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  • pharmacokinetics  (417)
  • Drosophila  (116)
  • Springer  (533)
  • 1980-1984  (533)
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  • 1940-1944
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  • 1
    Electronic Resource
    Electronic Resource
    A note on the rôle of generalized inverse Gaussian distributions of circulatory transit times in pharmacokinetics (1984)
    Springer
    Journal of mathematical biology 20 (1984), S. 95-102 
    Details
    ISSN: 1432-1416
    Keywords: pharmacokinetics ; generalized inverse Gaussian distribution ; recirculatory model ; renewal theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Mathematics
    Notes: Abstract Based on a stochastic pharmacokinetical model (which mirrors topological properties of the circulatory system) it is shown by reinterpreting results of Wise (1974) that if the transit times of circulating drug molecules have a generalized inverse Gaussian distribution the corresponding residence times are gamma distributed. The condition that the probability of elimination of a drug molecule in a single circulatory passage is sufficiently small appears to be valid for most drugs. Thus theoretical evidence is given for fitting blood concentration-time curves following bolus injection of a single dose by power functions of time.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00275864
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  • 2
    Electronic Resource
    Electronic Resource
    On the relation between genetic and environmental variability in animals (1982)
    Springer
    Journal of molecular evolution 18 (1982), S. 310-314 
    Details
    ISSN: 1432-1432
    Keywords: Neutral mutation theory ; Natural selection ; Protein evolution ; Levene model ; Environmental variability ; Genetic variability ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary If a phenotypic character is under stabilizing selection, the selective disadvantage of a nonoptimal genotype will decrease exponentially to zero as the proportion of phenotypic variation that is environmental in origin -V e /V p - increases. Under the modified mutation-drift hypothesis of genetic polymorphism, the proportion of mutations that are effectively neutral and average heterozygosity should increase with this ratio. Invertebrates, because of their small size, fast development, and low degree of homeostasis (relative to vertebrates), are expected to show a larger environmental component of phenotypic variation than vertebrates. This may help explain why invertebrates are in general more genetically variable than vertebrates and why, when laboratory populations ofDrosophila are maintained in heterogeneous environments, genetic variability is lost less rapidly than when they are kept in constant conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01733897
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  • 3
    Electronic Resource
    Electronic Resource
    Adaptation ofDrosophila enzymes to temperature. III. Evolutionary conservatism in mitochondrial enzymes (1980)
    Springer
    Journal of molecular evolution 16 (1980), S. 37-46 
    Details
    ISSN: 1432-1432
    Keywords: Evolution ; Drosophila ; Temperature ; Mitochondrial enzymes ; Kinetic properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The evolutionary behavior of two mitochondrial enzymes (L-glycerol 3-phosphate:cytochrome c oxidoreductase E.C.1.1.1.95,αGPO, and L-malate: NAD+ oxidoreductase, E.C.1.1.1.37, m-MDH) obtained from several temperate and tropicalDrosophila species was examined by comparing their catalytic properties, which related to temperature (Km-Ea-Q10-Thermostability). MitochondrialαGPO or m-MDH obtained either from temperate or from tropical species was found to exhibit similar catalytic properties while for both cytosolic enzymes, theαGPDH and s-MDH, Km patterns were similar among species from the same thermal habitat and different between thermal habitats. In combination with other observations reported in the literature these facts support the view that the function, and probably the structure, of mitochondrial enzymes are better conserved in evolution than those of the corresponding enzymes found in the cytosol. It is proposed that the relative invariance of the mitochondrial enzymes structure is probably linked to a necessary relative invariance of molecular interactions inside the mitochondrion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01732068
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  • 4
    Electronic Resource
    Electronic Resource
    Adjacent chromosomal regions can evolve at very different rates: Evolution of theDrosophila 68C glue gene cluster (1984)
    Springer
    Journal of molecular evolution 20 (1984), S. 251-264 
    Details
    ISSN: 1432-1432
    Keywords: Drosophila ; Genome evolution ; 68C Glue gene cluster ; Drosophila melanogaster species subgroup
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The 68C puff is a highly transcribed region of theDrosophila melanogaster salivary gland polytene chromosomes. Three different classes of messenger RNA originate in a 5000-bp region in the puff; each class is translated to one of the salivary gland glue proteins sgs-3, sgs-7, or sgs-8. These messenger RNA classes are coordinately controlled, with each RNA appearing in the third larval instar and disappearing at the time of puparium formation. Their disappearance is initiated by the action of the steroid hormone ecdysterone. In the work reported here, we studied evolution of this hormone-regulated gene cluster in themelanogaster species subgroup ofDrosophila. Genome blot hybridization experiments showed that five other species of this subgroup have DNA sequences that hybridize toD. melanogaster 68C sequences, and that these sequences are divided into a highly conserved region, which does not contain the glue genes, and an extraordinarily diverged region, which does. Molecular cloning of this DNA fromD. simulans, D. erecta, D. yakuba, andD. teissieri confirmed the division of the region into a slowly and a rapidly evolving protion, and also showed that the rapidly evolving region of each species codes for third instar larval salivary gland RNAs homologous to theD. melanogaster glue mRNAs. The highly conserved region is at least 13,000 bp long, and is not known to code for any RNAs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02104731
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  • 5
    Electronic Resource
    Electronic Resource
    Developmental studies on two ecdysone deficient mutants ofDrosophila melanogaster (1980)
    Springer
    Development genes and evolution 189 (1980), S. 57-67 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Ecdysone deficient mutants ; Ecdysteroid titer ; Ring gland ; Fine structure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary This paper describes two ecdysone-deficient, recessive-lethal mutants,lethal(1)giant ring gland (grg) andlethal(1)suppressor of forked mad-ts (mad-ts: Jürgens and Gateff 1979) and compares their ecdysteroid titers with that of the wild-type. Mutant larvae show a much reduced ecdysteroid content, amounting to 1/10 to 1/30 of the wild-type values, but never a true titer peak. They fail to pupate and die after 1–3 weeks. Ecdysteroid feeding elicits different responses in the larvae of the two mutants.mad-ts larvae pupate within 24 h, thus showing that their low ecdysteroid titer is directly connected to their inability to pupate.mad-ts resembles the mutantlethal (3)ecdysone-1 ts (Garen et al. 1977). Thegrg mutant larvae, on the other hand, fail to pupate after 20-hydroxyecdysone feeding as well as injection. The primary defect of thegrg mutant is not entirely clear. Thegrg larval salivary gland cells appear to possess normal ecdysteroid receptors. Furthermore, the low ecdysteroid titer ingrg is not the result of an increased ecdysteroid catabolism. The primary defect in the mutant may lie in the malfunctioning neurosecretory cells which do not show neurosecretion in histological preparations. Further support for this notion comes from electronmicrographs of the enlargedgrg ring glands which, in contrast to the wild-type, do not possess nerve endings. In the wild-type three ecdysteroid peaks were found: one shortly before puparium formation, the second at approximately 12 h and the third at about 30 h after pupation. The ecdysteroid titer peak in late third instar, wild-type larvae is mainly due to the presence of 20-dydroxyecdysone as shown by radioimmunoassays after thin layer chromatography and derivatization followed by gas liquid chromatography and mass spectroscopy. In addition, a number of unidentified polar and apolar metabolites were also present.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848567
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  • 6
    Electronic Resource
    Electronic Resource
    Imaginal disc development in a non-pupariating lethal mutant inDrosophila melanogaster (1981)
    Springer
    Development genes and evolution 190 (1981), S. 11-21 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Ecdysteroid ; Lethal mutant ; Morphogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Imaginal disc development in the non-pupariating lethall(1)npr-1, a mutant that maps to an ecdysone early puff site, is studied in situ, in vitro and in transplanted discs. Disc development is slightly abnormal from the middle of the third instar with severe abnormalities appearing after the rise in 20-hydroxyecdysone that triggers metamorphosis. The mutant discs only partly evaginate and do not undergo any of the detailed morphological changes characteristic of metamorphosis. Treatment of the mutant dises in vitro with colcemid and trypsin facilitates evagination but the appendages remain morphologically abnormal. A number of differentiative processes occur in mutant discs in situ and in discs transplanted into wild type hosts in spite of the absence of normal morphogenesis. Implications of the observations for normal disc development are discussed. Possible modes of action of thel(1)npr-1 gene are also discussed in light of the observation that the mutant gene maps to a locus which is thought to have a regulatory function in development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00868698
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  • 7
    Electronic Resource
    Electronic Resource
    A maternal effect mutation leading to deficiencies of organs and homeotic transformations in the adults ofDrosophila (1981)
    Springer
    Development genes and evolution 190 (1981), S. 132-138 
    Details
    ISSN: 1432-041X
    Keywords: Maternal effect mutant ; Homeotic-mutants ; Pattern formation ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The temperature sensitive mutationfs(l)h is characterized at the restrictive temperature of 29°C by both a maternal effect responsible for the early embryonic lethality and pupal zygotic lethality. The two phenotypes are inseparable and map at a short deletion in the X chromosome (7Dl, 7D5-6). At semipermissive temperatures, hemizygous mutant females produce adults with morphological defects, such as organ deficiencies and homeotic transformations of haltere to wing and third leg to second leg. These defects depend on the maternal genotype and are governed by an early temperature sensitive period, which covers the end of oogenesis and the first hours of embryogenesis. Furthermore, this maternal effect mutation interacts with some dominant mutations of the bithorax system. These properties suggest thatfs(l)h is somehow involved in segmental determination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00867798
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  • 8
    Electronic Resource
    Electronic Resource
    The role of the peripodial membrane in the morphogenesis of the eye-antennal disc ofDrosophila melanogaster (1983)
    Springer
    Development genes and evolution 192 (1983), S. 164-170 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal disc ; Morphogenesis ; Tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The early morphogenesis of the eye-antennal disc ofDrosophila in response to 20-hydroxy ecdysone involves the curling of the eye anlagen dorsally over the antenna. During this process, the area of the peripodial membrane is substantially reduced. The peripodial membrane is taut at this stage, and if it is cut the curling of the disc cannot continue, and the eye anlagen returns to its original position within one minute of the operation. In contrast, cutting the columnar epithelium between the eye and antennal anlagen does not disrupt curling, but actually facilitates it. During curling, the cells of the peripodial membrane appear healthy, and exhibit basal extensions. We suggest that the curling of the eye is mediated by the conversion of cuboidal peripodial membrane cells into pseudostratified columnar epithelium at the edges of the peripodial membrane. Subsequently, cells of the peripodial membrane secrete first a pupal cuticle, and then an imaginal cuticle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848686
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  • 9
    Electronic Resource
    Electronic Resource
    Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster (1984)
    Springer
    Development genes and evolution 193 (1984), S. 267-282 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Larval cuticle ; Pattern formation ; Embryonic lethal mutations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In a search for embryonic lethal mutants on the second chromosome ofDrosophila melanogaster, 5764 balanced lines isogenic for an ethyl methane sulfonate (EMS)-treatedcn bw sp chromosome were established. Of these lines, 4217 carried one or more newly induced lethal mutations corresponding to a total of 7600 lethal hits. Eggs were collected from lethal-bearing lines and unhatched embryos from the lines in which 25% or more of the embryos did not hatch (2843 lines) were dechorionated, fixed, cleared and scored under the compound microscope for abnormalities of the larval cuticle. A total of 272 mutants were isolated with phenotypes unequivocally distinguishable from wild-type embryos on the basis of the cuticular pattern. In complementation tests performed between mutants with similar phenotype, 48 loci were identified by more than one allele, the average being 5.4 alleles per locus. Complementation of all other mutants was shown by 13 mutants. Members of the complementation groups were mapped by recombination analysis. No clustering of loci with similar phenotypes was apparent. From the distribution of the allele frequencies and the rate of discovery of new loci, it was estimated that the 61 loci represent the majority of embryonic lethal loci on the second chromosome yielding phenotypes recognizable in the larval cuticle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848156
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  • 10
    Electronic Resource
    Electronic Resource
    The role of the peripodial membrane of leg and wing imaginal discs ofDrosophila melanogaster during evagination and differentiation in vitro (1984)
    Springer
    Development genes and evolution 193 (1984), S. 180-186 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal disc ; Morphogenesis ; Tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The thin region of the peripodial membrane is confined to the area overlying the distal anlagen in thoracic discs. During the early stages of evagination the peripodial membrane is greatly stretched, but does not rupture. The appendage then evaginates through the stalk, probably by means of a contraction of the peripodial membrane. The cells of the peripodial membrane of leg and wing discs persist and differentiate sheets of trichomes characteristic of the ventral and lateral thorax. This is discussed in relation to imaginal disc fate maps.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848893
