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  • pharmacokinetics  (96)
  • Drosophila  (42)
  • Springer  (138)
  • Annual Reviews
  • Blackwell Publishing Ltd
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  • 2020-2024
  • 2005-2009
  • 1990-1994  (138)
  • 1980-1984
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  • 1992  (138)
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  • 1990-1994  (138)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular evolution 35 (1992), S. 51-59 
    ISSN: 1432-1432
    Keywords: Drosophila ; Gart locus ; Chironomus tentans ; Purine nucleotide biosynthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The Drosophila Gart locus consists of two genes. One gene encodes three enzymes in the de novo purine nucleotide biosynthesis pathway [glycinamide ribonucleotide synthetase (GARS), aminoimidazole ribonucleotide synthetase (AIRS), and glycinamide ribonucleotide transformylase (GART)]. The second gene lies within an intron of the purine gene and encodes a cuticle protein. To investigate the evolution of the Gart locus, the Chironomus tentans homolog was cloned by screening a genomic DNA library with a polymerase chain reaction product. This study shows that the interesting structural features of this locus conserved in two distant Drosophila species are not found in the Chironomus homolog. These features include the cuticle protein gene nested within an intron and the existence of an alternative transcript to yield a monofunctional enzyme. In addition, the extremely rapid divergence of coding sequence seen for members of the tandemly duplicated AIRS domain in Drosophila is found to be much less rapid in Chironomus.
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  • 2
    ISSN: 1432-1432
    Keywords: Drosophila ; per gene ; Threonine-Glycine ; repeat sequence ; melanogaster subgroup phylogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The Threonine-Glycine (Thr-Gly) region of the period gene (per) in Drosophila was compared in the eight species of the D. melanogaster subgroup. This region can be divided into a diverged variable-length segment which is flanked by more conserved sequences. The number of amino acids encoded in the variable-length region ranges from 40 in D. teissieri to 69 in D. mauritiana. This is similar to the range found within natural populations of D. melanogaster. It was possible to derive a Thr-Gly “allele” of one species from that of another by invoking hypothetical Thr-Gly intermediates. A phylogeny based on the more conserved flanking sequences was produced. The results highlighted some of the problems which are encountered when highly polymorphic genes are used to infer phylogenies of closely related species.
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  • 3
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    Journal of molecular evolution 34 (1992), S. 130-140 
    ISSN: 1432-1432
    Keywords: Drosophila ; Sophophora ; cDNA-DNA hybridization ; Phylogenetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have performed DNA-DNA hybridization experiments among several species of Drosophila using the evolutionarily conserved portion of the genome representing sequences coding for amino acids of proteins. This was done by using as tracer, radioactively labeled complementary DNA that was reverse transcribed from adult mRNA. We show that this procedure extends phylogenetically the distance over which the technique can be applied to fast-evolving groups such as Drosophila. The major phylogenetic conclusions are (1) the subgenus Sophophora is a monophyletic lineage; (2) within Sophophora the melanogaster subgroup is closer to the obscura group than either group is to the willistoni group; (3) the subgenus Drosophila is complex with most major lineages originating deep in the phylogeny; the subgenus may not be monophyletic; (4) as with most groups classically placed in Drosophila, the Hawaiian Drosophila originate early, supporting the notion that this lineage is older than the extant islands; and (5) the virilis/repleta lineage is monophyletic within Drosophila.
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  • 4
    ISSN: 1420-9071
    Keywords: Aromatic plants ; essential oils ; Drosophila ; insecticides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Effects of the essential oils (EOs) extracted from eleven aromatic plants belonging to the Lamiaceae family (common in the Greek flora) were examined upon three different developmental stages ofDrosophila auraria. All of the EOs examined exhibited insecticidal effects, either by preventing egg hatching, or by causing the death of larvae and adult flies. In several cases, malformation and/or prohibition of puparium formation was also observed.
