 85.7% homology for accessions within species, and 53.8% homology for accessions between species. The value of RAPD data in systematics is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00985359
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  • 11
    Electronic Resource
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    Phylogeny, diversity, and distribution inExostema (Rubiaceae): Implications of morphological and molecular analyses (1998)
    Springer
    Plant systematics and evolution 212 (1998), S. 215-246 
    Details
    ISSN: 1615-6110
    Keywords: Rubiaceae ; Exostema ; Morphology ; ITS sequences ; cladistics ; phylogeny ; diversity ; Caribbean biogeography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The neotropical genusExostema comprises 25 species of trees and shrubs, ranging in distribution from Bolivia to Mexico and throughout the West Indies, with most species endemic to the Greater Antilles. Infrageneric relationships and species-level patterns of evolution were investigated in phylogenetic analyses using morphological, molecular, and combined data sets. All data sets resolved three main species groups which correspond to the three sections recognized byMcDowell (1996). However, the analyses of ITS sequence data placed the two South American species basal to the three main clades. Otherwise, the morphological and molecular data are highly compatible, and produce a more robust yet consistent phylogeny in the combined data analysis. Morphological evolution inExostema involves many specializations for xeric habitats, reflecting repeated ecological shifts from moist forest to exposed, seasonally dry environments during the diversification of the genus. Both moth and bee pollination syndromes are found inExostema, and shifts in pollination ecology appear pivotal to the differentiation of the three sections. Biogeographically,Exostema likely originated in South America and migrated via Central America to the Greater Antilles, where the morphological diversification and speciation are most extensive.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01089740
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  • 12
    Electronic Resource
    Electronic Resource
    Chloroplast DNA restriction site mapping and the phylogeny ofRanunculus (Ranunculaceae) (1998)
    Springer
    Plant systematics and evolution 213 (1998), S. 1-19 
    Details
    ISSN: 1615-6110
    Keywords: Ranunculaceae ; Ranunculus ; Chloroplast DNA ; phylogeny ; restriction site maps
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A chloroplast DNA restriction site map forRanunculus sceleratus (Ranunculaceae) was constructed using 14 restriction endonucleases. The total size of the chloroplast genome is 152.4kb. No inversions were detected relative to the tobacco chloroplast DNA. Cladistic analyses of chloroplast DNA restriction site polymorphism were employed in order to elucidate the phylogeny among 76 species of the genusRanunculus in a wide sense and one species ofTrautvetteria. A total of 341 informative restriction site changes were detected. Parsimony jackknifing, bootstrapping and decay analysis were undertaken in order to evaluate the amount of support for the monophyletic groups. The results suggest that the analysed species ofRanunculus are divisible into two main clades. Only few of the traditional sections and subgenera ofRanunculus are monophyletic. The genusTrautvetteria is nested within a clade comprising, e.g.Ranunculus cymbalaria, R. andersonii, R. lapponicus andR. ficaria. SubgenusBatrachium lies within a larger clade containing, e.g.R. sceleratus andR. hyperboreus. Contractions of the inverted repeat due to parallel deletions of 200–300 bp close to the JSB have occurred in many clades and the phylogenetic distribution of this size reduction was mapped among the species.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00988905
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  • 13
    Electronic Resource
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    Family relationships of the enigmatic rosid generaBarbeya andDirachma from the Horn of Africa region (1998)
    Springer
    Plant systematics and evolution 213 (1998), S. 103-119 
    Details
    ISSN: 1615-6110
    Keywords: Barbeyaceae ; Dirachmaceae ; Elaeagnaceae ; Rhamnaceae ; Rosaceae ; Ulmaceae ; Urticales ; Barbeya ; Dirachma ; Actinorhizal symbiosis ; plastid DNA ; monotypic plant families ; phylogeny ; rbcL ; rosids ; trnL-F ; Africa ; Arabia ; Socotra ; Somalia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Barbeya is a monotypic genus in the Horn of Africa and adjacent parts of Arabia. It is usually treated as the familyBarbeyaceae and regarded as an aberrant member ofUrticales. Dirachma, with one species on Socotra and one in Somalia, is usually treated as the familyDirachmaceae, inGeraniales, but a position inMalvales has also been suggested. Analyses of molecular data, from bothrbcL andtrnL-F, indicate thatBarbeya andDirachma are closely related inter se as well as toRhamnaceae andElaeagnaceae. In an analysis based on morphologyBarbeya groups withElaeagnaceae, andDirachma withRhamnaceae andUlmaceae. In a combined molecular and morphological analysisBarbeya is the sister group ofElaeagnaceae andDirachma is the sister group of the wholeBarbeya-Elaeagnaceae-Rhamnaceae clade. However, the support for these arrangements is weak and, rather than mergingBarbeyaceae withDirachmaceae as suggested by the molecular analysis or withElaeagnaceae as suggested by the morphological and combined analyses, it seems best to retain bothBarbeyaceae andDirachmaceae in their present circumscriptions, but in both cases in completely new positions in the angiosperm system. The results are compatible with a new circumscription ofRhamnales comprisingRhamnaceae, Elaeagnaceae, Dirachmaceae andBarbeyaceae.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00988911
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  • 14
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    Taxonomy and Philosophy of Names (1998)
    Springer
    Biology and philosophy 13 (1998), S. 233-244 
    Details
    ISSN: 1572-8404
    Keywords: reference ; meaning ; individual ; class ; definition ; clade ; evolution ; phylogeny ; phylogenetic taxonomy ; systematics ; tree-thinking ; cladistics ; intention ; extension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Philosophy
    Notes: Abstract Although naming biological clades is a major activity in taxonomy, little attention has been paid to what these names actually refer to. In philosophy, definite descriptions have long been considered equivalent to the meaning of names and biological taxonomy is a scientific application of these ideas. One problem with definite descriptions as the meanings of names is that the name will refer to whatever fits the description rather than the intended individual (clade). Recent proposals for explicit phylogenetic definitions of clade names suffer from similar problems and we argue that clade names cannot be defined since they lack intension. Furthermore we stress the importance of “tree-thinking” for phylogenetic reference to work properly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006583910214
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  • 15
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    Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)
    Springer
    Investigational new drugs 16 (1998), S. 19-27 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016066529642
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  • 16
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    Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 319-324 
    Details
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006293830585
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    Pharmacokinetics and Relative Bioavailability of Carboxyamido-Triazole with Respect to Food and Time of Administration: Use of a Single Model for Simultaneous Determination of Changing Parameters (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 673-687 
    Details
    ISSN: 1573-8744
    Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020750923542
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  • 18
    Electronic Resource
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    ‘Candidatus Phytoplasma australiense’ is the phytoplasma associated with Australian grapevine yellows, papaya dieback and Phormium yellow leaf diseases (1998)
    Springer
    European journal of plant pathology 104 (1998), S. 619-623 
    Details
    ISSN: 1573-8469
    Keywords: 16S rRNA gene ; 16S/23S spacer region ; phylogeny ; sequence analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Sequence comparisons and phylogenetic analysis of the 16S rRNA genes and the 16S/23S spacer regions of the phytoplasmas associated with Australian grapevine yellows, papaya dieback and Phormium yellow leaf diseases revealed minimal nucleotide differences between them resulting in the formation of a monophyletic group. Therefore, along with Australian grapevine yellows, the phytoplasmas associated with Phormium yellow leaf and papaya dieback should also be considered as ‘Candidatus Phytoplasma australiense’.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008693904427
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  • 19
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    Lumping of Whole-Body Physiologically Based Pharmacokinetic Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.