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  • 11
    Electronic Resource
    Electronic Resource
    The morphological response of Kc-H cells to ecdysteroids: Hormonal specificity (1980)
    Springer
    Development genes and evolution 189 (1980), S. 1-15 
    Details
    ISSN: 1432-041X
    Keywords: Cell line ; Drosophila ; Ecdysone ; Ecdysterone ; Hormones
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Cells of the line Kc, derived fromDrosophila melanogaster embryos, extend long processes when exposed to ecdysteroid hormones. We have devised a quantitative assay for this morphological response, using the subline Kc-H. The assay was used to characterize the conditions required for the response. A halfmaximal response is elicited by approximately 10−8M 20-hydroxyecdysone; the response is saturated by 10−7M 20-hydroxyecdysone, which causes detectable elongation within a few hours, and a maximal response after 2–3 days. The response occurs substantially normally in the absence of serum, during growth in suspension, and in over-crowded cultures. It is not elicited by cyclic nucleotides, vertebrate growth factors, or a variety of other non-ecdysteroid reagents. Of 60 ecdysteroid compounds tested, only those which were active in other insect test systems elicited the response, and the concentrations required were approximately proportional to the concentrations active in other in vitro systems. We conclude that the response of Kc cells to 20-hydroxyecdysone retains basic features of the ecdysteroid response of intact tissues and therefore that Kc cells are a useful model system for studying ecdysteroid action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848562
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  • 12
    Electronic Resource
    Electronic Resource
    Crosslinking of theDrosophila chorion involves a peroxidase (1980)
    Springer
    Development genes and evolution 189 (1980), S. 187-196 
    Details
    ISSN: 1432-041X
    Keywords: Eggshell ; Chorion ; Peroxidase ; Crosslinking ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary TheDrosophila chorion contains an endogenous peroxidase activity which remains inactive until late stage 14 when it catalyzes the crosslinking of the chorionic proteins. Using explanted follicles developing in vitro, premature, but otherwise normal crosslinking can be induced with hydrogen peroxide and normal crosslinking can be prevented with peroxidase inhibitors. Inhibition or premature activation of the shell peroxidase allows characterization of chorionic filament specific proteins and establishes new criteria for the identification of eggshell components.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00868677
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  • 13
    Electronic Resource
    Electronic Resource
    A cell arrangement specific to thoracic ganglia in the central nervous system of theDrosophila embryo: Its behaviour in homoeotic mutants (1981)
    Springer
    Development genes and evolution 190 (1981), S. 370-373 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Homoeotic mutants ; Ventral cord
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We describe a set of cells in the central nervous system of theDrosophila embryo which are restricted to the thoracic ganglia in the wildtype. Taking these cells as indication of thoracic identity, we find that the ventral cord of embryos homozygous mutant for different bithorax functions and for Polycomb undergoes homoeotic transformations equivalent to those observed in the larval cuticle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00863276
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  • 14
    Electronic Resource
    Electronic Resource
    A clonal analysis of cell lineage and growth in the male and female genital disc ofDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 42-55 
    Details
    ISSN: 1432-041X
    Keywords: Clonal analysis ; Growth ; Cell lineage ; Genital disc ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary InDrosophila, the terminalia (i.e. internal and external analia and genitalia, except the gonads) are formed by the genital disc. Comparative studies suggested that this disc may have evolved through fusion of the imaginal primordia of the last 3 or 4 abdominal segments. The present report describes the clonal relationships within the complex genital disc. Genetically marked cell clones were induced in male and female embryos and larvae heterozygous for cell marker mutations. 1) Frequencies and sizes of clones suggest that the embryonic disc anlage consists of 14–17 precursor cells: 4–6 for the analia, some 7 for the male genitalia, and 3–4 for the female genitalia. These cells grow exponentially during larval development. 2) In both sexes, the clones were confined to either analia or genitalia, suggesting two separate cell lineages already established at blastoderm. 3) Internal and external genitalia remain in the same compartment at least up to 60 h (end of first instar). 4) A clonal restriction appeared around 84 h (mid second instar), separating a dorsal from a ventral part in the male genitalia. The ventral compartment comprises the ventral part of the lateral plate and clasper, hypandrium, and all internal genitalia. No such boundary was detected in the female. 5) In the female, analia and parovaria originate from the same precursors; another cell lineage forms eighth tergites, vaginal plates, oviduct, receptacle, and spermathecae. 6) In female analia, dorsal and ventral plate share common precursors at least up to 84 h. A medio-lateral boundary may appear at 84 h in the ventral anal plate. No clonal restriction was found in the male analia. 7) At all times, clones could cross between left and right sides of the symmetrical terminalia; they consistently did so via ventral structures. 8) The results are discussed in a phylogenetic context, and we propose that the clonal relations reflect the evolution of the complex genital disc.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848545
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  • 15
    Electronic Resource
    Electronic Resource
    Maternal effects of zygotic mutants affecting early neurogenesis inDrosophila (1982)
    Springer
    Development genes and evolution 191 (1982), S. 191-201 
    Details
    ISSN: 1432-041X
    Keywords: Neurogenic mutants ; Maternal effects ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The size of the neurogenic region ofDrosophila melanogaster is under the control of several genes of zygotic expression. Lack of function from any of those genes produces an increase of the size of the neurogenic region at the expense of the epidermal anlage. However, differences exist in the extent of neuralisation achieved by each of the genetic loci upon mutation. The present results show that in the case ofN andmam phenotype differences are due to different contributions of maternal gene expression. This could be shown by studying the phenotype which appeared in mutant embryos when the oocytes developed from homozygous mutant precursor cells. Clones of mutant cells were induced in the germ line of females heterozygous for the neurogenic mutationin trans over germ line dependent, dominant female sterile mutations. After removing maternal information the phenotype ofN andmam mutants became identical in both cases. Furthermore maternal information fromN + was found to be necessary for viability of the wildtype.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848335
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  • 16
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    Clonal analysis ofsex-lethal, a gene needed for female sexual development inDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 211-214 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Clonal analysis ; Sex determination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The mutationSxl f , located on the X-chromosome, is a sex-limited recessive lethal that specifically kills 2X; 2A flies while it does not affect X; 2A flies (Cline 1978). We have analyzed the role ofSxl f on sex determination by a clonal analysis of a new spontaneous allele,Sxl fLS . Female embryos and larvae heterozygous forSxl fLS were irradiated at different times of development to generate homozygousSxl fLS clones which were recognized by linked marker mutations. We have studied the phenotype of such clones on sexually dimorphic regions of the fly (foreleg basitarsus, 5th, 6th and 7th tergites, analia and external genitalia). Despite their female (2X; 2A) chromosomal constitution, clones homozygous forSxl fLS differentiated male structures. These results confirm and extend the preliminary report of Cline (1979). They show that the wildtype product ofSxl f is required for female development.
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    URL: http://dx.doi.org/10.1007/BF00848339
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  • 17
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    Effects of the “sexcombless” chromosome (In(1)sx) on males and females ofDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 264-269 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Sexcombless ; Foreleg basitarsus ; Genital disc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The chromosome which carries the mutationsexcombless (In(1)sx) affects males and females ofD. melanogaster. In the male foreleg basitarsi the number of sexcomb teeth is dramatically reduced from 10 to 0.7 and the number of transverse rows of bristles is increased from 6 to 8. Females homozygous forIn(1)sx show a normal bristle pattern in the foreleg basitarsus. The genital disc derivatives of both male and femaleIn(1)sx flies are strongly affected. While the external genitalia show a duplicated or a reduced bristle pattern, the internal genitalia are mostly absent. However, the sexually dimorphic tergites and sternites of the abdomen remain unaffected. The male-specific effect on the basitarsus and the general effects on the genital disc derivatives are proposed to represent two different phenotypic effects ofIn(1)sx which may derive from mutations at different gene loci in the inverted chromosome.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848414
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  • 18
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    Growth is required for cell competition in the imaginal discs ofDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 289-291 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Cell competition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Imaginal wing discs from late third-instar larvae were gammairradiated to induce clones of rapidly growingMinute − cells in a background of slowly growingMinute cells and culturedin vivo for periods up to 18 days. Clones in discs cultured for 16 to 18 days did not grow significantly larger than clones in uncultured controls, indicating that competition between populations of cells having potentially different mitotic rates does not occur in imaginal discs after their growth is completed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00848419
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  • 19
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    Changes in the distribution of gap junctions inDrosophila melanogaster wing discs during the third larval and early pupal stages of development (1984)
    Springer
    Development genes and evolution 193 (1984), S. 187-196 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Gap junction ; Imaginal disc ; Pattern formation ; EM Stereology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Developmental changes in the distribution of gap junctions in early, mid and late third larval stage wing discs and in pupariation+6 h and pupariation+24 h stage wing discs fromDrosophila melanogaster were analyzed by quantitative electron microscopy. Gap junctions occur in all 12 intradisc regions examined in each of the five developmental stages. Their distribution is non-random and changes during development which suggests that they are developmentally regulated. The gap junctions are not static structures, rather they grow and regress during development. The changes tend to be gradual ones without sudden increases or decreases. Gap junctions continuously form and grow in size throughout the third larval stage and during the first 6 h following pupariation. Their surface density, number, percent of the lateral plasma membrane area, and absolute area as well as the lateral plasma membrane surface density all increase during this time. Between pupariation+ 6 h and pupariation+24 h all but one of these parameters decrease indicative of gap junctional breakdown. Gap junctions are most numerous and change least during development in the apical cell regions where intercellular contacts are close and stable. They change most in the basal cell regions where intercellular contacts tend to be looser and change during development. The most dramatic change is in the absolute area which increases by a factor of 23 between the early third larval stage and pupariation+24 h. At pupariation the rate of gap junction growth undergoes a transient increase before the phase of disassembly begins. Developmental changes in gap junction surface density are closely coupled with changes in the lateral plasma membrane surface density which suggests that these may be coregulated. Evidence from mutants suggests that when the number and density of gap junctions fail to increase in proportion to lateral plasma membrane growth, wing disc development will be abnormal. Our results support the idea that some minimum gap junction density is required for normal development and that this must increase as development proceeds. The results are consistent with the notion that gap junctions are involved in pattern formation and growth control and are discussed with respect to the acquisition of competence for metamorphosis, disc growth, disc morphogenesis and changes in the hormonal environment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01260338
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  • 20
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    Expression of the zygotic genome in blastoderm stage embryos ofDrosophila: Analysis of a specific protein (1980)
    Springer
    Development genes and evolution 188 (1980), S. 153-156 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Embryogenesis ; mat (3) 1 mutation ; Two-dimensional gels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The synthesis of a protein which has been detected in blastoderm cells but not in pole cells (Gutzeit and Gehring 1979) has been studied further by means of two-dimensional gel electrophoresis. This protein could not be detected at the nuclear multiplication stage. The protein is translated from mRNA which is transcribed at the blastoderm stage since it is not synthesized in detectable amounts when embryos are injected with α-amanitin prior to the blastoderm stage. Also the protein could not be detected when RNA from freshly laid eggs was translated in vitro. Embryos from females which are homozygous for the mutationmat (3) 1 form pole cells but no blastoderm cells (Rice and Garen 1975). Thesemat (3) 1 embryos, as we will call them in this report, express the protein if aged for a period of time sufficient for completion of blastoderm cell formation in control wild-type embryos.mat (3) 1 embryos and embryos injected with α-amanitin show the same syndrome of visible developmental anomalies; however, the studied protein could only be detected inmat (3) 1 embryos but not in α-amanitin injected embryos.