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  • 5
    ISSN: 1432-041X
    Keywords: Muscle ; Salivary glands ; Gut ; Programmed cell death ; Steroid hormones ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In holometabolous insects, the steroid molting hormone 20-OH-ecdysone (ecdysterone) orchestrates the diverse developmental events of metamorphosis, in large part by regulating gene expression. In Drosophila, the Broad Complex (BR-C) is one of the first loci to be induced by ecdysterone at the end of larval life, and is essential for translating the hormonal signal into the behavioral and anatomical events which herald the onset of metamorphosis. BR-C products are believed to act by binding to and modifying the transcriptional activities of other hormone-sensitive genes. In addition to abnormalities of the epidermis, BR-C mutants dying during metamorphosis manifest a syndrome of multiple internal tissue defects which represent a failure of the larval-to-adult transition. We have reported features of central nervous system metamorphosis requiring BR-C function, notably morphogenetic movements and optic lobe organization. In this paper we describe defective development of salivary glands, flight muscles, and gut in BR-C mutants, including: persistence of larval salivary glands; failure of the adult salivary glands to extend into the thorax; abnormalities of midgut transition and of proventriculus structure and location; and absence of dorsal-ventral indirect flight muscles. Some of these abnormalities represent defects in programmed cell death. Distinct patterns of phenotypes were seen in mutants of each of the three lethal complementation groups comprising the BR-C. The patterns of phenotypes suggest overlapping but distinct functions encoded by this complex locus.
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  • 6
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Pattern formation ; rotund
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary InDrosophila imaginal discs, pattern formation requires the activity of three positional information systems, antero-posterior (A/P), dorso-ventral (D/V) and proximo-distal (P/D). Three genes,Decapentaplegic, Distal-less androtund (rn), involved in pattern formation along the P/D axis have been characterized. Thern gene is required in a sub-distal region, localized at a similar position along the P/D axis in all appendages; it encodes two major transcripts, m1.7 and m5.3, both expressed in the central region of all the major imaginal discs. The present study of these transcripts in severalrn mutant favours m5.3 as encodingrn morphogenetic function in the imaginal discs. The fine characterization of its distribution partitions all major imaginal discs in domains along the P/D axis. The ventral and dorsal discs appear to be similarly but not identically organized: two P/D domains are evident in the wing and haltere discs whilst the leg and antenna discs appear to be composed of at least three. We also show that m5.3 is sex-regulated in the genital disc and thatrn function is required for proper development of a sub-distal structure of the female genitalia. This suggests that the primordia of the female genitalia may be organized in a similar way to the other imaginal discs, and strongly supports the hypothesis thatrn function is specific to pattern formation along the P/D axis and that it may be involved in the establishment or maintenance of this pattern.
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  • 7
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    Development genes and evolution 201 (1992), S. 364-375 
    ISSN: 1432-041X
    Keywords: Drosophila ; Tissue culture ; In vitro ; Invertebrate embryogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have devised techniques to culture whole, dissected embryos of Drosophila melanogaster. We examine multiple aspects of the morphological and physiological development of the epidermis, musculature, nervous system, and internal organs in this cultured preparation, and show that in vitro development closely parallels normal embryogenesis. These techniques permit a wide range of experimental manipulations during embryogenesis and allow us to extend observations through late embryonic stages, after cuticle deposition. Applications of this technique are presented.