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    URL: http://dx.doi.org/10.1023/A:1023272707390
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  • 20
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    Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 133-161 
    Details
    ISSN: 1573-8744
    Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
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    URL: http://dx.doi.org/10.1023/A:1020505722924
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  • 21
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    Rapid Attainment of Steady State Plasma Drug Concentrations Within Precise Limits (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023285426388
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  • 22
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    Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 289-317 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
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    URL: http://dx.doi.org/10.1023/A:1023233409550
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  • 23
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    Levels of Homoplasy in the Evolution of the Mammalian Skeleton (1998)
    Springer
    Journal of mammalian evolution 5 (1998), S. 113-126 
    Details
    ISSN: 1573-7055
    Keywords: homoplasy ; Mammalia ; phylogeny ; skeleton
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract It is commonly believed that there are differences in the evolutionary lability of the crania, dentition, and postcrania of mammals, the latter two being more prone to homoplasy because of strong selective pressures for feeding and locomotion, respectively. Further, because of the fragmentary nature of fossils, phylogenetic analyses of extinct taxa often must utilize characters based on only one of these systems. In this paper the levels of homoplasy (as measured by the consistency index; CI) were compared in characters based on these three anatomical systems in therian mammals. No statistically significant differences were found in the overall CIs of 41 data sets based on dental, cranial, or postcranial characters. Differences in homoplasy within data sets with two or three kinds of data were not statistically significant. These findings suggest that dental, cranial, and postcranial characters can be equally prone to homoplasy and none should be automatically dismissed, disregarded, or systematically weighted in phylogenetic analyses. The level of homoplasy in characters derived from a given region of the skeleton may differ depending on the taxonomic level of the taxa considered. Dental, cranial, and postcranial characters may not constitute “natural” classes, yet examination of the phylogenetic signal of these subsets of data previous to a simultaneous analysis can shed light on significant aspects of the evolutionary process.
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    URL: http://dx.doi.org/10.1023/A:1020549505177
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  • 24
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    Molecular Systematics of the Subfamily Caprinae (Artiodactyla, Bovidae) as Determined from Cytochrome b Sequences (1998)
    Springer
    Journal of mammalian evolution 5 (1998), S. 217-236 
    Details
    ISSN: 1573-7055
    Keywords: phylogeny ; parsimony ; Bovidae ; Caprinae ; cytochrome b ; a priori weighting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We have sequenced the complete mitochondrial DNA cytochrome b gene from 18 species of the subfamily Caprinae and two outgroup taxa. Additional sequences retrieved from the literature were used to constitute a data set of 32 cytochrome b sequences comprising all genera usually included within the Caprinae. Phylogenetic relationships were assessed by PAUP using three new weighting schemes based on homoplasy analyses. Each type of substitution considered at each of the three codon positions was weighted according to its homoplasy level, as measured by the consistency index (CI), the slope of saturation (S), or their product (CIS). These differentially weighted parsimony analyses indicate that (1) the subfamily Caprinae is monophyletic, but only with the exclusion of Saiga from the group; (2) there is no support for monophyly of the four tribes currently recognized (Caprini, Rupicaprini, Ovibovini, and Saigini), suggesting relationships different from those traditionally accepted; (3) the caprine group consists of three major clades corresponding to (a) Budorcas and Ovis, (b) Capricornis, Ovibos, and Naemorhedus, and (c) Capra, Hemitragus, and Pseudois; and (4) the basal branching pattern is very weakly supported by bootstrap or branch support values except for the sister-group relationship of Pantholops with all other caprines, and the phylogenetic positions of Ammotragus, Oreamnos, and Rupicapra remain unclear.
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    URL: http://dx.doi.org/10.1023/A:1020560412929
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    Optimal Experimental Design for Precise Estimation of the Parameters of the Axial Dispersion Model of Hepatic Elimination (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615 
    Details
    ISSN: 1573-8744
    Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.
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    URL: http://dx.doi.org/10.1023/A:1023229318017
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    Single-Dose Pharmacokinetics of Rifapentine in Women (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85 
    Details
    ISSN: 1573-8744
    Keywords: rifapentine ; pharmacokinetics ; gender differences ; female
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.
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    URL: http://dx.doi.org/10.1023/A:1023276808298
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    Pharmacokinetic and Pharmacodynamic Evaluation for Tissue-Selective Inhibition of Cholesterol Synthesis by Pravastatin (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 329-347 
    Details
    ISSN: 1573-8744
    Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
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    URL: http://dx.doi.org/10.1023/A:1023237510458
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  • 28
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    Mathematical Formalism and Characteristics of Four Basic Models of Indirect Pharmacodynamic Responses for Drug Infusions (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 385-408 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; indirect response models ; infusions ; inhibition ; stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.
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    URL: http://dx.doi.org/10.1023/A:1021060000789
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    Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 559-579 
    Details
    ISSN: 1573-8744
    Keywords: acetaminophen ; age ; antipyretic ; fever ; ibuprofen ; pediatrics ; pharmacokinetics ; pharmacodynamics ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
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    URL: http://dx.doi.org/10.1023/A:1023225217108
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    Dose-Dependence and Repeated-Dose Studies for Receptor/Gene-Mediated Pharmacodynamics of Methylprednisolone on Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 619-648 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect pharmacodynamic response models ; glucocorticoid receptor ; Northern hybridization ; mRNA ; down-regulation ; tyrosine aminotransferase ; dose dependence ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
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    URL: http://dx.doi.org/10.1023/A:1020746822634
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    Characterization of Pharmacodynamic Recession Slopes for Direct and Indirect Response Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 409-436 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamic recession slope ; Hill function ; k · m product ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).
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    Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1609-1613 
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    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
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    Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 47-52 
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    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
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    Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 93-97 
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    ISSN: 1573-904X
    Keywords: cocktail dosing ; pharmacokinetics ; plasma free fraction ; ultrafiltration ; HPLC/APCI/MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 μg⋅hr/ml and the Cmax values ranged from 0.04 to 2.17 μg/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 μg⋅hr/ml, and 0.001 to 0.119 μg/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.
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    Elucidation of Human Amphotericin B Pharmacokinetics: Identification of a New Potential Factor Affecting Interspecies Pharmacokinetic Scaling (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1630-1636 
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    ISSN: 1573-904X
    Keywords: amphotericin B ; pharmacokinetics ; human ; gender-differences ; disposition function differences ; interspecies scaling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.
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    Phylogenetic relationships ofSphaerophoraceae (Ascomycetes) inferred from SSU rDNA sequences (1998)
    Springer
    Plant systematics and evolution 209 (1998), S. 75-83 
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    ISSN: 1615-6110
    Keywords: Fungi ; Ascomycetes ; Caliciales ; Lecanorales ; Sphaerophoraceae ; Stereocaulaceae ; Lichens ; molecular evolution ; phylogeny ; small subunit ; ribosomal DNA ; 18S rDNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract SSU rDNA was sequenced from the lichenized fungiBunodophoron scrobiculatum andLeifidium tenerum (Sphaerophoraceae), andStereocaulon ramulosum andPilophorus acicularis (Stereocaulaceae) and analysed by maximum parsimony with 44 homologous ascomycete sequences in a cladistic study. A small insertion (c. 60 nt.) was found in the sequence ofLeifidium tenerum. Sphaerophoraceae constitutes a strongly supported monophyletic group which groups together withLecanora dispersa and theStereocaulaceae. Together withPorpidia crustulata, this larger group is a sistergroup to thePeltigerineae. This analysis thus supports theLecanorales as monophyletic, includingSphaerophoraceae and thePeltigerineae, but does not provide strong support for this monophyly. The analysis also suggests that the prototunicate ascus in theSphaerophoraceae is a reversion to the plesiomorphic state. Based on morphological, anatomical and chemical reasons,Sphaerophoraceae is proposed to belong to one of the groups presently included in the paraphyletic suborderCladoniineae within theLecanorales.