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    Characterization by isoelectric focusing of chorion protein variants inDrosophila melanogaster and their use in developmental and linkage analysis (1980)
    Springer
    Development genes and evolution 189 (1980), S. 17-24 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Geographic strains ; Chorion proteins ; Electrophoretic variants ; Chorion gene linkage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Drosophila melanogaster chorion proteins are characterized on one-dimensional isoelectric focusing (IF) gels. The six major chorion components previously identified on SDS gels are shown to resolve into at least 11 components in our IF system. IF screening of 102 geographic strains ofDrosophila melanogaster revealed seven cases of variation in major chorion components. Two strains, Crimea and Falsterbo, which were monomorphic for a variant B1 protein and two strains, Skafto and Lausanne, which were monomorphic for a variant C1 protein, were chosen for further study. After IF developmental analysis of F1 hybrids had indicated that the sources of the variation resided in the structural genes for these proteins, each variant was crossed to a multiply marked and inverted strain (BLT) to determine the linkage group of the variant gene. To localize genes to more specific sites multiply marked 3rd (SKERO) or X-chromosomal (CB1) (X-PLE) mapping strains were used. In both Crimea and Falsterbo the gene for the B1 protein is located near map location 26 on the 3rd chromosome. In both Lausanne and Skafto the C1 gene is located on the X chromosome. Hence, for the first time, we have demonstrated genetically the non-linkage of two chorion genes, B1 and C1.
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    Timing and heritability of theNasobemia transformation inDrosophila (1980)
    Springer
    Development genes and evolution 189 (1980), S. 147-153 
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    ISSN: 1432-041X
    Keywords: Homeotic mutant ; Drosophila ; Clonal analysis ; Timing of gene action ; Determination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Nasobemia (Ns) is a dominant homeotic mutant ofDrosophila melanogaster which converts parts or all of the antenna to mesothoracic leg.Ns has a temperature sensitive period between 48 and 60 h. The hypothesis thatNs acts during this period and is not required thereafter to maintain the homeotic transformation to leg was tested by removingNs fromNs/+ cells at different stages of development through X-ray induced somatic recombination. The expression of theNs homeotic transformation in recombinant wild type (+/+) cells increased sharply between 48 and 65 h. In clones induced after 65 h the expression of the leg transformation was equal in large and small +/+ clones. We interpret these results as supporting the hypothesis that transient action ofNs between 48 and 65 h switches antennal cells to a clonally stable leg determined state whose maintenance does not require futherNs action.
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    Normal and lectin-mediated aggregation in aDrosophila cell line (1981)
    Springer
    Development genes and evolution 190 (1981), S. 118-122 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Aggregation ; Lectins ; Cell surface ; Embryo-derived cell line
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In this paper we describe the aggregation of cells from embryo-derived cell lines ofDrosophila, measured by examining the ability of single cells to adhere to one another when suspended in culture medium and swirled on a rotary shaker. Using this method we demonstrated the presence of receptors for Concanavalin A, soybean agglutinin, and possibly wheat germ agglutinin on the surface of Schneider's line-2 cells. Our work provides basic descriptive and background information for further studies onDrosophila cells, including those isolated from imaginal discs.
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    Evidence for myosin heterogeneity inDrosophila melanogaster (1981)
    Springer
    Development genes and evolution 190 (1981), S. 297-300 
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    ISSN: 1432-041X
    Keywords: Myosins ; Drosophila ; muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Electrophoresis of myosin extracts from larvae and adult tissues ofDrosophila melanogaster under non-dissociating conditions indicate that two of the bands seen are myosins. They stain for Ca2+ ATPase activity and when cut and re-run under dissociating conditions are found to contain a myosin heavy chain that co-migrates with rabbit skeletal muscle myosin heavy chain. One of the forms of myosin seen is found primarily in extracts from the leg. The other is common to the adult fibrillar flight muscles and the larval body wall muscles. The electrophoretic evidence for two myosin types is strengthened by the histochemical demonstration of two myofibrillar ATPases on the basis of their lability to acid or alkali preincubation. The myofibrillar ATPase in the leg and the Tergal Depressor of the Trochanter (TDT) are shown to be relatively acid labile and alkali stable. The larval body wall muscles and the adult fibrillar flight muscles have an ATPase which is acid stable and alkali labile. This distribution of the two myofibrillar ATPase coincides with that predicted by electrophoresis of extracts from whole tissue and also locates the two myosins to specific muscle types.
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    Homologies of positional information in thoracic imaginal discs ofDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 293-300 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Positional information ; Homology ; Intercalary regeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The regulative behavior of fragments of the imaginal discs of the wing and first leg was studied when these fragments were combined with fragments of other thoracic imaginal discs. A fragment of the wing disc which does not normally regenerate when cultured could be stimulated to regenerate by combination with certain fragments of the haltere disc. When combined with a haltere disc fragment thought to be homologous by the criteria of morphology and the pattern of homoeotic transformation, such stimulated intercalary regeneration was not observed. Combinations of first and second leg disc fragments showed that a lateral first leg fragment could be stimulated to regenerate medial structures when combined with a medial second leg disc fragment but not when combined with a lateral second leg disc fragment. Combinations of wing and second leg disc fragments showed that one fragment of the second leg disc is capable of stimulating regeneration from a wing disc fragment while another second leg disc fragment fails to stimulate such regeneration. It is suggested that absence of intercalary regeneration in combinations of fragments of different thoracic imaginal discs is a result of homology or identity of the positional information residing in the cells of the fragments. The pattern of correspondence of positional information revealed by this analysis is consistant with the pattern of homology determined by morphological observation and by analysis of the positional specificity of homoeotic transformation among serially homologous appendages. The implications of the existence of homologous positional information in wing and second leg discs which share a common cell lineage early in development are discussed.
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    Gap junctions are non-randomly distributed inDrosophila wing discs (1982)
    Springer
    Development genes and evolution 191 (1982), S. 335-339 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Gap junction ; Wing disc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The distribution of gap junctions in mature larvalDrosophila melanogaster wing discs was analyzed by means of quantitative electron microscopy. Gap junctions are non-randomly distributed in the proximal-distal disc axis and in the apical-basal cell axis of the epithelium. In the epithelial cells, the surface density, number and length of gap junctions are greatest in the apical cell region and distal disc region. The average gap junction surface density is 0.0572 μm−1 and 2.77% of the lateral cell surface is composed of gap junctions. In the adepithelial cells, the gap junction surface density is 0.0005 μm−1 and 0.06% of the cell surface is composed of gap junctions. No gap junctions were observed between epithelial cells and adepithelial cells. The absolute area of gap junctions was estimated in a proximal-distal strip of cells in the disc and is considerably less in the folded regions of the epithelium compared to the flat notum and wing pouch regions. The results are discussed with respect to pattern formation and growth control in imaginal discs.
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    Embryogenesis inDrosophila: Can a single mechanism explain the developmental segregation of germ-line and somatic cells and their subsequent determination? (1980)
    Springer
    Development genes and evolution 188 (1980), S. 179-185 
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    ISSN: 1432-041X
    Keywords: Determination ; Germ-line ; Somatic cells ; Inhibitor gradient hypothesis ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary A hypothesis is presented which explains the segregation of germ cells from somatic cells, and the subsequent determination of both cell types with a single mechanism. This hypothesis is in part based on that of Meinhardt (1977) and can be summarized as follows: In the newly fertilized egg, the action of a sink in the pole plasm leads to the formation of an anterior-posterior gradient of an inhibitor. The concentration of this inhibitor in the posterior 20% of the egg is below that needed to repress synthesis of an activator. When, during the nuclear division stage, nuclei enter this posterior region, synthesis of the activator begins. As the activator is autocatalytic, this leads to the formation of a peak of activator in this region; and since the activator also catalyses the synthesis of the inhibitor, a peak of inhibitor is formed in the same place. The inhibitor then diffuses anteriorly through the periplasm, forming a posterior-anterior gradient. The presence of this inhibitor in the periplasm causes the nuclei that enter the periplasm to form blastoderm cells and to take up particular segmental states appropriate to their position, while those that remain in the yolk-containing plasm develop into vitellophages. The action of the sink in the pole plasm is postulated to result in the formation of the pole cells, and subsequently to direct some of these into forming cells of the germ-line.
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    The effect of temperature onshibire ts cell clones in the compound eye ofDrosophila melanogaster (1980)
    Springer
    Development genes and evolution 188 (1980), S. 55-63 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Compound eye ; shibire ts ; Development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have analysed the effect of temperature on both developing and adult eye cell clones homozygous forshi ST139, a temperature-sensitive mutant ofDrosophila melanogaster. The mutant gene, autonomous in its cellular expression, causes structural modifications of ommatidial cells when adult clones of cells are exposed to the restrictive temperature (29°C) for several days. However, the mutant phenotype reverses to normal within 4 days at the permissive temperature (20°C). The results of pulse, shift-up and shift-down experiments show that the temperaturesensitive period for developing compound eye cells is from the late second instar up to the early pupa. Cytodifferentiation of compound eye cells is blocked by restrictive temperature treatment during this period, whereas cell proliferation does not seem to be directly affected. These results are discussed with regard to the other known aspects of the phenotype observed in mutant individuals.
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    Compartments and distal outgrowth in theDrosophila imaginal wing disc (1980)
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    Development genes and evolution 188 (1980), S. 157-161 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Compartments ; Distal outgrowth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Peripheral tissue of the imaginal wing disc gives rise to the proximal mesothoracic structures of the adult. Pieces of peripheral tissue, which have no regenerative capacity when cultured as intact fragments, are capable of distal outgrowth (regeneration) after dissociation and reaggregation. This ability depends on the region of the disc periphery from which the fragment is taken. Extensive distal outgrowth occurs in reaggreages of a fragment containing equal proportions of tissue from anterior and posterior developmental compartments. The extent of outgrowth decreases as the proportion of posterior tissue is reduced, so that a fragment containing only anterior tissue shows no regeneration after dissociation. Limited distal outgrowth occurs in reaggregates of a wholly posterior fragment, but the regenerative capacity is increased greatly when a small amount of anterior tissue is included. It is concluded that distal outgrowth in the wing disc requires an interaction between cells of the anterior and posterior compartments.
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    Is regeneration inDrosophila the result of epimorphic regulation? (1980)
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    Development genes and evolution 189 (1980), S. 91-96 
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    ISSN: 1432-041X
    Keywords: Epimorphic regulation ; Drosophila ; Imaginal discs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary It has been known for many years that when a wing disc ofDrosophila is bisected, and the fragments cultured in adult females, regulation occurs and either a complete disc is regenerated or the fragment is duplicated. We have investigated how this regeneration process occurs. To establish which cells contribute to the regenerate, and thus determine if regeneration is the result of epimorphic regulation, fragments of discs, after culture in an adult for one to five days, were exposed to3H-thymidine to label replicating cells. Imaginal discs, both whole and as regenerating fragments, undergo some DNA replication which is distributed throughout the disc, but cut discs frequently show clusters of labelled cells around the wound, indicating that regeneration is probably epimorphic.
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    Wound healing and regeneration in the imaginal wing disc ofDrosophila (1981)
    Springer
    Development genes and evolution 190 (1981), S. 185-190 
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    ISSN: 1432-041X
    Keywords: Wound healing ; Regeneration ; Imaginal discs ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary When complementary fragments of an imaginal disc ofDrosophila are cultured for several days prior to metamorphosis, usually one fragment will regenerate while the other will duplicate. It has been proposed that wound healing plays an important part in disc regulation (French et al. 1976; Reinhardt et al. 1977) by initiating cell proliferation and determining the mode of regulation. We tried to delay the wound healing process by leaving a region of dead cells between the wound edges. In “06” fragments (Bryant 1975a) wound healing has occurred after 1–2 days of culture and the regeneration of missing structures after 2–4 days of culture. We observed that leaving a region of dead cells between the wound edges delays both wound healing and the regeneration of missing structures by 2 days. When disc fragments are cultured in female abdomens and then exposed to3H-thymidine to label replicating cells, then the label is found to be localised around the wound. We observed that delaying wound healing does not delay this localisation of labelled nuclei indicating that wound healing may not be required to initiate DNA replication.