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  • 8
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    Development genes and evolution 201 (1992), S. 105-112 
    ISSN: 1432-041X
    Keywords: Drosophila ; Genital disc ; tra-2 ts ; Differentiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Diplo-X flies homozygous for the transform-er-2 ts (tra-2 ts) mutation develop into females at 16° C, while they develop into males at 29° C (Belote and Baker 1982). By means of this conditional mutation, we have carried out a detailed analysis of the development of the genital disc. Temperature shifts between 16 and 29° C, in both directions, and temperature pulses at 29° C, have been applied during the larval growth of tra-2 ts homozygous diplo-X flies, and the external derivatives of the genital disc have been analysed. Genital discs shifted from 16 to 29° C rapidly lose their capacity to differentiate female genital structures, while they become able to differentiate male genital structures whose inventory is more complete the earlier in larval development the temperature shift is carried out; moreover, duplicated male genital structures were observed. In the shift from 29 to 16° C, the genital disc loses its capacity to differentiate male genital structures, while it becomes able to differentiate female genital structures. The inventory of male structures is smaller, and the inventory of the female structures is more complete, the earlier in larval development the temperature is shifted. No duplicated female or male genital structures were observed in the downshift experiment. With respect to the analia, the shift from 16 to 29° C resulted in the quick formation of pure male anal plates, while in the opposite shift the formation of pure female anal plates occurred gradually. Moreover, the time course for the dorsal and ventral anal plates to show normal female phenotype was different: when the dorsal anal plates were completely normal, it was still possible to find incomplete ventral anal plates. In the pulse experiment at 29° C, the genital disc is able to differentiate both female and male genital structures, although the inventory of the latter ones was not complete. In addition, the capacity of the genital disc to differentiate male genital structures depended on the duration of the temperature pulse. The anal plates were always female, although they showed a reduction in their size, the ventral female anal plate being more affected than the dorsal one. No male anal plates were observed. The results have revealed that the genital disc follows a sequence in its capacity to differentiate female or male adult structures. We suggest that this sequence reflects the sequence of determination events occurring in the genital disc during its larval growth. In addition, results shown here provide evidence for the existence in the female genital primordium of a set of cells capable of giving rise either to female genital structures (ventral vaginal plates) or to male genital structures (hypandrium and penis apparatus). We also present evidence supporting the previous idea of two primordia for the anal plates.
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  • 9
    ISSN: 1432-041X
    Keywords: Drosophila ; Homeotic gene regulation ; Antennapedia ; Development ; β-galactosidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary In order to study the regulation of spatial and temporal expression of the homeotic gene Antennapedia (Antp) in Drosophila melanogaster, we have constructed fusion genes which contain Antp sequences linked to the reporter gene lac Z of Escherichia coli. In one case of P-element transformation, a fusion gene construct integrated into the endogenous Antp gene close to one of the two promoters (P1). The spatial expression from the reporter gene in this transformant line, as analysed by the detection of β-galactosidase activity, was found to exactly mimic the normal expression from the P1 promoter of the Antp gene. We have used this unique transformant as a tool for studying the expression of the P1 promoter in embryonic, larval and adult development. Parallel lines transformed with the same fusion gene construct did not confer a correct P1 pattern of expression. The position in the genome was, therefore, crucial for the expression pattern of the reporter gene. Experiments aiming at the detection of autoregulatory control of Antp gene expression were designed. The results did not, however, support models of positive or negative autoregulation of P1 expression by Amp protein.
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  • 10
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    Development genes and evolution 201 (1992), S. 120-123 
    ISSN: 1432-041X
    Keywords: Integrin ; Drosophila ; In vitro ; Imaginal disc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Drosophila imaginal disc cell lines show a characteristic pattern of aggregation in culture, which appears to be due to cell-cell rather than cell-substrate interactions. We have examined the distribution of PS integrins in wing and leg cell lines, and find that these integrin homologues are expressed preferentially in aggregates. Cell sheets, small cell clumps and chains of cells express antigen at points of cell-cell contact only.
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  • 11
    ISSN: 1432-041X
    Keywords: Drosophila ; Pattern formation ; Segment polarity genes ; gooseberry ; Cell interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Segment polarity genes define the cell states that are required for proper organization of each metameric unit of the Drosophila embryo. Among these, the gooseberry locus has been shown to be composed of two closely related genes which are expressed in an overlapping single-segment periodicity. We have used specific antibodies raised against the protein product of the gooseberry proximal (gsb-p) gene to determine the spatial distribution of this antigen in wild type embryos, and to monitor the effects of segment polarity mutants on the pattern of the gsb-p protein distribution. We find that the gsb-p protein accumulates beneath each posterior axonal commissure in the progeny of neuroblasts deriving from the epidermal compartments of wingless (wg) and engrailed (en) expression. The results of this analysis support the idea that gsb-p has a specific role in the control of cell fates during neurogenesis, and indicate that en and wg provide critical positional cues to define the domain in which gsbp will be activated. Furthermore, these data suggest that, in order to be expressed in the embryonic CNS, gsb-p may preliminarily require activity of the gooseberry-distal gene in the epidermis.