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    The potential of AFLPs in biosystematics: A first application inSolanum taxonomy(Solanaceae) (1998)
    Springer
    Plant systematics and evolution 210 (1998), S. 87-103 
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    ISSN: 1615-6110
    Keywords: Solanaceae ; Solanum ; AFLP markers ; DNA fingerprinting ; phylogeny ; polyploids ; potato ; tomato
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Using the AFLP technique highly informative DNA fingerprints were generated from 19 taxa ofSolanum sect.Petota (potatoes) and three taxa ofSolanum sect.Lycopersicum (tomatoes). Both phenetic and cladistic analyses were conducted from the individual genotypic level to the species level. An AFLP fingerprint, using a combination of suitable AFLP primers, generated 12 to 71 scorable fragments per genotype which was sufficient for taxonomic interpretation. The classifications based on the molecular markers were generally in agreement with current taxonomic opinions. Unexpectedly,S. microdontum was associated with ser.Megistacroloba rather than with ser.Tuberosa, andS. demissum (ser.Demissa) and species of ser.Acaulia appeared closely affiliated. AFLP is an efficient and reliable technique to generate biosystematic data and therefore a promising tool for evolutionary studies.
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    Collapse ofIsertieae, re-establishment ofMussaendeae, and a new genus ofSabiceeae (Rubiaceae); phylogenetic relationships based onrbcL data (1998)
    Springer
    Plant systematics and evolution 211 (1998), S. 71-92 
    Details
    ISSN: 1615-6110
    Keywords: Gentianales ; Rubiaceae ; Isertieae ; Mussaendeae ; Sabiceeae ; Tamridaea ; Chloroplast DNA ; rbcL ; phylogeny ; Socotra
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The circumscription of theIsertieae has been under debate for a long time and recently a phylogeny based on morphological data has been presented (Andersson 1996), contradicting the classification ofRobbrecht (1988, 1993). Our investigation of molecular data neither supports the phylogeny ofAndersson nor the classification ofRobbrecht, but instead indicates totally new relationships ofIsertieae, Mussaendeae, andSabiceeae. TheIsertieae are a bigeneric tribe of subfam.Cinchonoideae, whileMussaendeae andSabiceeae are two separate tribes of subfam.Ixoroideae. We have also referred a species from Socotra (Yemen) with disputed position to the tribeSabiceeae and we place it in a new genus,Tamridaea, with the single speciesT. capsulifera comb. nov. NewrbcL sequences of 20 taxa are presented and analysed, fromGentianaceae:Gentianella; fromLoganiaceae:Spigelia; and fromRubiaceae:Amphidasya, Aoranthe, Chomelia, Coussarea, Gonzalagunia, Heinsia, Hippotis, Isertia (three taxa),Mussaenda, Pseudomussaenda, Pseudosabicea, Rondeletia, Sabicea, Schradera, Tamridaea, andVirectaria.
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    Allozyme divergence among four species ofPodaechmea s. l. and the status ofUrsulaea (Bromeliaceae, Bromelioideae) (1998)
    Springer
    Plant systematics and evolution 213 (1998), S. 207-215 
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    ISSN: 1615-6110
    Keywords: Bromeliaceae ; Aechmea ; Podaechmea ; Systematics ; phylogeny ; allozymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The genetic relationships ofAechmea mexicana, A. lueddemanniana, A. macvaughii andA. tuitensis were investigated using starch gel electrophoresis. Eight enzyme systems encoded by ten putative gene loci were resolved in seventeen populations.Nei's (1978) genetic distances were obtained from allelic frequencies and used with UPGMA algorithm. Results indicate that some populations belonging to different species display genetic similarities closer to each other than to some conspecific populations. Our results do not support the proposed genusUrsulaea (Read & Baensch 1994), sinceA. tuitensis was closer toA. lueddemanniana andA. mexicana than toA. macvaughii.
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    Rhizobium strains that nodulate Trifolium semipilosum Fres. are phylogenetically distinct (1998)
    Springer
    Plant and soil 207 (1998), S. 147-154 
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    ISSN: 1573-5036
    Keywords: inoculation ; rDNA ; phylogeny ; Rhizobium ; Trifolium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The genetic relationships of Rhizobium isolated from temperate and tropical perennial Trifolium species were investigated using PCR-based nucleotide sequence analysis of 16S and 23S rDNA regions. Comparative analysis of partial 23S rDNA sequences clustered Rhizobium isolates effective with T. semipilosum, T. repens, T. pratense, T. hybridum and T. fragiferum into two distinct groups. These groups were consistent with the pattern of symbiotic effectiveness observed in cross-inoculation experiments. Our data suggested that strains from T. semipilosum were more closely related phylogenetically to R. etli, indicating that these strains do not belong in the R. leguminosarum bv trifolii group. Further differentiation of Rhizobium strains effective on T. semipilosum was reflected in the broader metabolic profile observed using the BIOLOG MicroPlate TM system to evaluate carbon utilization.
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    rRNA based identification and detection systems for rhizobia and other bacteria (1998)
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    Plant and soil 204 (1998), S. 1-19 
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    ISSN: 1573-5036
    Keywords: hybridization ; in situ identification ; phylogeny ; probe design ; rhizobia ; rRNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Ribosomal ribonucleic acids are excellent marker molecules for the elucidation of bacterial phylogeny; they also provide useful target sites for identification and detection with nucleic acid probes. Based on the currently available 16S rRNA sequence data, bacteria of the rhizobial phenotype (plant nodulation, nitrogen fixation) are members of three moderately related phylogenetic sub-groups of the α-subclass of the Proteobacteria: i.e. the rhizobia group, the bradyrhizobia group, and the azorhizobia group. All rhizobia, azo-, brady-, meso- and sinorhizobia are closely related to and in some cases phylogenetically intermixed with, non-symbiotic and/or non-nitrogen-fixing bacteria. Especially in the case of Bradyrhizobium japonicum strains, the 16S rRNA sequence data indicate substantial heterogeneity. Specific probe design and evaluation are discussed. A multiprobe concept for resolving specificity problems with group specific probes is presented. In situ identification with group specific probes of rhizobia in cultures as well as rhizobia and cyanobacteria within plant material is shown.
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    Rough periwinkle polymorphism on the east coast of Yorkshire: comparison of RAPD-DNA data with morphotype (1998)
    Springer
    Hydrobiologia 378 (1998), S. 71-78 
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    ISSN: 1573-5117
    Keywords: RAPD ; Littorina saxatilis ; L. neglecta ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A genetic analysis of ‘morphotypes’ of Littorina saxatilis from two locations on the north-east coast of England (Filey and Ravenscar), using randomly amplified DNA polymorphisms (RAPD) generated with a single primer, revealed quite different patterns of variation. Thin shelled, wide-apertured (H-form) animals from Ravenscar tended to cluster separately from thick shelled (M) forms, indicating genetic differentiation of these morphs. Animals of similar morphology (H and M) from Filey (about 30 km distant) did not display such an obvious pattern, and although there was still evidence of differentiation from discriminant analysis of RAPD data, levels of correct classification were reduced at Filey. This suggests that the utility of a single RAPD primer for separation of such forms varies over a relatively small distance. L. arcana from Ravenscar, included as an outgroup, were generally well differentiated from L. saxatilis and were noted to exhibit less variation, a phenomenon that has been noted previously in some allozyme and RAPD analyses. A similar RAPD analysis undertaken on small, barnacle dwelling, brooding forms from Peak Steel, Ravenscar revealed that animals appeared to have as great a tendency to cluster together on a microgeographic scale (by collection patch) as by ‘species’ ( L. neglecta or L. saxatilis b) although predominance of certain species in individual patches largely explains this. Discriminant analysis of RAPD presence/absence data did correctly place over 90% of barnacle dwelling animals to their respective species, and we consider this as evidence of separate gene pools. RAPD is taken to be a useful tool for screening genetic variation in this complex of animals on a local scale when either a pre-selected informative primer is utilised or a battery of primers is used, but its efficacy may be reduced when a single primer is employed for screening animals from different shores.