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    Effect of the l(1)su(f)ts67g mutation ofDrosophila melanogaster on glue protein synthesis (1981)
    Springer
    Development genes and evolution 190 (1981), S. 308-312 
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    ISSN: 1432-041X
    Keywords: Drosophila ; ts-Suppressor mutant ; Glue proteins ; Intermolt puffs ; Electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The l(1)su(f)ts67g mutation has been shown to suppress the developmentally regulated expression of glue protein genes at 30°C. Transferring mutant larvae to the restrictive temperature before the end of the second larval instar results in the absence or extreme reduction of glue protein synthesis while general protein synthesis is unaffected. At the same time, the three glue protein correlated chromosomal regions 3C, 25B, and 68C continue to show prominent puffs. The results suggest that the mutation may be affecting the processing or translatability of specific mRNAs rather than the translational machinery itself.
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    Dicephalic — ADrosophila mutant affecting polarity in follicle organization and embryonic patterning (1982)
    Springer
    Development genes and evolution 191 (1982), S. 28-36 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Polarity ; Maternal effect ; Nurse cells ; Embryogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The mutationdicephalic (dic) affects follicle development and thereby alters the antero-posterior polarity of embryonic patterning. It maps at a single locus (3–46.0±1.0) and can be characterized as a semi-dominant maternal effect mutation with low penetrance. Indic follicles, the 15 nurse cells form two clusters located at opposite poles of the oocyte; the numerical distribution of the nurse cells among the clusters varies from 7:8 to 1:14. Thedic egg shell carries a micropyle (anterior marker) at either pole, but the misshapen respiratory appendages are restricted to one of the two poles in most eggs. The malformed eggs rarely yield larvae and these are always abnormal anteriorly and/or posteriorly. The segment pattern expressed in their cuticle may represent two anterior parts of opposite polarities (double head type), two posterior parts of opposite polarities (double abdomen type, rare) or show uniform polarity. Lability of organization at the cystocyte stage appears as the primary developmental defect of the mutant.
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    Correlation between adult transformation and aldehyde oxidase staining pattern in wing discs ofApterous genotypes inDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 285-288 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; homoeosis ; Compartments ; Aldehyde oxidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The aldehyde oxidase staining pattern in wing discs ofDrosophila melanogaster bearing the genotypesap blt /ap blt andap blt andap blt /ap 73n showns changes from the wild-type pattern. Extensive areas of the presumptive dorsal posterior wing blade, which are normally unstained, have enzyme activity in these mutants. In wings of these genotypes, dorsal posterior structures are replaced by dorsal anterior wing structures. A strong correlation has been found between the frequencies of various staining patterns in the discs and the extent of transformation in the cuticular structures of the wing, which is consistent with the idea that aldehyde oxidase activity can be used as an indicator in the wing disc of this transformation. Unlike the homoeotic mutationengrailed, apterous has not been interpreted as a selector gene yet the work reported here shows thatapterous alleles can cause changes resembling those of theengrailed phenotype both in aldehyde oxidase staining behaviour and in the cuticular transformation.
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    On the phenotype and development of mutants of early neurogenesis inDrosophila melanogaster (1983)
    Springer
    Development genes and evolution 192 (1983), S. 62-74 
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    ISSN: 1432-041X
    Keywords: Early neurogenesis ; Neurogenic mutants ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The central nervous system (CNS) ofDrosophila develops from precursor cells called neuroblasts. Neuroblasts segregate in early embryogenesis from an apparantly undifferentiated ectoderm and move into the embryo, whereas most of the remaining ectodermal cells continue development as epidermal cell precursors. Segregation of neuroblasts occurs within a region called the neurogenic field. We are interested in understanding how the genome ofDrosophila controls the parcelling of the ectoderm into epidermal and neural territories. We describe here mutations belonging to seven complementation groups which effect an abnormal neurogenesis. The phenotypes produced by these mutations are similar. Essential features of these phenotypes are a conspicuous hypertrophy of the CNS accompanied by epidermal defects; the remaining organs and tissues of the mutants are apparently unaffected. The study of mutant phenotype development strongly suggests this phenotype to be due to misrouting into the neural pathway of development of ectodermal cells which in the wildtype would have given rise to epidermal cells, i.e. to an initial enlargement of the neurogenic region at the expense of the epidermogenic region. These observations indicate that the seven genetic loci revealed by the mutations described in this study contribute to control the neurogenic field. The present results suggest that in wildtype development neurogenic genes are supressed within all derivatives of the mesoderm and endoderm and some derivatives of the ectoderm, and conditionally expressed in the remaining ectoderm. The organisation of the neurogenic field in the wildtype is discussed.
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    The evagination of the genital imaginal discs ofDrosophila melanogaster (1983)
    Springer
    Development genes and evolution 192 (1983), S. 275-279 
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    ISSN: 1432-041X
    Keywords: Evagination ; Morphogenesis ; Metamorphosis ; Female genital disc ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The morphology of the evaginating female genital disc ofDrosophila melanogaster was examined at different stages of metamorphosis. The observations show that the internal genital organs are derived from the anterior half of the disc and that their morphogenesis is mainly a protrusion of the different primordial areas of the disc epithelium. The external genital and anal derivatives originate from the posterior half of the disc, which undergoes complex rearrangements during metamorphosis. The disc opens along the posterior margin and the dorsal and ventral epithelia evert and thereby completely reverse their anteroposterior orientation. Dramatic elongation has been observed during the formation of the seminal receptacle. The cells of the repressed male genital primordium do not form any recognizable structures and are assumed to be eliminated during metamorphosis.
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    The effect of 5-azacytidine and cytidine analogs onDrosophila melanogaster cells in culture (1983)
    Springer
    Development genes and evolution 192 (1983), S. 299-302 
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    ISSN: 1432-041X
    Keywords: Differentiation ; Teratogens ; Drosophila ; 5-Azacytidine ; Methylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The effects of cytidine and cytidine analogs were studied inDrosophila embryonic cell cultures and two wild-type established cell lines, Oregon-R and Schneider line 2. Primary embryonic cultures have been shown to be an excellent system for the study of embryonic development; a number of cell types undergo normal differentiation in vitro. Treatment of these cultures with putative teratogens resulted in an inhibition of muscle and/or neuron differentiation in our study. Treatment of these cells with cytidine and seven other analogs had no effect on neuron and muscle differentiation. The compound 5-azacytidine, when added to primary cell cultures, inhibited normal differentiation at subtoxic doses while inducing the production of three proteins that comigrate with the heat-shock proteins, hsp 23, 22a and 22b. 5-Azacytidine did not stimulate differentiation in Oregon-R or SchneiderDrosophila cell lines. The in vitro blockage of differentiation by 5-azacytidine suggests that it may act as a teratogen.
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    Topological specificity of phenotype expression of neurogenic mutations inDrosophila (1983)
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    Development genes and evolution 192 (1983), S. 317-326 
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    ISSN: 1432-041X
    Keywords: Neurogenic mutations ; Topological specificity ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Neurogenic mutations have been found to cause the neuralization of certain regions of the ectoderm and yet to permit normal development of the remaining embryonic cells. Thus, it seems that the activity of the wild-type alleles of these genes is dispensable in a considerable fraction of the embryo during wild-type development. This effect might be a consequence of the cells' position within the embryo; alternatively, it might be independent of the position but be due rather to the genetic activity experienced by the cells previous to their commitment. The results described in this paper indicate that genes controlling patterning along the embryonic dorso-ventral perimeter (dorsal and Toll) are epistatic to genes controlling neurogenesis, their activity deciding which ectodermal cells are susceptible to neurogenesis. Using alleles with low expressivity, evidence was obtained showing that the tracheal placodes define the boundary of the territory which has neurogenic abilities at thoracic and abdominal levels.
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    Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster (1984)
    Springer
    Development genes and evolution 193 (1984), S. 296-307 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Larval cuticle ; Pattern formation ; Embryonic lethal mutations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In order to identify X-chromosomal genes required inDrosophila for early patterning and morphogenesis, we examined embryos hemizygous for EMS-induced lethal mutations to determine which of those mutations cause gross morphological defects. Embryos from 2711 lethal lines, corresponding to 3255 lethal point mutations were studied. Only 21% caused death during embryogenesis and of these, only one-sixth, or 3% of the total lethals, were associated with defects visible in the final cuticle pattern. Of the 114 point mutants causing visible cuticle defects, 76 could be assigned to 14 complementation groups. An additional 25 mutations mapping to regions of the X-chromosome not covered by male fertile duplications were assigned to six complementation groups based on similarities of map position and phenotype. Thirteen mutations could not be assigned to complementation groups. All mutations allowed normal development through the cellular blastoderm stage, the first defects associated with the earliest acting loci being observed shortly after the onset of gastrulation. The phenotypes of the various loci range from alterations in segment pattern or early morphogenetic movements to defects in final pigmentation and denticle morphology. Cuticle preparations were also examined for 63 deletions spanning in total 74% of the X-chromosome, as well as for 8 deletions and point mutations derived in saturation mutagenesis screens of the fourth chromosome (Hochman 1976). With the exception of defects in head morphology and defects in cuticle differentiation, none of the hemizygous deletions showed phenotypes other than those predicted by point mutations known to lie in those regions. No deletion caused new or unknown alterations in gastrulation, segmentation or cuticle pattern.These results suggest that the number of genes required zygotically for normal embryonic patterning is small and that most, if not all such loci, are represented by point mutations in our collection.
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    Early neurogenesis in wild-typeDrosophila melanogaster (1984)
    Springer
    Development genes and evolution 193 (1984), S. 308-325 
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    ISSN: 1432-041X
    Keywords: Neurogenesis ; Pattern of neuroblasts ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary This paper deals with morphological aspects of early neurogenesis inDrosophila, in particular with the segregation of neuroblasts from the neurogenic region of the ectoderm and the pattern formed by those wells within both the germ band and the procephalic lobe. The neurogenic ectoderm was found to contain neural precursors intermingled with epidermal precursors, extending from the midline up to the primordia of the tracheal tree along the germ band and laterodorsally in the procephalic lobe. Germ band neuroblasts segregate from the neurogenic ectoderm during a period of several hours according to characteristic spatial and temporal patterns. During the first half of the segregation process the pattern of germ band neuroblasts was found to be the same in different animals in both spatial arrangement and number of cells; this permitted the identification of individual neuroblasts from different embryos. Later in development several difficulties were encountered which precluded an exact description of the neuroblast pattern. The constitution of the neurogenic region is discussed in relation to the phenotype of mutants affecting neurogenesis.
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    URL: http://dx.doi.org/10.1007/BF00848159
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    The spatial arrangement of germ line cells in ovarian follicles of the mutantdicephalic inDrosophila melanogaster (1984)
    Springer
    Development genes and evolution 193 (1984), S. 388-393 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Oogenesis ; Ring canals ; Oocyte determination ; Polarity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The pattern of intercellular connections between germ line cells has been studied in follicles of the mutantdicephalic (dic), which possess nurse cell clusters at both poles. Staining of follicles with a fluorescent rhodamine conjugate of phalloidin reveals ring canals and cell membranes and thus allows us to reconstruct the spatial organization of the follicle. Each germ line cell can be identified by the pattern of cell-cell connections which reflect the mitotic history of individual cells in the 16-cell cluster. The results indicate that in both wild-type anddicephalic cystocyte clusters one of the two cells with four ring canals normally becomes the pro-oocyte. However, in some follicles (dicephalic and wild-type) oocytes were found with fewer or more than four ring canals. Indic follicles, one or several nurse cells may become disconnected from the other cells during oocyte growth at stage 9–10. Such disconnected cells cannot later on empty their cytoplasm into the oocyte. This, in turn, might be of consequence for the determination of axial polarity of the embryo.