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  • 12
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    Development genes and evolution 201 (1992), S. 88-94 
    ISSN: 1432-041X
    Keywords: Fate map ; Drosophila ; Flight muscle ; Mosaics ; Cell lineage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary A blastoderm fate map has been prepared for Drosophila, using mosaics of a temperature-sensitive mutation, shibire (shi). The mutation can cause abnormal flight muscle morphology, inducible only by a short heat pulse in early metamorphosis. Thus muscle lineage and development are unperturbed until the heat pulse in the early pupa. The developmental focus of the shi muscle phenotype maps to the ventral thorax at the expected site of thoracic mesoderm, and probably indicates the blastoderm progenitors of the adult flight muscle. The fate map provides greater detail than previously available for the dorsolongitudinal fibers (DLM) of flight muscle, showing wide separation of the fibers of flight muscle. DLM fibers a and b map close together, and far anterior to fibers e and f, which also map together. On a fate map, common developmental focus indicates a common blastoderm origin. Thus, the observed pattern for DLM fibers suggests that the blastoderm progenitors for each of these syncytial fiber pairs (a, b; e, f) include only one or two cells. It follows that there is usually a single genotype within each fiber pair (a, b; e, f), and that this genotype is directly reflected in the fiber phenotype. In a large number of cases, DLM fibers a and b differ in phenotype from other DLM fibers, in parallel with their other differences (e.g., timing of development in pupa, innervation, motor activity). The separation of fate map locations of the developmental focus for DLM fibers within mesoderm suggests that specific fibers of flight muscle may, in normal development, originate in all three thoracic mesodermal parasegments.
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  • 13
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    Development genes and evolution 202 (1992), S. 23-35 
    ISSN: 1432-041X
    Keywords: Ecdysteroid ; Imaginal disc ; Drosophila ; Cell line
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have investigated the action of the moulting hormone 20-hydroxy ecdysone (20-HOE) on our leg and wing imaginal disc cell lines. At the morphological level, cells stop dividing and there is some cell death. The remaining cells elongate and aggregate, often producing long processes which form connections between different aggregates. 20-HOE acts within the first one or two days of a passage, at an optimum concentration of 10 ng/ml, this being about 1/100 of the optimum for ecdysone. One cloned wing cell line, C9, has been found to be relatively insensitive to the action of 20-HOE. We have been able to select for resistance to 20-HOE by growing cells in gradually increasing concentrations of hormone followed by passages in hormone-free medium. This has enabled us to isolate a wing cell line C1.8R from its parent cloned line C1.8+. This shows no response to 20-HOE, and cell growth continues even at hormone concentrations as high as 150 ng/ml. We have measured chitin synthesis by the incorporation of radioactive glucosamine into a cell fraction resistant to extensive alkali hydrolysis. The residue was incubated with chitinase, which resulted in a 50% reduction in labelled product. Treatment with 10 ng/ml of 20-HOE dramatically increased chitin synthesis in line C1.8+, but had no effect in the line C1.8R, selected for resistance to hormone.