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    Phylogenetic relationships of phylum Rotifera with emphasis on the families of Bdelloidea (1998)
    Springer
    Hydrobiologia 287-388 (1998), S. 101-107 
    Details
    ISSN: 1573-5117
    Keywords: Acanthocephala ; aschelminthes ; cladistics ; evolution ; Gnathostomulida ; phylogeny ; pseudocoelomates ; Rotifera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We investigated phylogenetic relationships of phylum Rotifera using cladistic analysis to uncover all most-parsimonious trees from a data set comprising 60 morphological characters of nine taxa: one Acanthocephala, six Rotifera, and two outgroups (Turbellaria, Gnathostomulida). Analysis of our matrix yielded a single most-parsimonious tree. From our analysis we conclude the following: (1) Class Digononta is paraphyletic; (2) it is still premature to reject rotiferan monophyly; (3) the classification hierarchy that best conforms to this morphologically based, cladistic analysis is similar to several traditional schemes. In spite of these results, it is significant that this analysis yielded a tree that is incongruent with those trees developed from molecular data or by using the principles of evolutionary taxonomy.
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    Phylogenetic relationships of phylum Rotifera with emphasis on the families of Bdelloidea (1998)
    Springer
    Hydrobiologia 387-388 (1998), S. 101-107 
    Details
    ISSN: 1573-5117
    Keywords: Acanthocephala ; aschelminthes ; cladistics ; evolution ; Gnathostomulida ; phylogeny ; pseudocoelomates ; Rotifera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We investigated phylogenetic relationships of phylum Rotifera using cladistic analysis to uncover all most-parsimonious trees from a data set comprising 60 morphological characters of nine taxa: one Acanthocephala, six Rotifera, and two outgroups (Turbellaria, Gnathostomulida). Analysis of our matrix yielded a single most-parsimonious tree. From our analysis we conclude the following: (1) Class Digononta is paraphyletic; (2) it is still premature to reject rotiferan monophyly; (3) the classification hierarchy that best conforms to this morphologically based, cladistic analysis is similar to several traditional schemes. In spite of these results, it is significant that this analysis yielded a tree that is incongruent with those trees developed from molecular data or by using the principles of evolutionary taxonomy.
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    A higher-plant type ζ-carotene desaturase in the cyanobacterium Synechocystis PCC6803 (1998)
    Springer
    Plant molecular biology 36 (1998), S. 725-732 
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    ISSN: 1573-5028
    Keywords: ζ-Carotene desaturase gene ; J852 ; lycopene ; neurosporene ; phylogeny ; Synechocystis PCC6803
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The genomic DNA sequence of Synechocystis was analysed for putative ζ-carotene desaturase genes. Two promising candidates slr0940 and slr0033 were found with similarities to the structurally different ζ-carotene desaturase genes from higher plants and Anabaena, respectively. Only the expression product of the analogue to the plant gene, slr0940, was able to mediate the 2-step desaturation of ζ-carotene via neurosporene to lycopene after complementation of this pathway in Escherichia coli. When enzyme reactions were carried out with this protein, activity was obtained with either ζ-carotene or neuroporene as substrates. The in vitro reaction was inhibited by the pyrimidine derivative J852 which is effective as experimental herbicide in plants. The occurrence of two different types of ζ-carotene desaturases among cyanobacteria and the phylogenetic consequences on chloroplast evolution are discussed.
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    Directional mutational pressure affects the amino acid composition and hydrophobicity of proteins in bacteria (1998)
    Springer
    Genetica 102-103 (1998), S. 383-391 
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    ISSN: 1573-6857
    Keywords: directional mutational pressure ; genomic GC content ; amino acid composition ; hydrophobicity ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The relationship between change in genomic GC content and protein evolution in bacteria was studied by simple correlational analysis (at the genus level) and by Felsenstein's (1985) independent contrast test. We first used the dnaA gene in bacteria as an example to show (1) that the amino acid composition of a protein can be dramatically affected by mutational pressure (the genomic GC content), (2) that surprisingly, deleting relatively closely-related genera may increase rather than decrease the correlation between genomic GC content and amino acid composition, and (3) that most unexpectedly, as the genomic GC content increases, both strongly hydrophobic and strongly hydrophilic amino acids tend to change to ambivalent amino acids, suggesting that the majority of these amino acid substitutions are not caused by positive Darwinian selection. These patterns were then also shown to hold for the 14 other genes studied, indicating their generality for the evolution of bacterial proteins. As directional mutation pressure can affect the amino acid composition of proteins, it may mislead phylogenetic inference, even if protein instead of DNA sequences are used.
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    Evolution of the Monotremes: Phylogenetic Relationship to Marsupials and Eutherians, and Estimation of Divergence Dates Based on α-Lactalbumin Amino Acid Sequences (1998)
    Springer
    Journal of mammalian evolution 5 (1998), S. 95-105 
    Details
    ISSN: 1573-7055
    Keywords: monotremes ; echidna ; platypus ; phylogeny ; α-lactalbumin ; lysozyme
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The amino acid sequences of the α-lactalbumins of the echidna, Tachyglossus aculeatus, and the platypus, Ornithorhynchus anatinus, were compared with each other and with those of 13 eutherian and 3 marsupial species. Phylogenetic parsimony analyses, in which selected mammalian lysozymes were used as outgroups, yielded trees whose consensus indicated that the two monotremes are sister taxa to marsupials and eutherians and that the latter two clades are each other's closest relatives. The data do not support the notion of a Marsupionta (monotreme–marsupial) clade. Pairwise comparison between the α-lactalbumins yielded maximum-likelihood distances from which divergence dates were estimated on the basis of three calibration points. The distance data support the view that the echidna and platypus lineages diverged from their last common ancestor at least 50 to 57 Ma (million years ago) and that monotremes diverged from marsupials and eutherian mammals about 163 to 186 Ma.