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    URL: http://dx.doi.org/10.1007/BF00848229
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    Cell interactions during the fusionin vitro ofDrosophila eye-antennal imaginal discs (1984)
    Springer
    Development genes and evolution 193 (1984), S. 406-413 
    Details
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal disc ; Morphogenesis ; Tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The fusion of the eye-antennal discs during culturein vitro has been investigated, and the complex morphogenetic movements which occur during the formation of the head capsule of the insect are described. The initial contact between the eye anlagen is by means of cell processes spanning the gap between the two discs. Subsequently the two epithelia become firmly apposed, and then the integrity of the epithelium in the region of fusion breaks down, cells appearing to move to new positions in order to form an epithelium which unites the two discs. The epithelium eventually secretes a pattern of cuticular structures which is continuous between the derivatives of the two discs. Bristles on either side of the line of fusion are perfectly aligned, and structures such as the median ocellus, which are formed jointly by the cells of the two discs, differentiate normally. This is also found when left and right eye-antennal discs of different genotypes are placed side-by-side, indicating that processes of pattern regulation can occur in culture.
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    URL: http://dx.doi.org/10.1007/BF00848232
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    Sequential gene activation by ecdysteroids in polytene chromosomes ofDrosophila melanogaster (1982)
    Springer
    Development genes and evolution 191 (1982), S. 103-111 
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    ISSN: 1432-041X
    Keywords: Drosophila ; Polytene Chromosomes ; Ecdysteroids ; Fat Body
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Changes in polytene chromosome 3 L puffing patterns in the fat body ofDrosophila melanogaster larvae and prepupae are compared to those in the salivary gland. While some general features are common to the two tissues, there are differences which reflect their different developmental roles. In vitro experiments with fat body chromosomes show that they have a distinct response to ecdysteroids which is different from that of salivary gland chromosomes, and which does not,in this culture system, reproduce the changes observed in normal development. In short term culture experiments, the fat body chromosomes appear more sensitive to ecdysteroids than the salivary gland chromosomes and, although 20-OH ecdysone is more active than ecdysone in these assays, the possibility is not excluded that ecdysone has a role in normal development as it appears to alter gene activity at physiological levels in these cells.
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    Clinical pharmacokinetics and oral bioavailability of ketobemidone (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 45-50 
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    ISSN: 1432-1041
    Keywords: ketobemidone ; narcotic analgesic ; N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The basic pharmacokinetics and oral bioavailability of ketobemidone have been studied in 6 patients after surgery. Plasma concentrations were first determined following intravenous administration of Ketogin® 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and then, on the second postoperative day, following oral administration of 2 tablets of Ketogin®, each containing ketobemidone chloride 5 mg and the spasmolytic agent 25 mg. The average oral bioavailability of ketobemidone was 34%±16% (SD, n=6). The mean plasma half-life of elimination (t1/2β) was about the same following oral (2.45±0.73 h; SD, n=5) as after intravenous administration (2.25±0.35 h; SD, n=6). The low oral bioavailability and rapid elimination of ketobemidone demonstrated in this study suggest that the usual dosage recommendation for oral Ketogin® (ketobemidone 5–10 mg every 6–7 h) in patients with severe pain is too low.
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    URL: http://dx.doi.org/10.1007/BF00561676
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    Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 71-77 
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    ISSN: 1432-1041
    Keywords: sodium valproate ; epileptic patients ; pharmacokinetics ; plasma concentration ; prediction ; maintenance dosage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination (β phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.
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  • 46
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    Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, in man (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 81-86 
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    ISSN: 1432-1041
    Keywords: prenalterol ; beta1-adrenoceptor agonist ; metabolic effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective β1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables — triglycerides, glucose, lactate, pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.
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    Pharmacokinetic and clinical observations on prolonged administration of flunitrazepam (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 189-196 
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    ISSN: 1432-1041
    Keywords: flunitrazepam ; prolonged administration ; pharmacokinetics ; clinical observations ; sleep parameters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eight patients were given flunitrazepam 2 mg orally, once daily for 28 consecutive days. The time-course of the plasma concentration of unchanged flunitrazepam and its principal metabolites were studied in detail after the first and last doses. Additional blood samples were collected immediately before administration of the tablet on days 4, 7, 11, 14, 18, 21 and 25. Clinically there were no changes during the trial period in the onset of sleep, duration of sleep, depth of sleep measured as number of spontaneous awakenings, or in the patients' condition on awakening. The time-course of the plasma concentration of flunitrazepam could be described by a three-compartment model, assuming that the rate constants remained unchanged during treatment. Maximal plasma concentrations of unchanged flunitrazepam, found two hours after intake, reached 10–15 ng/ml after the first and 15–20 ng/ml after the last dose. The β-half-life was found to be between 20 and 36 h.
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    Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 209-213 
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    ISSN: 1432-1041
    Keywords: disopyramide ; bioavailability ; controlled-release tablets ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations and bioavailability of disopyramide following repeated administration of standard capsules and controlled-release tablets have been compared. Ten patients were randomized into two groups; Group I received disopyramide capsules 150 mg every 6 h for five days and subsequently disopyramide controlled-release tablets 300 mg every 12 h for further five days. Group II received the same preparations in the reverse order. There was a more rapid rise in disopyramide concentration after the capsules: the maximum of 10.7±0.6 µmol/l (mean ± SEM) was reached within 1.8±0.4 h as compared to 10.6±0.4 µmol/l within 4.0±0.3 h after the controlled-release tablets. No significant difference in the fluctuations in individual plasma concentrations during each dose interval at steady state were observed after ordinary capsules compared to controlled-release tablets. The extent of bioavailability was the same. Eight patients reported some side-effects during the capsule period and nine during the controlled-release tablet period.
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    URL: http://dx.doi.org/10.1007/BF00561902
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    Systemic availability of orally administered L-dopa in the elderly Parkinsonian patient (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 215-221 
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    ISSN: 1432-1041
    Keywords: L-dopa ; elderly ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous studies have suggested that the absorption of L-dopa in the elderly Parkinsonian patient might be unusually efficient. In the present investigation, the systemic availability of L-dopa was examined in 5 elderly Parkinsonian patients (mean age=77 years) and 6 young, healthy volunteers (mean age=26 years) following a single oral 300 mg dose of L-dopa. Quantitation of plasma levels of intact L-dopa was effected by ion-exchange column chromatography and spectrofluorimetry. The L-dopa plasma concentration-time profiles obtained confirmed the considerable intersubject variability in the absorption of L-dopa previously reported in the literature. Maximum plasma concentrations of L-dopa generally occurred within 60 min of administration of the dose. The existence of more than one plasma peak of L-dopa concentration was displayed in 45% of the subjects studied. This characteristic was not confined exclusively to either subject group. There was a significantly larger (P〈0.02) area under the plasma L-dopa concentration-time curve (AUC o ∞ ) in the elderly Parkinsonian patients (mean=234.69 µg · min/ml; SD=84.70) compared to the young, healthy volunteers (mean=82.33 µg · min/ml; SD=31.00). A significant (P〈0.01) correlation existed between AUC o ∞ and age (r=0.7970; n=11) among the subjects studied. The apparent elimination phase plasma half-life of L-dopa in the elderly Parkinsonian patients (mean=66.0 min; SD=11.1) was not significantly different to that observed in the young, healthy volunteers (mean=74.0 min; SD=18.1). These results suggest that there may be an age-related alteration to the disposition of orally administered L-dopa in the elderly Parkinsonian patient.
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    URL: http://dx.doi.org/10.1007/BF00561903
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    Altered prazosin pharmacokinetics in congestive heart failure (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 425-428 
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    ISSN: 1432-1041
    Keywords: prazosin ; congestive heart failure ; pharmacokinetics ; oral dose ; comparison with healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of prazosin (Minipress®) were studied in nine patients with NYHA Class 3 or 4 congestive heart failure and in five healthy controls. After a single 5 mg oral dose, plasma concentrations of prazosin, as reflected in the area under the plasma concentration-time curve (AUC) and prazosin plasma half-life, were approximately double in the patients in comparison to the control group. Reduction in hepatic blood flow, altered gastrointestinal absorption of the drug or diminished intrinsic hepatic metabolic activity in the patient group may have contributed to the observed changes in prazosin disposition. The finding of higher prazosin plasma concentrations in patients with refractory heart failure demonstrates the need for close monitoring of these individuals following administration of the drug in the treatment of chronic congestive heart failure.
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    Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 25-30 
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    ISSN: 1432-1041
    Keywords: pethidine ; norpethidine ; placental transfer ; pharmacokinetics ; newborns
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The literature data available on pethidine and norpethidine kinetics in women in labour and in their newborns is reviewed and compared with recent personal observations. In pregnant women the apparent blood half-life of pethidine is not different from that in healthy controls, however, apparent volume of distribution and total body clearance are reduced. Norpethidine blood levels are measurable after 10–20 min and tend to increase with time. The amount of drug transferred to the foetus is clearly linked to the dose administered to the mother, the dosing-delivery interval and to the metabolic capability of the mother. An equilibrium between maternal and umbilical venous blood is reached 2–3 h after dosing for pethidine and later for norpethidine. In the neonate, the apparent pethidine half-life is 2 to 7 times longer than in adults with values ranging from 7 to 32 h. Norpethidine is actively formed in the newborn with peak blood levels at 12–36 h and an apparent blood half-life of 20–36 h. At the doses usually recommended blood concentrations at birth are frequently higher than those required for analgesia and close to or within toxic ranges. An effort toward a more individualized dosage as well as toward a better understanding of the possible role of norpethidine with regard to adverse effects is needed.
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    Disposition and pharmacodynamics of diuretics and antihypertensive agents in renal disease (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 109-116 
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    ISSN: 1432-1041
    Keywords: diuretics ; antihypertensive agents ; renal disease ; dispositon ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic actions and disposition of diuretic and antihypertensive agents may be significantly modified in subjects with renal disease. Most studies on this question have dealt with alterations in the elimination kinetics of these drugs and, while they generate descriptive data, minimal insight about changes in dose-response relationships or mechanisms of drug action are provided by such investigations. Several basic principles which may serve as useful guidelines in determining how renal failure will influence the response to drugs have been considered. They include the following: degree of renal malfunction, intrinsic toxicity of the drug, alternative pathways for drug metabolism and elimination, elimination pharmacokinetics and dose-response characteristics. Several classes of diuretic agents (thiazides, furosemide) and antihypertensive drugs (hydralazine, methyldopa, propranolol, prazosin, and clonidine) have been used as models to define how basic knowledge of renal and non-renal pathways for elimination of drugs and their pharmacodynamic actions may assist in establishing rational therapeutic regimens for these agents in patients with renal failure.
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    Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 517-520 
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    ISSN: 1432-1041
    Keywords: desmethyldiazepam ; oxazepam ; cimetidine ; hepatic elimination ; pharmacokinetics ; interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.
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    An integrated study of pharmacokinetics and pharmacodynamics of chlormethiazole in healthy young volunteers (1981)
    Springer
    European journal of clinical pharmacology 19 (1981), S. 263-269 
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    ISSN: 1432-1041
    Keywords: chlormethiazole ; pharmacokinetics ; pharmacodynamics ; sedatives ; blood concentrations ; amnesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n=5) and 113 min (Phase 2, n=5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.15 l · min−1, SD 0.49; and 1.05 l · min−1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (137 l, SD 62; and 125 l, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (308 l, SD 91; and 224 l, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg · l−1 (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.