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  • 14
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    Development genes and evolution 202 (1992), S. 49-60 
    ISSN: 1432-041X
    Keywords: Drosophila ; Delta ; Enhancers ; Suppressors ; Neurogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have screened for dominant enhancers and suppressors of the wing phenotype associated with two Delta alleles: Dl 9P39, an amorphic allele, and Dl FE32, an antimorphic allele. The interactions of some of the modifiers with Delta are due to haplo-insufficient expression of the corresponding genes. Although not explicitly shown for the remaining cases, we assume that haploin-sufficiency is also the basis for the relationships of these genes to Delta, since no allele specific interactions were observed. The modifiers found define 22 genes with pleiotropic expression, which can be classified into two groups: genes required for wing vein pattern formation and for neurogenesis, and genes which are not required for neurogenesis. Among the genes of the first group, Hairless and Star were previously known to participate in neural development. One further modifier was found which may correspond to a new neurogenic gene. The second group of genes is larger and includes already known loci, e.g., Plexate, blistered, plexus, etc, as well as other previously unidentified genes, which function during wing morphogenesis.
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  • 15
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    Development genes and evolution 201 (1992), S. 1-11 
    ISSN: 1432-041X
    Keywords: Drosophila ; Neurogenesis ; Signals ; Delta ; Notch
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The ectodermal germ layer of Drosophila melanogaster gives rise to two major cell lineages, the neural and the epidermal. Progenitor cells for each of these lineages arise from groups of cells, whose elements must decide between taking on either fate. Commitment of the progenitor cells to one of the developmental fates implies two factors. One is intrinsic to the ectodermal cells and determines a propensity to take on neural fate; this factor is probably represented by the products of the so-called proneural genes, which are differentially distributed throughout the ectoderm. The other factor in the cells' decision to adopt one of the two alternative fates is intercellular communication, which is mediated by the products of the so-called neurogenic genes. Two types of interactions, one inhibiting and the other stimulating neural development, have been inferred. We discuss here the assumed role of various neurogenic genes, in particular Notch and Delta, in these processes.
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  • 16
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    Development genes and evolution 201 (1992), S. 194-220 
    ISSN: 1432-041X
    Keywords: Drosophila ; Enhancer trap lines ; Embryogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Embryos of 171 Drosophila lines carrying a P-lacZ insertion on the second or third chromosome were analyzed regarding their pattern of lacZ expression. All lines were selected from a larger screen of about 4000 lines (Bier et al. 1989). Tissue specificity and time of onset of lacZ expression was documented for each line. Thereby, a comprehensive list of markers for the various tissue and cell types of the Drosophila embryo could be assembled. With the help of several P-lacZ lines the development of a number of structures was studied which so far had been described only insufficiently or not at all. In particular, the embryonic origin and early development of the oenocytes, imaginal discs, histoblasts, fat body, dorsal vessel, and perineurial cells was analyzed. Several previously unknown cell types associated with the dorsal vessel, trachea, and epidermis were discovered. By combining data regarding the origin of the different mesodermally derived organs it was possible to generate in some detail a fate map of the mesoderm of the stage 11 Drosophila embryo.
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  • 17
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    Cellular and molecular life sciences 48 (1992), S. 623-629 
    ISSN: 1420-9071
    Keywords: Drosophila ; heat shock ; stress ; heat shock protein ; gene regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Major alterations in genetic activity have been observed in every organism after exposure to abnormally high temperatures. This phenomenon, called the heat shock response, was discovered in the fruit flyDrosophila. Studies with this organism led to the discovery of the heat shock proteins, whose genes were among the first eukaryotic genes to be cloned. Several of the most important aspects of the regulation of the heat shock response and of the functions of the heat shock proteins have been unraveled inDrosophila.