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    The Phylogeny of the Myrmecophagidae (Mammalia, Xenarthra, Vermilingua) and the Relationship of Eurotamandua to the Vermilingua (1998)
    Springer
    Journal of mammalian evolution 5 (1998), S. 237-265 
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    ISSN: 1573-7055
    Keywords: Xenarthra ; anteaters ; Eurotamandua ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A cladistic investigation of the phylogenetic relationships among the three extant anteater genera and the three undoubted extinct myrmecophagid genera is performed based upon osteological characteristics of the skull and postcranial skeleton. One hundred seven discrete morphological characters are analyzed using the computer program PAUP. Characters are polarized via comparison to the successive xenarthran outgroups Tardigrada (represented by the living sloth Bradypus) and Cingulata (represented by the recent armadillos Dasypus and Euphractus). The analysis results in a single most-parsimonious tree (TL = 190, CI = 0.699, RI = 0.713). The tree corroborates the monophyly of the subfamilies Cyclopinae and Myrmecophaginae, the former including the extant Cyclopes and the Pliocene genus Palaeomyrmidon. Within the Myrmecophaginae the Miocene genus Protamandua is the sister taxon to a clade including the remaining three genera. The recent Tamandua is in turn the sister taxon to the extant Myrmecophaga plus the Pliocene genus Neotamandua. Contrary to the suggestions of recent authors, weak support is provided for the taxonomic distinctiveness of the latter genus from the recent Myrmecophaga. The monophyly of the Myrmecophagidae is supported by 15 unequivocal synapomorphies. The monophyly of the Cyclopinae and Myrmecophaginae is supported by 3 and 13 unambiguous synapomorphies, respectively. The enigmatic Eocene genus Eurotamandua, from the Messel fauna of Germany, is coded for the 107 morphological characters above and included in two subsequent PAUP analyses. The palaeanodont Metacheiromys is also added to these two analyses as a nonxenarthran outgroup to test for the possibility that Eurotamandua lies outside the Xenarthra. In the first analysis, Eurotamandua is constrained a priori to membership in the Vermilingua. The single most-parsimonious tree (TL = 224, CI = 0.618) that results places Eurotamandua as the sister group to the remaining anteater genera, contra Storch and Habersetzer's (1991) assignment of Eurotamandua to the vermilinguan subfamily Myrmecophaginae. Eurotamandua shares six unequivocal synapomorphies with other anteaters, including the absence of teeth and the presence of a lateral tuberosity on the fifth metatarsal. The remaining vermilinguans are united by 11 unequivocal synapomorphies, plus an additional 10 ambiguous synapomorphies. In the second analysis, the position of Eurotamandua is unconstrained. The resulting single most-parsimonious tree (TL = 219, CI = 0.632) places Eurotamandua outside Vermilingua as the sister group to the Pilosa (Vermilingua plus Bradypus). The monophyly of this node is supported by four unambiguous synapomorphies in the unconstrained analysis. Further manipulation of this second analysis shows that placement of Eurotamandua as the sister group to the Xenarthra or to the Palaeanodonta adds three steps to the shortest tree but is more parsimonious than its placement as a sister group to the Vermilingua is the previous analysis. The addition of pangolins to the analysis does little to alter the major phylogenetic conclusions of the study. The allocation of Eurotamandua to the Xenarthra, but as a sister group to the Pilosa, is a novel arrangement which leaves open the biogeographic question of how a xenarthran reached Western Europe during the Eocene.
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    Identification and phylogeny of ascomycetous yeasts from analysis of nuclear large subunit (26S) ribosomal DNA partial sequences (1998)
    Springer
    Antonie van Leeuwenhoek 73 (1998), S. 331-371 
    Details
    ISSN: 1572-9699
    Keywords: Ascomycetous yeasts ; phylogeny ; ribosomal DNA ; systematics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Approximately 500 species of ascomycetous yeasts, including members of Candida and other anamorphic genera, were analyzed for extent of divergence in the variable D1/D2 domain of large subunit (26S) ribosomal DNA. Divergence in this domain is generally sufficient to resolve individual species, resulting in the prediction that 55 currently recognized taxa are synonyms of earlier described species. Phylogenetic relationships among the ascomycetous yeasts were analyzed from D1/D2 sequence divergence. For comparison, the phylogeny of selected members of the Saccharomyces clade was determined from 18S rDNA sequences. Species relationships were highly concordant between the D1/D2 and 18S trees when branches were statistically well supported.
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    Morphological evidence for the evolutionary origin of Astigmata (Acari: Acariformes) (1998)
    Springer
    Experimental and applied acarology 22 (1998), S. 559-594 
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    ISSN: 1572-9702
    Keywords: Astigmata ; Oribatida ; Malaconothroidea ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A century ago, Antonio Berlese first discussed the close phylogenetic relationship between the large mite groups Oribatida and Astigmata. Since then, information having phylogenetic value has greatly increased and the paradigms within which we interpret it have changed. Herein I refine the general hypothesis that Astigmata originated within oribatid mites and suggest Malaconothridae as a possible sister group. Among the 14 apomorphies used to support the origin of Astigmata within oribatid mites are possession of lateral opisthosomal glands, regression of hysterosomal setal pair f1, paired prelarval denticles, partially internalized chelicerae with incomplete adaxial walls, an atelobasic rutellum, pretarsal condylophores that articulate posteriorly with the tarsus, a dorsally fused palp tibia and tarsus and transdehiscent ecdysis. A further 13 apomorphies support the origin of Astigmata at some level within Malaconothroidea. These include absence of an oblique labiogenal articulation, presence of a distal rutellar lamella, shortening of the palp tarsus, larval regression of hysterosomal seta f2, loss of the bothridial seta in all instars, and several losses and modifications of leg setae. The hypothesis brings to light evolutionary questions that were previously obscured by incorrect or inappropriate classifications. The nomenclatural problems that arise from it are best solved by considering Astigmata as a subgroup within Oribatida.
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    Host plant associations in the spider mite Tetranychus urticae (Acari: Tetranychidae): insights from molecular phylogeography (1998)
    Springer
    Experimental and applied acarology 22 (1998), S. 201-214 
    Details
    ISSN: 1572-9702
    Keywords: Mitochondrial COI ; ribosomal ITS2 ; host race formation ; phylogeny ; Tetranychidae ; geographic structure.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract This article integrates studies on the genetic variation of T. urticae populations and the interspecific variation of several tetranychid species. It aims at obtaining insights into the roles of the historical, geographical and ecological factors in the partitioning of variation of species. Two types of molecular markers were used to determine whether the patterns of genetic variation in mites inhabiting different host plants can shed light on the existence of host plant associations. The ribosomal sequences of the second internal transcribed spacer (ITS2), which evolves through concerted evolution, are good indicators of long-term isolation between populations and reveal exceptional homogeneity in a worldwide sampling of T. urticae. The mitochondrial cytochrome oxidase I (COI) sequences do not disclose old divergences related to host plant in this mite but rather suggest recent geographic colonization patterns of the species. Allozyme variation on a fine scale gives some evidence of host associations in the case of citrus trees. However, if any divergence of mites related to this host plant exists, it probably prevails in local populations only and it should not be old enough to be revealed by a phylogenetic analysis of mitochondrial COI sequences. The phyletic constraint in the evolution of feeding specificity in the family Tetra-nychidae is investigated based on a phylogenetic analysis of mitochondrial sequences. The results provide some support for the hypothesis that an evolutionary trend towards polyphagy has occurred in the family. Overall, it seems that the major characteristic of T. urticae is its high colonization potential. Polyphagy has enhanced its successful spread and may have led to connectivity between populations worldwide. © Rapid Science Ltd. 1998
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    The evolutionary relationships of rotifers and acanthocephalans (1998)
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    Hydrobiologia 287-388 (1998), S. 83-91 
    Details
    ISSN: 1573-5117
    Keywords: phylogeny ; acanthocephala ; rotifera ; bilateria ; evolution ; 18S rRNA gene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Advances in morphological and molecular studies of metazoan evolution have led to a better understanding of the relationships among Rotifera (Monogononta, Bdelloidea, Seisonidea) and Acanthocephala, and their relationships to other bilateral animals. The most accepted morphological analysis places Acanthocephala as a sister group to Rotifera, although other studies have placed Acanthocephala as a sister taxon to Bdellodea or Seisonidea. Molecular analyses using nuclear 18S rRNA and mitochondrial 16S rRNA genes support Acanthocephala as a sister taxon to Bdelloidea, although no molecular data is available for Seisonidea. Combining molecular and morphological analyses of Bilateria leads to a tree with Platyhelminthes, Rotifera, Acanthocephala and Gnathostomulida (and probably Gastrotricha) as a sister group to the annelid-mollusc lineage of the Spiralia (Lophotrochozoa).