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    The pharmacokinetics of intravenous and oral sulpiride in healthy human subjects (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 385-391 
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    ISSN: 1432-1041
    Keywords: sulpiride ; pharmacokinetics ; serum clearance ; renal clearance ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulpiride was studied in 6 healthy volunteers after intravenous and oral (tablets) administration of 100 mg. An open two- and in two subjects a three-compartment model was applied following intravenous administration. The average total distribution volume during the terminal slope was 2.72±0.66 l/kg and total systemic clearance was 415±84 ml/min. The serum half-life of the terminal slope following intravenous administration averaged 5.3 h (range 3.7–7.1 h) according to the two-compartment model. In two subjects the half-lives were 11.0 and 13.9 h when the three-compartment model was applied. Determination of urinary excretion rates of unchanged sulpiride indicated a half-life of 7.15 h. Following intravenous administration, 70±9% of the dose was recovered unchanged in urine within 36 h; the mean renal clearance was 310±91 ml/min. Sulpiride was absorbed slowly, with peak concentrations appearing between 3 and 6 h after oral administration. The recovery of unchanged drug in urine following oral administration was 15±5% of the dose, with a mean renal clearance of 223±47 ml/min. The bioavailability determined from combined plasma and urine data was only 27±9%. The low bioavailability was probably due to incomplete absorption.
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    Clinical pharmacokinetics of alcuronium chloride in man (1980)
    Springer
    European journal of clinical pharmacology 17 (1980), S. 449-457 
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    ISSN: 1432-1041
    Keywords: alcuronium ; single dose ; multiple dose ; plasma levels ; neuromuscular response ; pharmacokinetics ; anaesthesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t1/2β), apparent volume of distribution (Vdβ), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 µg/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 µg/ml.
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    Pharmacokinetics and dosage of digoxin in neonates and infants (1980)
    Springer
    European journal of clinical pharmacology 18 (1980), S. 69-74 
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    ISSN: 1432-1041
    Keywords: digoxin ; neonates ; infants ; pharmacokinetics ; dosage schedules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As a therapeutic principle, a disease should be treated with the lowest effective dose of a drug. Accumulating information indicates that satisfactory contractile response of the myocardium is produced in young paediatric patients by doses of digoxin below existing recommendations. In addition, toxicity appears to be more frequent in neonates and infants treated with digoxin than previously thought. Therefore, dose calculations have been performed, based on pharmacokinetic parameters, with the aim of reaching and maintaining an average serum concentration of the glycoside of 2 nmol/l. This level is common in infants (〉1 month of age) during digoxin maintenance therapy and its adequacy is well supported by experience from adult cardiac patients. The calculations show that although current dosage schedules maintain the desired digoxin serum level in infants, they are often excessive for digitalization purposes. In neonates, the prevailing schemes do not sufficiently consider the immature state of the eliminating organs. Overdigitalization could therefore easily occur and continue in these patients, particularly in the premature newborns. This is in agreement with toxicity reports in the literature. The calculated doses should be less hazardous by being better adapted to the eliminating capacity of the various paediatric age-groups.
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    Pharmacokinetics of propranolol and sotalol in hyperthyroidism (1982)
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    European journal of clinical pharmacology 21 (1982), S. 373-377 
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    ISSN: 1432-1041
    Keywords: propranolol ; sotalol ; thyrotoxicosis ; bioavailability ; serum tri-iodothyronine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p〈0.05) and its clearance was increased (p〈0.005), whereas there was no difference in its serum t1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.
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    Studies of the different metabolic pathways of antipyrine in man (1982)
    Springer
    European journal of clinical pharmacology 21 (1982), S. 433-441 
    Details
    ISSN: 1432-1041
    Keywords: antipyrine ; antipyrine metabolites ; drug metabolism ; route of administration ; healthy volunteers ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.
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    URL: http://dx.doi.org/10.1007/BF00542332
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    Pharmacokinetic aspects of caffeine in premature infants with apnoea (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 47-52 
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    ISSN: 1432-1041
    Keywords: apnoea ; caffeine ; premature infants ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of caffeine was examined in 13 premature infants (gestational age 25–34 weeks, birth weight 920–2060 g, postnatal age 1–42 days) who received the drug for treatment of opnoea. Caffeine (1% aqueous solution) was given i.v. in single doses; guided by the clinical response infants received between one and seven (mean 2.6) doses of 15 mg/kg. Mean (± SE; range) Clb was extremely slow − 8.5 ml/kg/h (±0.4; 5.8–12.2), t1/2 was prolonged − 65.0 h (±3.7; 48.2–87.5 h) and Vd was 0.781/kg (±0.04; 0.47–1.01). No significant correlation was found between Clb, t1/2 and postnatal age in the whole group or in individual infants. Effective plasma concentrations varied over a wide range (12–36 µg/ml) and overlapped with subtherapeutic concentrations (⩽24 µg/ml). Single doses of 15 mg/kg i.v. or p.o. prevented apnoea in most cases, if necessary followed by additional doses. Monitoring the blood level of caffeine in infants receiving frequent repeated doses is necessary to prevent toxicity.
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    Drug-related problems causing admission to a medical clinic (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 193-200 
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    ISSN: 1432-1041
    Keywords: drug problems ; patient compliance ; adverse drug reactions ; interview ; pharmacokinetics ; inadequate therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The association between hospital admission and drug-related problems was evaluated in 285 consecutive admissions to two medical wards in a Swedish university hospital. Standardised definitions and criteria for causality were used. A drug-related problem was judged to have been the main reason for admission of 36 patients, and a strongly contributory reason for 9. These 45 patients comprised 16% of all patients, and 19% of those receiving medication prior to admission. For 19 patients the problem was considered to be failure to achieve the desired therapeutic effect. 11 of these 19 took less medication than prescribed, and an inadequate dose had been presented for the other 8 patients. In 26 patients there was an excessive or otherwise adverse effect. In 10 it was an intentional or accidental poisoning, and 16 had an adverse drug reaction. Non-compliance with the prescribed regimen caused almost half of the drug-related admissions: 11 took too little and 10 took too much of the prescribed drugs. The majority of the other problems could probably have been prevented by better application of pharmacokinetic principles to the prescribing.
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    URL: http://dx.doi.org/10.1007/BF00544597
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    Disposition of intravenous diazepam in young men and women (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 207-213 
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    ISSN: 1432-1041
    Keywords: diazepam ; benzodiazepines ; N-desmethyldiazepam ; plasma ; saliva ; pharmacokinetics ; pharmacodynamics ; psychomotor ; impairment ; oral contraceptives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of a single intravenous dose of diazepam (10 mg) was studied in 11 young, healthy subjects (6 males and 5 females on oral contraceptives). Plasma samples were obtained over 28 days and diazepam and N-desmethyldiazepam plasma concentrations and diazepam free fractions were determined. The salivary excretion of diazepam and N-desmethyldiazepam was studied over 72 h. A series of psychomotor performance tests were administered over the first 8 h. Interindividual variation in mean diazepam disposition over time is not principally related to variation in plasma protein binding; 93% of the variation in clearance is accounted for by variation in intrinsic clearance. Interindividual variation in diazepam disposition is modest but the plasma clearance of diazepam in women on oral contraceptives (median 14.0 ml/min) is significantly (p=0.004) less than in men (median 23.4 ml/min) and the area under the curve (AUC) of diazepam is highly correlated with the AUC of the principal active metabolite (r=0.90, p〈0.001). The AUC of N-desmethyldiazepam (median 9.2 µg·h/ml) in women is greater (p=0.06) than in men (median 7.5 µg·h/ml). On chronic administration of diazepam, therefore, women taking oral contraceptives will have greater plasma concentrations per unit dose of both diazepam and N-desmethyldiazepam than men. The clearance of diazepam in control groups of 11 young men (median 23.8 ml/min) and 10 young women not taking oral contraceptives (median 26.8 ml/min) is not significantly different. Plasma and salivary concentratrions of diazepam are correlated (p〈0.001) but the predictive value of this correlation is limited (r=0.70) since the ratio of salivary to plasma concentrations varies significantly over the day. The use of calculated free diazepam plasma concentrations does not improve the correlation (r=0.68) but the slope of this regression (1.00) is that predicted by theory.
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    Pharmacokinetics of parenteral paracetamol and its analgesic effects in post-operative dental pain (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 215-218 
    Details
    ISSN: 1432-1041
    Keywords: paracetamol ; acetaminophen ; dental pain ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A double-blind, randomised, crossover trial was undertaken to compare the analgesic effects of a single dose of paracetamol (1000 mg i. v.) with placebo in the immediate post-operative period following removal of impacted lower third molars. There was no significant difference in the pain relief between paracetamol and placebo in the first hour following injection. Thereafter, there was significantly less pain (P〈0.05) after treatment with paracetamol than after placebo. Plasma concentrations of paracetamol were measured and pharmacokinetic variables were determined. Over the four hour period of investigation there was no clear relationship between analgesia and paracetamol concentration in either central or peripheral compartments.
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    Does cantharides blister fluid provide access to the peripheral compartment? (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 327-330 
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    ISSN: 1432-1041
    Keywords: bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10–22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.
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    The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 343-347 
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    ISSN: 1432-1041
    Keywords: valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p〈0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p〈0.01) than in fasting samples (10–50%,p〈0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p〈0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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    Pharmacokinetics of pancuronium in man: A linear system (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 369-372 
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    ISSN: 1432-1041
    Keywords: neuromuscular blockade ; pancuronium ; non-depolarizing neuromuscular blocking agent ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pancuronium in bolus doses of 40 to 350 µg/kg was administered to surgical patients in order to evaluate the linearity of its pharmacokinetics. The profile of the plasma decay curve and of its urinary elimination were compared with reference to the administered dose. It was possible to superimpose the dose-normalized plasma decay-curves. The parameters of the two compartment-open model used to describe the pharmacokinetics of pancuronium were not influenced by the dose. The elimination half-life was 89±20 min and the plasma clearance was 1.84±0.38 ml/min/kg. The profiles of cumulative urinary excretion were also dose-independent. After 6 and 24 h, 57% and 69% of the administered dose, respectively, had been excreted in the urine. The results indicate that the pharmacokinetics of pancuronium is linear.
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    Overdosage of antidepressants: Clinical and pharmacokinetic aspects (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 513-521 
    Details
    ISSN: 1432-1041
    Keywords: amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
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    Pharmacokinetics and tolerance of slow-release indomethacin tablets in rheumatoid arthritis (1982)
    Springer
    European journal of clinical pharmacology 23 (1982), S. 349-351 
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    ISSN: 1432-1041
    Keywords: indomethazine ; rheumatoid arthritis ; pharmacokinetics ; tolerance ; side effects ; slow-release tablets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (tmax 3.7 h and 〈 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.
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    Pharmacokinetics of theophylline in Ethiopian children of differing nutritional status (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 89-92 
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    ISSN: 1432-1041
    Keywords: theophylline ; kwashiorkor ; marasmus ; children ; nutritional status ; pharmacokinetics ; dosage recommendation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of theophylline in Ethiopian children of differing nutritional status was studied. In 8 children of normal weight, the t1/2β (4.93 h) plasma clearance (1.22 ml/min/kg and Vd area (504 ml/kg) were similar to those of Swedish children of normal weight. In children with marasmus or kwashiorkor there was an increased volume of distribution. The increase in Vd was reflected in an increased biological half-life, in spite of a slight but not significant increase in clearance in both of these groups of children. The pharmacokinetic changes in clearance and volume of distribution found in malnutrition should counteract each other, so from a clinical point of view theophylline can be given to Ethiopian children according to the standard dosage recommendation, regardless of nutritional status.