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  • 18
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    Oecologia 92 (1992), S. 183-187 
    ISSN: 1432-1939
    Keywords: Drosophila ; Resource exploitation ; Decaying-herbage breeding ; Host choice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The Drosophila fauna of a deciduous flood plain forest rich in undergrowth near the river Isar, close to Munich, Germany, was surveyed in summer 1990. Decaying herbage baits (decay artificially induced) were set out to study the exploitation of that resource by Drosophila. Sixteen plant species belonging to several families dominant in the collecting area were tested. All attracted and produced drosophilid flies. Ten Drosophila species utilized decaying plant material as breeding sites; at least eight of the ten are polyphagous. Decaying stalks and leaves of Angelica sylvestris (Apiaceae) were examined in detail. In the case of the most frequent species of Drosophila attracted to A. sylvestris, the number of adults collected did not correlate with the number of flies emerging from the substrate. This was particularly true of D. limbata and D. phalerata. When oviposition and larval development of D. limbata and D. phalerata on A. sylvestris was tested in the laboratory, the number of offspring per female was the same in both species. The difference between these two species of the quinaria group in the exploitation of A. sylvestris in the field is therefore not due to differential suitability of the substrate.
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  • 19
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    European journal of clinical pharmacology 42 (1992), S. 101-105 
    ISSN: 1432-1041
    Keywords: Rufloxacin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urine kinetics of rufloxacin were assessed in healthy volunteers after single (100, 200, 400 and 800 mg) and multiple (300 mg followed by 150 mg daily, Group 1, and 400 mg followed by 200 mg daily, Group 2) oral doses. The kinetics of a single oral dose of 800 mg was assessed in fasting and non-fasting subjects to assess the influence of food intake on drug absorption. The AUCs were 134, 266 and 375 μg · h · ml−1 after 100, 200 and 400 mg, respectively. The AUC after 800 mg p. o. was 715 μg · h · ml −1 in fasting subjects and 614 μg · h · ml−1 in non-fasting subjects. The parameters of the model and the mean renal clearance values indicated some departure from linearity in rufloxacin kinetics. After multiple doses the plasma drug levels during the 6th treatment day were similar to those after the first dose in Group 1 and were about 30–40% higher after the first dose in Group 2. The half-lives after the last dose were much shorter than those estimated in the single dose studies (33–36 h and 50–80 h, respectively).
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  • 20
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    European journal of clinical pharmacology 42 (1992), S. 535-538 
    ISSN: 1432-1041
    Keywords: Meropenem ; Carbapenem ; pharmacokinetics ; uraemia ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 μg·ml−1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.
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  • 21
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    European journal of clinical pharmacology 42 (1992), S. 559-560 
    ISSN: 1432-1041
    Keywords: Mefloquine ; Thai subjects ; pharmacokinetics ; Primaquine ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 22
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    European journal of clinical pharmacology 42 (1992), S. 689-691 
    ISSN: 1432-1041
    Keywords: Diphemanil methylsulphate ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of oral diphemanil methylsulphate have been evaluated in six healthy male volunteers. Absorption of the drug was slow (tmax=2 to 4 h), the mean half-life was 8.35 h, and the amount of the drug recovered in urine within 48 h ranged from 0.6 to 7.4% of the administered dose. The results suggest low bioavailability, assuming that the drug is poorly metabolized.
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  • 23
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    European journal of clinical pharmacology 42 (1992), S. 693-694 
    ISSN: 1432-1041
    Keywords: Loperamide ; loperamide oxide ; diarrhoea ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of loperamide, after oral administration of increasing doses (1 to 16 mg) of loperamide oxide, has been investigated in 10 healthy male volunteers, using a randomised cross-over design. Comparison of the maximum plasma loperamide concentration and AUC demonstrated that the bioavailability of loperamide was proportional to the dose of loperamide oxide administered.