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    Notentera ivanovi Joffe et al., 1997: a contribution to the question of phylogenetic relationships between ‘turbellarians’ and the parasitic Plathelminthes (Neodermata) (1998)
    Springer
    Hydrobiologia 383 (1998), S. 245-250 
    Details
    ISSN: 1573-5117
    Keywords: parasite ; morphology ; phylogeny ; Plathelminthes ; Neodermata
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Notentera ivanovi is a parasitic platyhelminth found in the gut of a polychaete, Nephthys ciliata. N. ivanovi has no mouth, pharynx, or intestine; the dorsal epidermis of adult animals forms a thick pad which is very similar to gut epithelia even at the light microscopic level. Structure of ciliary rootlets and dermal glands with peculiar striated secretion bodies point to close relationships with the Fecampiidae, though other important characters imply placing the genus Notentera in a separate family. In mature sperm of N. ivanovi, the axonemes are fully incorporated; they are directed from proximal to distal, as in the Neodermata. We argue that new family, Notenteridae, should be included in the taxon Fecampiida. We also suggest that all Plathelminthes with neodermatan type of spermiogenesis (Fecampiidae, Urastomidae, and Neodermata) form a monophyletic branch within the Plathelminthes Neoophora.
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    A new species of giant planarian from Lake Baikal, with some remarks on character states in the Dendrocoelidae (Platyhelminthes, Tricladida, Paludicola) (1998)
    Springer
    Hydrobiologia 383 (1998), S. 69-75 
    Details
    ISSN: 1573-5117
    Keywords: Platyhelminthes ; Tricladida ; Dendrocoelidae ; Bdellocephala ; Baikal ; taxonomy ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract On the basis of newly collected material the subspecies Bdellocephala angarensis bathyalis Timoshkin & Porfirjeva, 1989 is raised to full species status, B. bathyalis Timoshkin & Porfirjeva, 1989. Specimens of this species have been collected in Lake Baikal from depths ranging between 610 and 1060 m. The species is characterized by a light, uniform brown pigmentation, absence of eyes, distinct atrial folds, and large size. It is suggested that two features may be useful in elucidating the phylogenetic relationships between dendrocoelid genera: pharynx musculature, and presence of an extra layer of circular muscle in the ventral subepidermal body musculature.
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    A phylogeny of the Platyhelminthes: towards a total-evidence solution (1998)
    Springer
    Hydrobiologia 383 (1998), S. 155-160 
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    ISSN: 1573-5117
    Keywords: Platyhelminthes ; total-evidence ; phylogeny ; ultrastructure ; rRNA ; cladistics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We advocate a total-evidence approach for the reconstruction of working phylogenies for the Turbellaria and the phylum Platyhelminthes. Few morphology-based character matrices are available in the systematic literature concerning flatworms, and molecular-based phylogenies are rapidly providing the only means by which we can estimate phylogenies cladistically. Character matrices based on gross morphology and ultrastructure are required and should be internally consistent, i.e. character coding should follow a set of a priori guidelines and character duplication and contradiction is avoided. In order to test our molecular phylogenies we need complementary data sets from morphology. To understand morphological homology we need phylogenetic evidence from independent (e.g. molecular) data. Fully complementary morphological and molecular data sets enable us to validate phylogenetic hypotheses and the combination of these sets in phylogenetic reconstruction utilises all statements of homology. Working phylogenies which include all phylogenetic information not only shed light on individual character evolution, but form a strong basis for comparative studies investigating the origin and evolutionary radiation of the taxonomic group under scrutiny.
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    Selected characters of the copulatory organs in the land planarian family Bipaliidae and their taxonomic significance (Tricladida: Terricola) (1998)
    Springer
    Hydrobiologia 383 (1998), S. 77-82 
    Details
    ISSN: 1573-5117
    Keywords: Terricola ; land planarian ; Bipalium ; copulatory organs ; numerical taxonomy ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Preliminary analysis was made of 76 species in the monotypic family Bipaliidae, for which the copulatory apparatus has been described. Four characters from the copulatory organs were selected: profile of the female organ (three character states), approachment of the ovovitelline ducts to the female organ (two states), shape of the penial papilla (two states), and shape of the male antrum wall (three states). Data were scored for five preliminary ingroup taxa, viz., the restricted genus Placocephalus, and four other a priori defined subgroups within the family, viz., the genus Bipalium sensu stricto and three other informal taxonomic groupings. An artificial outgroup taxon was constructed on the basis of character states generalized from the Geoplanidae subfamilies Caenoplaninae, Pelmatoplaninae and Rhynchodemidae subfamily Microplaninae. Analysis of the data matrix resulted in a single most parsimonious tree with the following topology: (outgroup (Placocephalus (Bipalium, group A (group B1, group B2)))).
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    On the phylogeny of families and genera within the Temnocephalida (1998)
    Springer
    Hydrobiologia 383 (1998), S. 263-268 
    Details
    ISSN: 1573-5117
    Keywords: Epidermis ; musculature ; phylogeny ; plathelminthes ; sucker ; systematics ; tentacles ; Temnocephalida
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Temnocephalida includes species demonstrating many intermediate steps presenting the transition from commensalism to parasitism. Dramatic morphological changes also occurred within this group but the number of supraspecific taxa is small, making the Temnocephalida an excellent model for evolutionary studies. Having summarised original and relevant published morphological data, we suggest a cladogram (phylogenetic tree) which nearly fully resolves the order of branching of families and main genera within the Temnocephalida. We also introduce a new family, the Diceratocephalidae nov. fam.
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    Flatworm phylogeny from partial 18S rDNA sequences (1998)
    Springer
    Hydrobiologia 383 (1998), S. 147-154 
    Details
    ISSN: 1573-5117
    Keywords: Platyhelminthes ; Acoelomorpha ; phylogeny ; 18S rDNA ; cladistic ; decay index ; jack-knife
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Partial 18S rDNA sequences from 29 flatworms and 2 outgroup taxa were used in a cladistic analysis of the Platyhelminthes. Support for the clades in the resulting single most parsimonious tree was estimated through bootstrap analysis, jack-knife analysis and decay indices. The Acoelomorpha (Acoela and Nemertodermatida) were absent from the most parsimonious tree. The Acoela and the Fecampiidae form a strongly supported clade, the sister group of which may be the Tricladida. There is some support for monophyly of the rhabdocoel taxon Dalyellioida, previously regarded as paraphyletic. The sister group of the Neodermata remains unresolved.
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    The Philodinavidae (Rotifera Bdelloidea): a special family (1998)
    Springer
    Hydrobiologia 385 (1998), S. 77-85 
    Details
    ISSN: 1573-5117
    Keywords: Bdelloidea ; Philodinavidae ; rotatory apparatus ; phylogeny ; SEM ; systematics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Here we focus on the fine morphology and present observations on the biology of representatives of family Philodinavidae. Philodinavus paradoxus and Henoceros falcatus were collected and cultured under laboratory conditions. Rotifers of both species are tiny, about 200 μm long, have protrudable trophi and creep with leech-like movements. A very specific feature of these rotifers is their corona; a V-shaped lower lip contours the mouth opening, bilaterally bordered by two arched cuticular structures (‘cheeks’). The presence of the cheeks is a feature shared by the third genus, Abrochtha. On the basis of the morphology and biology of the three genera, we advance the hypothesis that Philodinavus is a primitive bdelloid, and that it can have originated Henoceros and Abrochtha, from which the other bdelloids could have stemmed.