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    Bioavailability and pharmacokinetics of theophylline in plain uncoated and sustained-release dosage forms in relation to smoking habit I. Single dose study (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 79-87 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; smoking habit ; absolute bioavailability ; pharmacokinetics ; sustained release preparation ; plain tablet preparation ; antipyrine pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of theophylline from a plain uncoated and 2 newly designed, sustained-release tablet formulations, as compared to intravenous aminophylline, were studied in 12 healthy adult male volunteers. The subjects were divided into two groups (n=6) with respect to smoking habit and on 4 separate occasions each received, on a randomized cross-over basis, a single dose of 400 mg equivalent of theophylline from every dosage form. The intravenous aminophylline study showed that habitual smoking had a significant (p〈0.05) effect on plasma theophylline clearance (0.051±0.006 vs 0.035±0.004 l/kg/h). Smoking significantly reduced the raw AUC from the 4 dosage forms (p〈0.05), but did not change the characteristics of absorption of each formulation. There was a non-significant trend towards reduced absolute bioavailability of theophylline from sustained-release formulations in smokers (percentage mean difference — 16% for one formulation and 13% for another). The trend was not observed for the plain uncoated tablet, which was rapidly absorbed (p〈0.01 to 0.05 in Ka, tmax and Cmax compared to sustained-release tablets). Similarity of the in vitro dissolution profiles of the two sustained-release formulations did not imply similarity of the in vivo absorption characteristics. Plasma clearances of theophylline and antipyrine were significantly correlated (p〈0.05,r=0.693,n=10). Thus, smoking enhanced the elimination of theophylline regardless of the dosage form administered. However, the extent to which habitual smoking may affect the hepatic first-pass effect on theophylline from sustained-release formulations requires further study. The results also suggest that theophylline and antipyrine may share a similar or common and presumably polycyclic hydrocarbon-inducible form(s) of microsomal drugmetabolizing enzyme.
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    Bioavailability of oral dexamethasone during high dose steroid therapy in neurological patients (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 103-108 
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    ISSN: 1432-1041
    Keywords: dexamethasone ; bioavailability ; pharmacokinetics ; ‘first-pass’ effect ; pre-systemic elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and oral biovailability of dexamethasone were studied in 6 patients with neurological disease being treated with high dosages of the drug. A specific high performance liquid chromatographic assay was used to measure dexamethasone concentrations. Unlike the previously published mean figure of 0.78 for the oral bioavailability of the drug given in single doses to healthy volunteers, the mean bioavailability of dexamethasone in the patients studied was 0.53±SD 0.40. It appeared more likely that this incomplete bioavailability was due to presystemic elimination than to poor absorption. The intravenous clearance of the drug was relatively high (0.4902±SD 2291 l kg−1, approximately 65% of expected hepatic plasma flow), the oral clearance higher (2.5804±SD 3.2181 l kg−1 h−1) while the absorption rate constant (4.8729±8.4998 h−1), suggested rapid absorption after oral administration. Prior phenytoin and possibly prior dexamethasone therapy is likely to have contributed to the higher clearance values of the drug in these patients than the values reported in healthy volunteers after single dose studies.
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    Pharmacodynamic and pharmacokinetic evaluation in man of the new sympathomimetic amezinium (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 185-190 
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    ISSN: 1432-1041
    Keywords: amezinium ; hypotension ; antihypotensive drug ; ECG ; concentration-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood pressure, ECG and plasma concentration were determined for up to 12h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton®) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r=0.78,p〈0.001) and between 0.75 and 5 h after i.v. administration (r=0.83,p〈0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
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    Plasma levels of sulfinpyrazone and of two of its metabolites after a single dose and during the steady state (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 231-235 
    Details
    ISSN: 1432-1041
    Keywords: sulfinpyrazone ; pharmacokinetics ; metabolites ; inhibition of platelet aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4×200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.
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    Pharmacokinetics of chlorambucil in man after administration of the free drug and its prednisolone ester (prednimustine, Leo 1031) (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 251-253 
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    ISSN: 1432-1041
    Keywords: chlorambucil ; prednimustine ; plasma concentrations ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of chlorambucil has been investigated in a cross over study after oral administration of the free drug (10 mg) and its prednisolone ester (prednimustine, 100 mg). The bioavailability of chlorambucil was about five times lower when given as prednimustine as compared to administration of the free drug. The peak plasma concentration was about twice as high and it was obtained more rapidly when the free drug was given. No intact prednimustine could be detected in plasma.
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    Clinical effect and pharmacokinetics of trimethoprim-sulphadiazine in children with urinary tract infections (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 267-271 
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    ISSN: 1432-1041
    Keywords: trimethoprim ; sulphadiazine ; urinary tract infection ; children ; pharmacokinetics ; urinary concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2–56 months. A suspension of TMP-SD (9+41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9–3.7 mg/kg/day) and SD (12.9–16.7 mg/kg/day) were also given to children of different ages. After 2–4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 µg/ml and 27 µg/ml, respectively, were found within 2–4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.
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    Disposition and clinical pharmacokinetics of theophylline after administration of a new sustained release tablet (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 39-44 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release tablet ; absolute bioavailability ; pharmacokinetics ; individual dosage regimen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard® 250 mg, Theolair S. R.®, Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard® 250 mg was 110.9±20.8% (mean ± SD). Maximal serum concentrations were reached after 7.3±3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h−1 (intestine), or biphasic with rate constants of 0.2 h−1 (stomach) and 0.8 h−1 (intestine). The peak levels accounted for 7.9±2.2 mg · 1−1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5±3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg · l−1 was 9.8±3.1 h.
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    May mothers taking acenocoumarol breast feed their infants? (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 61-64 
    Details
    ISSN: 1432-1041
    Keywords: acenocoumarol ; anticoagulant therapy ; breast feeding ; breast milk ; neonatal thrombotest ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 women receiving Sintrom® post partum, the acenocoumarol concentration in serum and breast milk at different times was measured. Even at the time of maximal serum concentration, or for the following 6 h, no acenocoumarol could be detected in the breast milk. In accordance with this finding, no effect of breast feeding on Thrombotest values of the infants could be demonstrated. These data suggest that mothers taking acenocoumarol for a short period may safely breast feed their infants.
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    URL: http://dx.doi.org/10.1007/BF00609589
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    Plasma and salivary pharmacokinetics of caffeine in man (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 45-52 
    Details
    ISSN: 1432-1041
    Keywords: caffeine ; pharmacokinetics ; plasma ; saliva ; urinary elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163±0.081 h−1 for 50 mg and 0.098±0.027 h−1 for 750 mg. The total body clearance was unaffected by dose and was 0.98±0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74±0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.
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    URL: http://dx.doi.org/10.1007/BF00609587
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    The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 387-390 
    Details
    ISSN: 1432-1041
    Keywords: valproic acid ; epilepsy ; uremia ; pharmacokinetics ; peritoneal dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 h after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.
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    URL: http://dx.doi.org/10.1007/BF00610060
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  • 80
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    The pharmacokinetics of ranitidine in patients with chronic duodenal ulceration: A comparison of responders and non-responders (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 441-447 
    Details
    ISSN: 1432-1041
    Keywords: ranitidine ; duodenal ulceration ; pharmacokinetics ; non-responders ; therapeutic response ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of orally administered ranitidine were studied in 17 male patients with chronic duodenal ulceration. The patients were divided into 2 groups, 10 responders and 7 nonresponders, on the basis of their endoscopic response to ranitidine treatment. The 10 responders were studied both after a single 150 mg dose (SD) and after multiple dosing (MD) with ranitidine 150 mg twice daily for 4 weeks. The area under the curve (AUC) and maximum concentration (Cmax) were significantly higher (p〈0.01 andp〈0.05, respectively) after MD than after SD, but the half-life (t1/2) and minimum concentration (Cmin) 12 h postdosing did not differ. The non-responders were studied after MD only and their pharmacokinetic characteristics were compared with those of responders. No differences between the 2 groups were found. However, 2 non-responders had particularly low plasma ranitidine levels and high acid output. Such patients may need larger doses of ranitidine for adequate suppression of gastric acid. Five patients (4 responders and 1 non-responder) received ranitidine 20 mg i.v. The drug followed a two-compartment model, with mean values for t1/2β, volume of distribution steady-state and total plasma clearance of 80 min, 701 and 680 ml/min, respectively. The oral bioavailability of ranitidine in these 5 patients showed wide variation (27–76%; mean 51%).
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    URL: http://dx.doi.org/10.1007/BF00609883
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    Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 503-507 
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    ISSN: 1432-1041
    Keywords: tocainide ; pharmacokinetics ; renal failure ; antiarrhythmic drug ; haemodialysis ; cirrhosis ; acetyldigoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.
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  • 82
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    Pharmacokinetics of sotalol during pregnancy (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 521-524 
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    ISSN: 1432-1041
    Keywords: sotalol ; beta-adrenoceptor antagonist ; pregnancy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
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    Pharmacokinetics of tryptophan, renal handling of kynurenine and the effect of nicotinamide on its appearance in plasma and urine following L-tryptophan loading of healthy subjects (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 137-142 
    Details
    ISSN: 1432-1041
    Keywords: tryptophan ; pharmacokinetics ; kynurenine ; 3-hydroxykynurenine ; renal clearance ; nicotinamide ; tryptophan pyrrolase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tryptophan, the temporal occurence of kynurenine (KYN) and 3-hydroxykynurenine (3-HK) in plasma and urine, and the effect of nicotinamide on tryptophan metabolism were studied in 6 healthy subjects after oral administration of L-tryptophan 100 mg per kg body weight. The peak concentration of tryptophan in plasma occurred after 1 to 2 h, tryptophan disappeared linearly from 2 to 5 h and exponentially from 5 to 8 h. Urinary tryptophan excretion was negligible. The peak concentration of KYN in plasma occurred after 4 h and it was correlated significantly with the area under the plasma curve (AUC) of KYN of the subjects investigated. The AUC in plasma of KYN was significantly correlated with urinary KYN excretion within individuals, but not in the group as a whole. The data suggest that KYN was reabsorbed by renal tubules and that the degree of reabsorption was subject to large interindividual variation. The peak concentration in plasma of 3-HK occurred 11 min later than that of KYN. The results suggest that the net tubular effect on 3-HK was secretion. Pre-treatment with nicotinamide (0.5 g three times daily) resulted in considerable decreases in AUC in plasma, and in urinary excretion of KYN and 3-HK, indicating inhibition of liver tryptophan pyrrolase. The concomitant increase in AUC in plasma of free and total tryptophan was insignificant. As only a relatively small amount of tryptophan is catabolized by tryptophan pyrrolase following an L-tryptophan load, cautious interpretation is recommended of urinary KYN excretion as an indicator of tryptophan break down in investigation of different subjects.
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    Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 127-135 
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    ISSN: 1432-1041
    Keywords: antidepressant ; bupropion ; pharmacokinetics ; oral administration ; radioimmunoassay ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bupropion hydrochloride, a structurally novel antidepressant agent, have been studied in healthy male and female subjects following administration of single oral doses of 50, 100 and 200 mg. Plasma drug concentrations were determined directly by a specific radioimmunoassay (r. i. a.), while urinary measurements required a prior solvent extraction to remove substances interfering in the assay. Bupropion appeared rapidly in the plasma, suggesting good absorption. Drug plasma concentration-time data were fitted well to a two-compartment open model of drug disposition by use of the computer program NONLIN. By comparison of AUC, Cmax and tmax values, the pharmacokinetics of bupropion were found to be linear across the 50–200 mg dose range in both sexes. When the data were normalized for subjects' body weights, no differences between pharmacokinetic parameters for male and female subjects were found. Mean disposition half-lives across treatments were 1.2–1.4 h for t1 2α and 10.7–13.8 h for the t1 2β. Bupropion was extensively bound (85%) to human plasma proteins over a wide drug concentration range. Less than 1% of a 200 mg oral dose of bupropion hydrochloride appeared in the urine of 16 subjects as unchanged drug, indicating extensive metabolism of the parent compound.
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    Chloramphenicol pharmacokinetics in Ethiopian children of differing nutritional status (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 819-823 
    Details
    ISSN: 1432-1041
    Keywords: chloramphenicol ; children ; pharmacokinetics ; oral dose ; absorption ; i.v. dose ; kwashiorkor ; marasmus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of i.v. chloramphenicol succinate and oral chloramphenicol palmitate were studied in Ethiopian children with different nutritional states. In children with kwashiorkor the plasma clearance of chloramphenicol was significantly lower than in children of normal weight (4.16 ml/min/kg versus 7.53 ml/min/kg). In consequence the mean half-life was prolonged (3.76 h versus 2.85 h) and this led to somewhat higher plasma levels in the kwashiorkor children. The influence of the pathophysiological changes offset one another so that plasma concentrations within the therapeutic range were obtained in children with kwashiorkor given recommended standard i.v. doses. The absorption of chloramphenicol after oral administration in severely malnourished children was erratic, which suggests that this route should be avoided in such patients.