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    The Philodinavidae (Rotifera Bdelloidea): a special family (1998)
    Springer
    Hydrobiologia 385 (1998), S. 77-85 
    Details
    ISSN: 1573-5117
    Keywords: Bdelloidea ; Philodinavidae ; rotatory apparatus ; phylogeny ; SEM ; systematics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Here we focus on the fine morphology and present observations on the biology of representatives of family Philodinavidae. Philodinavus paradoxus and Henoceros falcatus were collected and cultured under laboratory conditions. Rotifers of both species are tiny, about 200 μm long, have protrudable trophi and creep with leech-like movements. A very specific feature of these rotifers is their corona; a V-shaped lower lip contours the mouth opening, bilaterally bordered by two arched cuticular structures (‘cheeks’). The presence of the cheeks is a feature shared by the third genus, Abrochtha. On the basis of the morphology and biology of the three genera, we advance the hypothesis that Philodinavus is a primitive bdelloid, and that it can have originated Henoceros and Abrochtha, from which the other bdelloids could have stemmed.
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    The evolutionary relationships of rotifers and acanthocephalans (1998)
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    Hydrobiologia 387-388 (1998), S. 83-91 
    Details
    ISSN: 1573-5117
    Keywords: phylogeny ; acanthocephala ; rotifera ; bilateria ; evolution ; 18S rRNA gene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Advances in morphological and molecular studies of metazoan evolution have led to a better understanding of the relationships among Rotifera (Monogononta, Bdelloidea, Seisonidea) and Acanthocephala, and their relationships to other bilateral animals. The most accepted morphological analysis places Acanthocephala as a sister group to Rotifera, although other studies have placed Acanthocephala as a sister taxon to Bdellodea or Seisonidea. Molecular analyses using nuclear 18S rRNA and mitochondrial 16S rRNA genes support Acanthocephala as a sister taxon to Bdelloidea, although no molecular data is available for Seisonidea. Combining molecular and morphological analyses of Bilateria leads to a tree with Platyhelminthes, Rotifera, Acanthocephala and Gnathostomulida (and probably Gastrotricha) as a sister group to the annelid-mollusc lineage of the Spiralia (Lophotrochozoa).
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    A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 57-67 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; pharmacokinetics ; terephthalamidine ; NSC 57155 ; phthalanilides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p 〈 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.
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    Effect of Particle Size and Charge on the Disposition of Lipid Carriers After Intratumoral Injection into Tissue-isolated Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 128-132 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; liposome ; emulsion ; intratumoral injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. Methods. Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. Results. In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. Conclusions. The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.
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    Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1782-1786 
    Details
    ISSN: 1573-904X
    Keywords: bioavailability ; pharmacokinetics ; squalene synthase inhibitor ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38−40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111−120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.
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    Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 228-232 
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    ISSN: 1573-904X
    Keywords: risedronate ; gastrointestinal absorption ; gastrointestinal site ; bisphosphonate ; administration rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
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    Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 347-351 
    Details
    ISSN: 1573-904X
    Keywords: magnesium ; absolute bioavailability ; stable isotopes ; pharmacokinetics ; ICP-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011947525377
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    Blood-Brain Barrier Equilibration of Codeine in Rats Studied with Microdialysis (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 570-575 
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    ISSN: 1573-904X
    Keywords: microdialysis ; codeine ; morphine ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by micro-dialysis (MD). Methods. Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery. Results. Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 ± 0.25 and 0.95 ± 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 ± 0.12 for the exponential infusion. The half-lives were 25 ± 4 min, 22 ± 2 min in blood and 27 ± 5 min, 25 ± 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 ± 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCbIood,morphine/AUCblood,codeine ratio of 7.7 ± 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. Conclusions. Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.
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    Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 583-591 
    Details
    ISSN: 1573-904X
    Keywords: administration ; antisense ; bioavailability ; gastrointestinal ; intra-peritoneal ; intra-tracheal ; ISIS 3521 ; oligonucleotide ; oral ; pharmacokinetics ; subcutaneous
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (〈2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.
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    Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 883-888 
    Details
    ISSN: 1573-904X
    Keywords: transdermal access ; skin erosion ; transdermal ; dermal interstitial fluid ; sampling ; glucose ; monitoring ; diabetes mellitus ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7−21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3−17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.
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    Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 904-910 
    Details
    ISSN: 1573-904X
    Keywords: GS522 ; oligodeoxynucleotide ; pharmacokinetics ; tritiated ; biodistribution ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400μl, 31.46 μCi/ml) of 3H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t1/2 = 7.6−9.0 min, Cl = 22.0−28.0 ml/min, V = 83.9−132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and 〉0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p 〈 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p 〈 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.
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    Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1085-1089 
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    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
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    Guar Gum-Based Sustained Release Diltiazem (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1196-1201 
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    ISSN: 1573-904X
    Keywords: guar gum ; sustained release ; extended release ; diltiazem ; dissolution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions. Methods. Guar gum tablet formulations were prepared and evaluated under a variety of in vitro dissolution conditions. The formulations, along with Dilacor XR®, were administered to a group of eight fasted, healthy volunteers in a four period crossover study. Results. Varying the lot of guar gum as well as using guar from different suppliers had little effect on diltiazem dissolution. Also, dissolution of diltiazem from guar gum tablets was essentially independent of stir speed under normal conditions (USP Apparatus II). The stability of guar-based formulations under stressed conditions (40°C/75% relative humidity for 3 months) was also established. All four formulations gave similar plasma concentrations over time in the healthy volunteers pharmacokinetic study. Conclusions. Guar gum-based matrix tablets represent a simple and economical alternative to existing diltiazem sustained release dosage forms.
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    Pharmacokinetic and Pharmacoimmunodynamic Interactions Between Prednisolone and Sirolimus in Rabbits (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1888-1894 
    Details
    ISSN: 1573-904X
    Keywords: prednisolone ; sirolimus ; immunosuppressant ; interaction ; pharmacokinetics ; pharmacodynamics ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, 1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. Methods. After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along with blood granulocyte and T-helper cell counts. Ex vivo and in vitro whole blood lymphocyte proliferation marked lymphocyte reactivity. Results. Pred terminal half-life and clearance were 1.1 hr and 0.72 l/ hr/kg with no difference after Sir. Sir values were 13 hr and 0.16 1/hr/ kg and Pred produced no changes. Corticosterone production (0−12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. Conclusions. At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.
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    Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1895-1901 
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    ISSN: 1573-904X
    Keywords: IL-10 ; cytokines ; protein ; immunosuppression ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing. Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr. Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration. Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.
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    Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: propofol ; pharmacokinetics ; pharmacodynamics ; rats ; EEG ; fat emulsion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%®-like fat emulsion (Diprivan-10®, D) or as a 1%- or 6% emulsion in Lipofundin® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, λ2) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, λ2 (p 〈 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,1/2, keo) was observed compared to the other propofol formulations (p〈0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
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    Effect of GF120918, a Potent P-glycoprotein Inhibitor, on Morphine Pharmacokinetics and Pharmacodynamics in the Rat (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 599-605 
    Details
    ISSN: 1573-904X
    Keywords: morphine ; morphine-3-glucuronide ; P-glycoprotein ; pharmacokinetics ; pharmacodynamics ; antinociception ; central nervous system ; analgesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats. Methods. Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC. Results. Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; ke0 was significantly smaller for GF 120918- vs. vehicle-treated and control rats (0.060 ± 0.028 vs. 0.228 ± 0.101 vs. 0.274 ± 0.026 min−1, p=0.0023). EC50 and γ were similar between treatment groups. Conclusions. Pretreatment with GF 120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.
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    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
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    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
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    Correction for Non-Ideal Tracer Pharmacokinetic Disposition by Disposition Decomposition Analysis (DDA) (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1469-1473 
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    ISSN: 1573-904X
    Keywords: drug tracer ; labeling ; pharmacokinetics ; erythropoietin ; iodination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic (PK) studies assume that the tracer's PK is equivalent to the parent compound. This assumption is often violated. The aim of this work is to present a method enabling the ideal tracer PK, i.e. the PK of the parent compound, to be predicted from the non-ideal tracer. Methods. The procedure uses a disposition decomposition-recomposition (DDR) that assumes that the labeling mainly changes the elimination kinetics while the distribution kinetics is not significantly affected. In the DDR procedure an elimination rate constant correction factor (kCOR) is determined from a simultaneously fitting to plasma concentration data resulting from an i.v. injection of both the tracer and the parent compound. The correction factor is subsequently used to predict the ideal tracer PK behavior from the disposition function (i.v. bolus response) of the non ideal tracer. Results. The DDR method when applied to plasma level data of erythropoietin (r-HuEPO) and its iodinated tracer (l25I-r-HuEPO) from a high (4000U/kg) and a low (400U/kg) dosing of r-HuEPO in newborn lambs (n = 13) resulted in excellent agreements in the elimination rate corrected dispositions in all cases (r = 0.995, SD = 0.0095). The correction factor did not show a dose dependence (p 〉 0.05). The correction factors were all larger than 1 (kCOR = 1.94, SD = 0.519) consistent with a reduction in the EPO elimination by the iodination labeling. Conclusions. The DDR tracer correction methodology produces a better differentiation of the PK of endogenously produced compounds by correcting for the non-ideal PK behavior of chemically produced tracers.
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    Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1474-1479 
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    ISSN: 1573-904X
    Keywords: plasma clearance ; unbound plasma clearance ; inter-species scale-up in plasma clearance ; allometric analysis ; pharmacokinetics ; rat vs. human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the distribution of allometric exponents for relationship of total plasma clearance of 54 extensively metabolized drugs, with wide-ranging linear clearance values, between humans and rats, to provide a rationale for the observed data, and to discuss potential significance of the findings. Methods. Human and rat plasma clearance values of 54 drugs with markedly different physicochemical properties were obtained from the literature. Standard allometric analysis was performed for each drug using both rat and human data. Unbound vs. total plasma clearances were obtained for 15 out of 54 drugs and their correlations between humans and rats were compared. Results. The mean ± SD of the allometric exponent for the 54 drugs studied is 0.660 ± 0.190. The median clearance ratio based on unit body weight is 7.41 and the median exponent is 0.645. Excluding two outliers the correlation coefficient of plasma clearance between humans and rats was 0.745 (p 〈 0.0001). For the 15 drugs, use of unbound plasma clearance approach seems to significantly improve the correlation coefficient compared to total plasma clearance (0.940 vs. 0.841). Conclusions. The present study indicates that on average, humans and rats may eliminate extensively metabolized drugs at a rate similar to that expected from the allometric or body surface area relationship of basal metabolic rate between the two species. A simple statistical distribution hypothesis is used to rationalize the species difference in plasma drug clearance. Rat may serve as an useful animal model to predict (unbound) plasma clearance of drugs in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011974226596
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    Combined Use of Carboxyl-Directed Protein Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery System Optimizes Brain Uptake of Brain-Derived Neurotrophic Factor Following Intravenous Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 576-582 
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    ISSN: 1573-904X
    Keywords: pegylation ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peptide drug delivery to the brain requires optimization of (a) plasma pharmacokinetics and (b) blood-brain barrier (BBB) permeability. In the present studies, plasma pharmacokinetics are improved with protein pegylation and BBB transport is facilitated with the use of vector-mediated drug delivery using the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the BBB in vivo. Methods. A conjugate of OX26 and streptavidin (SA), designated OX26/SA, was prepared in parallel with the carboxyl-directed pegylation of brain-derived neurotrophic factor (BDNF). A novel bifunctional polyethyleneglycol (PEG) was used in which a hydrazide (Hz) was attached at one end and a biotin moiety was attached to the other end. This allowed for conjugation of BDNF-PEG-biotin to OX26/SA. Results. The brain uptake of BDNF-PEG-biotin was increased following conjugation to OX26/SA to a level of 0.144 ± 0.004% injected dose per g brain and a BBB permeability-surface area product of 2.0 ± 0.2 μL/min/g. Conclusions. These studies demonstrate that peptide drug delivery to the brain can be achieved with advanced formulation of protein-based therapeutics. The formulation is intended to (a) minimize rapid systemic clearance of the peptide, and (b) allow for vector-mediated drug delivery through the BBB in vivo. Following this dual formulation, the brain uptake of a neurotrophin such as BDNF achieves a value that is approximately 2-fold greater than that of morphine, a neuroactive small molecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011981927620
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    Alternative Cyanide-sensitive Oxidase Interacting with Photosynthesis in Synechocystis PCC6803. Ancestor of the Terminal Oxidase of Chlororespiration? (1998)
    Springer
    Photosynthetica 35 (1998), S. 223-231 
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    ISSN: 1573-9058
    Keywords: absorbance ; azide ; cyanobacteria ; cytochromes ; flash irradiation ; KCN ; NaN3 ; phylogeny ; respiration ; salicyl hydroxamic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Influence of respiration on photosynthesis in Synechocystis PCC6803 was studied by measuring the redox transients of cytochrome f (cyt f) upon excitation of the cells with repetitive single turnover flashes. Upon the addition of KCN the flash-induced oxidation of cyt f was increased and the rereduction of cyt f+ was accelerated. Dependence of these effects on the concentration of KCN clearly demonstrated the existence of two cyanide-sensitive oxidases interacting with photosynthesis: cyt aa3, which was sensitive to low concentrations of cyanide, and an alternative oxidase, which could be suppressed by using ≥1 mM KCN. The interaction between the photosynthetic and the respiratory electron transport chains was regulated mainly by the activity of the alternative cyanide-sensitive oxidase. The oxidative pathway involving the alternative cyanide-sensitive oxidase was insensitive to salicyl hydroxamic acid and azide. The close resemblance of the inhibition pattern reported here and that described for chlororespiration in algae and higher plants strongly suggest that an oxidase of the same type as the alternative cyanide-sensitive oxidase of cyanobacteria functions as a terminal oxidase in chloroplasts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006958706540
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    Pharmacokinetics of antipyrine in rats with different resistance to hypoxia in cold stress (1998)
    Springer
    Bulletin of experimental biology and medicine 126 (1998), S. 1098-1099 
    Details
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; antipyrine ; individual resistance to hypoxia ; cold stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It is shown that the parameters of antipyrine pharmacokinetics during cold exposure depend on individual resistance to hypoxia. High-resistant rats are characterized by less intense metabolism and more rapid normalization of pharmacokinetic parameters than lowresistant rats characterized by shortened elimination half-time corresponding to a more rapid metabolism of xenobiotics under conditions of cold stress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02447243
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