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    URL: http://dx.doi.org/10.1007/BF00607094
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    Proof of the linearity of the pharmacokinetics of alinidine in man (1981)
    Springer
    European journal of clinical pharmacology 21 (1981), S. 201-207 
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    ISSN: 1432-1041
    Keywords: alinidine ; pharmacokinetics ; radioimmunoassay ; computer model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of alinidine was investigated in two groups of volunteers: Group I (N=5) received on two different occasions single doses of14C-labelled drug given orally (40 mg) or intravenously (10 mg); Group II (N=6) received single oral doses 10, 30 or 90 mg dissolved in 20 ml water. The samples from Group I were analysed by two different and independent methods (RIA and counting total radioactivity). The results obtained by the two methods were identical, since the compound was not metabolized. The plasma concentrations and renal excretion data obtained from both groups were individually fitted to an open three compartment model. Independent of the route of administration and of the doses given, similar pharmacokinetic parameters were calculated for each group and each trial. The half lives of the distribution and elimination phases were t1/2α: 36–41 s, t1/2β : 9.9–11.1 min and t1/2γ: 2.7–3.8 h. There was a linear relationship between the dose administered and the resulting areas under the plasma concentration curves (AUC). Following a lag period (τ=0.19–0.22 h), the peak plasma concentration was reached 0.6–1.2 h after oral administration. Oral alinidine was 100% bioavailable.
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    URL: http://dx.doi.org/10.1007/BF00627921
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    Effect of ethanol intake on disopyramide elimination by healthy volunteers (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 103-105 
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    ISSN: 1432-1041
    Keywords: disopyramide ; ethanol ; pharmacokinetics ; interaction ; metabolic clearance ; renal clearance ; diuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of ethanol intake on disopyramide elimination was examined in an open cross-over study in six healthy volunteers. No effect of ethanol on the elimination half-life or total body clearance of disopyramide was found, although it did decrease the percentage of mono-N-dealkylated disopyramide excreted in the urine (p〈0.05) as well as the relative metabolic clearance of disopyramide (p〈0.05). The renal clearance of disopyramide was increased by 19±16% (p〈0.05) in subjects in whom ethanol caused a diuresis.
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    Pharmacokinetic aspects of guanfacine withdrawal syndrome in a hypertensive patient with chronic renal failure (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 463-466 
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    ISSN: 1432-1041
    Keywords: guanfacine ; hypertension ; phenobarbital ; withdrawal syndrome ; enzyme induction ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The unusual observation of a withdrawal syndrome due to guanfacine in a hypertensive patient with chronic renal failure led to a study of the kinetics of the drug in this patient. The principal pharmacokinetic parameters of guanfacine were greatly altered, with extended biotransformation and a decrease in the half-life compared to the values observed in other cases of severe renal insufficiency. Associated treatment with phenobarbital had had a considerable effect, as shown by the results of a further kinetic study 2 months after withdrawal of the phenobarbital. The findings then were in good agreement with reference values which strongly suggests a consequence of the enzyme inducing effect of phenobarbital. Advice about the dosage regimen in such cases is given.
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    Disposition of 5-aminosalicylic acid, the active metabolite of sulphasalazine, in man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 511-515 
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    ISSN: 1432-1041
    Keywords: 5-aminosalicylic acid ; inflammatory bowel disease ; sulphasalazine disposition ; pharmacokinetics ; healthy volunteers ; urinary excretion ; biliary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of 5-aminosalicylic acid (5-AS), the therapeutically active metabolite of sulphasalazine (SZ), has been studied in patients with active inflammatory bowel disease, in patients with biliary tract disease and post-operative T-tube drainage, and in healthy volunteers. Subjects were treated 3 times a day either with 5-AS 0.5 g suppositories and a slow-release preparation or with SZ 1 g tid (equivalent to 5-AS 1.14 g/day). Plasma and urine concentrations of 5-AS and its acetylated major metabolite (AcAS) were monitored during one dosing interval. In a cross-over trial in 5 patients with ulcerative colitis no difference, was found in the dose-corrected mean (± SD) steady state plasma levels (Css) of 5-AS and AcAS between treatment with 5-AS suppositories (0.10±0.07 and 0.50±0.20 µg/ml, respectively) and SZ (0.12±0.14 and 0.67±0.14 µg/ml, respectively). Urinary excretion of total AS (5-AS+AcAS), too, was similar (192±70 and 179±79 mg/day) with both forms of treatment. The oral slow-release form of 5-AS produced slightly higher Css in 5 patients with Crohn's disease (5-AS 0.21±0.22 µg/ml; AcAS 0.83±0.40 µg/ml) and in 5 healthy volunteers (5-AS 0.28±0.14 µg/ml; AcAS 1.10±0.43 µg/ml). Urinary recovery of total AS averaged 20±6% (patients) and 27±10% (volunteers). The cross-over trial in 7 patients with a biliary T-tube revealed that after single doses of 5-AS 1 g and SZ 2 g between 0.01% and 0.75% could be recovered in collected bile (85–500 ml/day) as total AS (traces of free 5-AS, and acetylated and glucuronidated 5-AS), indicating some enterohepatic circulation.
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    Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 449-453 
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    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
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  • 91
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    Pharmacokinetics of methadone in methadone maintenance treatment: Characterization of therapeutic failures (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 497-501 
    Details
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; steady state ; addiction rehabilitation ; therapeutic failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the β-phase (t1/2β), volume of distribution during the postdistributive phase (Vdβ) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vdβ and Vdss were found between the two groups. The therapeutic failures had a smaller Vdβ and Vdss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p〈0.001) in the comparison group. However, the change in t1/2β was probably a consequence of the change in Vdβ, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.
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    Pharmacodynamic and pharmacokinetic study of oral and intravenous penbutolol (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 529-534 
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    ISSN: 1432-1041
    Keywords: penbutolol ; pharmacokinetics ; blood pressure effect ; heart rate effect ; dose response relationship ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n=8) or placebo (n=4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32–42 l. All doses were well tolerated.
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    Assessment of drug metabolism in hepatic disease: Comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 95-101 
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    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546715
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  • 94
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    Circadian profiles of blood glucose and plasma free insulin during treatment with Semisynthetic and Biosynthetic human insulin, and comparison with conventional monocomponent preparations (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 767-771 
    Details
    ISSN: 1432-1041
    Keywords: human insulin ; diabetes control ; blood glucose ; free insulin ; biosynthetic insulin ; semisynthetic insulin ; monocomponent insulin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen hospitalized insulin requiring diabetics treated with a single daily subcutaneous injection were randomly allocated either to a mixture of porcine Actrapid+Lente MC or a mixture of Regular+NPH—Biosynthetic human insulin (Study 1). In Study 2, 10 patients receiving two daily insulin injections were treated at random with either porcine Actrapid+Monotard, or Actrapid+Monotard—Semisynthetic human insulin or Regular+NPH—Biosynthetic human insulin. Once an optimal insulin regimen was obtained, circadian blood glucose and plasma free insulin profiles (7–9 time points) were determined with the two (Study 1) or three (Study 2) insulin preparations, keeping the doses of insulin constant. In Study 1 no significant difference in blood glucose (BG) or plasma free insulin (FIRI) profiles was observed. The mean daily blood glucose, the mean amplitude of glycaemic excursions (MAGE), the index of blood glucose control (M-value of Schlichtkrull), as well as the post-breakfast increases in blood glucose and mean free IRI, were similar with both types of insulin. In Study 2, BG and FIRI profiles were also similar, except for a significantly lower (p〈0.02) BG at 8.30 p.m. with both human insulins. No significant differences were found in free IRI at that time. Mean BG, M index, MAGE and mean FIRI were similar but the postbreakfast increase was significantly smaller with SHI. In conclusion, the pharmacokinetics of animal monocomponent, semisynthetic and biosynthetic human insulin appear similar, but evening BG control was better with both types of human insulins given twice daily.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542517
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  • 95
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    Electronic Resource
    Pharmacokinetics of midazolam in the aged (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 381-388 
    Details
    ISSN: 1432-1041
    Keywords: midazolam ; hypnotic drug ; benzodiazepine ; pharmacokinetics ; aged patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg−1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg−1h−1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg−1) and the young subjects studied previously (1.09±0.58 l kg−1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l−1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548771
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  • 96
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    Single and multiple dose kinetics of clobazam, and clinical effects during multiple dosage (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 499-503 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepines ; clobazam ; desmethylclobazam ; pharmacokinetics ; sedation ; accumulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542148
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  • 97
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    Electronic Resource
    Bioequivalence studies in humans of indomethacin capsules marketed in India (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 261-264 
    Details
    ISSN: 1432-1041
    Keywords: indomethacin capsules ; bioequivalence ; volunteers ; pharmacokinetics ; statistical significance ; bioavailability ; comparative bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630296
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  • 98
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    Electronic Resource
    Pharmacokinetics of cefoxitin administered by i.v. infusion to patients with a pleural effusion (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 389-392 
    Details
    ISSN: 1432-1041
    Keywords: cefoxitin ; beta-lactam antibiotics ; pharmacokinetics ; serum concentration ; pleural fluid concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548772
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  • 99
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    Electronic Resource
    Initiation and maintenance of beta-blockade with intravenous oxprenolol (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 7-14 
    Details
    ISSN: 1432-1041
    Keywords: oxprenolol ; coronary heart disease ; normals ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration profile of oxprenolol after intravenous bolus injection, during intravenous infusion and following sustained oral administration was studied in a total of 106 patients with coronary heart disease. Speed of onset of pharmacodynamic activity, as measured by suppression of isoprenaline tachycardia, was discernible within a few seconds of central injection and complete within 5 min in all patients; variability in response was small. Following both i.v. bolus and intravenous infusion, plasma oxprenolol concentrations showed considerable between patient variability The plasma concentration/time profile observed in 16 patients following single intravenous oxprenolol bolus therapy was substantially higher, particularly during the early distribution phase, than observed and predicted volunteer data. Higher plasma oxprenolol concentrations were also attained during the more extended time sampling of the infusion studies; these findings would be compatible with reduced oxprenolol clearance in patients with ischaemic heart disease. During chronic oral therapy there was a many-fold between-subject variability in plasma concentration achieved following a given ingested dose. Correlation of antagonism of exercise tachycardia inhibition with plasma oxprenolol concentration in 15 male volunteers demonstrated near complete blockade of exercise stimulation of chronotropic beta-adrenoceptors at an average plasma oxprenolol concentration of 150 ng/ml. In coronary heart disease, such plasma concentrations can most conveniently be achieved by a 4 mg oxprenolol intravenous bolus with simultaneous infusion of 0.05 mg/kg/h; however, these studies provide sufficient information to allow alternative regimens to be derived should lesser plasma concentrations be considered desirable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613920
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  • 100
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    Disposition kinetics of metronidazole in children (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 113-119 
    Details
    ISSN: 1432-1041
    Keywords: metronidazole ; trichomonas vaginitis ; children ; pharmacokinetics ; serum and saliva concentrations ; therapeutic dosage schedule ; anaerobic infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of metronidazole was studied in 20 paediatric patients aged 6 weeks and 4 to 14 years, who had trichomonal vaginitis or an anaerobic bacterial infection. The dosage of metronidazole was about 10 or 20 mg/kg b.i.d. orally. The serum concentrations found in children and the corresponding calculated kinetic parameters were similar to those in adults after intake of an equal, weight-related dose. Metronidazole shows rapid diffusion into the saliva with a concentration ratio of about 1.0. This can provide the basis for an efficient non-invasive method of drug monitoring.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613937
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