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  • 24
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    European journal of clinical pharmacology 43 (1992), S. 67-75 
    ISSN: 1432-1041
    Keywords: Morphine ; Patient-controlled analgesia ; opioids ; pharmacokinetics ; bolus-elimination-transfer ; computer-assisted continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bone marrow transplant patients having severe, prolonged oral mucositis pain (expected to last for one to three weeks) used a computer-controlled infusion system to self-administer morphine for pain control. Individual patient pharmacokinetic information, derived from a pretreatment bolus morphine dose, was used in a new bolus-elimination transfer algorithm to produce rapid adjustments of steady plasma morphine concentrations when the patient requested more or less drug. We evaluated the performance characteristics (bias and precision) of this pharmacokinetically based patient-controlled analgesic infusion system (PKPCA) in a group of 15 cancer patients over six to 14 days. Although we found a three- to fivefold pharmaco-kinetic variability in the tailoring morphine dose data, the PKPCA system was free of systematic bias (insignificant overall prediction error) during the patient-controlled infusions in this study population. The absolute prediction error was 19.9% for the group on the first study day and 25.6% over the entire study period (aggregate results; 6–14 days of continuous use). Two-thirds of the patients exhibited no bias throughout the study period, and individual bias in the others was symmetrically distributed (three patients with underpredictions and two overpredicted). Magnitude of prediction error during the patient-controlled morphine infusions was not related to the magnitude of pharmacokinetic deviation of individual subjects from group parameters. Our results indicate that this PKPCA system provides accurate control of plasma morphine concentration when used by patients to self-administer opioid for prolonged pain relief continuously over 1 to 2 weeks. Use of individual pharmacokinetic information, instead of population parameters, may account for superior performance characteristic of this computer-assisted continuous drug infusion system.
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  • 25
    ISSN: 1432-1041
    Keywords: Indomethacin ; steady-state ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state pharmacokinetic profile of indomethacin was examined in twelve healthy volunteers (4 m, 8 f; 20–34 y) and in 12 elderly subjects (7 m, 5 f; 70–88 y). Two formulations of indomethacin were examined, providing duplicate data for each subject group. The subjects received each formulation of indomethacin (25 mg tid) for 6 days in a single blind crossover fashion. On day 7, after an overnight fast, a final 25 mg dose of indomethacin was given and plasma concentrations measured over the following 12 h. Kinetic parameters Cpmin, tmx and AUC (0–12 h) were determined. There were no differences in the pharmacokinetic parameters between young and elderly subjects or between data for the two formulations of indomethacin. AUC values (μg · ml−1 · h), for example, for the two formulations in the young subjects were 5.85 and 6.85 while the values for the elderly subjects were 6.55 and 6.50 respectively. When each treatment period was considered independently there was a significant difference between young and elderly subjects with regard to compliance. The rates of non compliance (over and under compliance) using a capsule count technique were, however, low with a mean maximum value of 5.8% being recorded for the elderly subjects.
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  • 26
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    European journal of clinical pharmacology 42 (1992), S. 231-233 
    ISSN: 1432-1041
    Keywords: Isradipine ; Haemodialysis ; pharmacokinetics ; dialysability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed. The mean cmax, tmax, AUC, and t1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml−1, 1.4 h, 23.8 ng·h·ml−1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min−1). The t1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.
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  • 27
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    European journal of clinical pharmacology 42 (1992), S. 171-174 
    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; red blood cells ; plasma ; saliva ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of quinine has been studied in ten healthy adult Africans after intravenous infusion and oral ingestion of a 500 mg dose. Blood and saliva samples were collected over 48 h and quinine in plasma, red cells and saliva was determined by HPLC. Quinine was rapidly and almost completely absorbed after an oral dose, with absorption half-life of 0.53 h, a tmax of 1–3 h and a bioavailability of 88%. Analysis of the i. v. data gave an apparent volume of distribution of 3.6 1·kg−1 and a plasma clearance of 0.19 l·kg−1·h−1. The concentration-time curves for plasma, red cells and saliva had declining phases were approximately parallel, giving a similar half-life that in all three media. The half-lives after the i. v. infusion also did not different from those after oral administration. The dose was well tolerated by both methods of administration.
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  • 28
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    European journal of clinical pharmacology 42 (1992), S. 175-179 
    ISSN: 1432-1041
    Keywords: 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) ; Triflusal ; triflusal metabolite (HTB) ; pharmacokinetics ; protein binding ; ultrafiltration ; binding constant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied. Rats were given a single oral dose of 50 mg·kg−1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC. HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K1=1.4×105 l·mol−1, n1=1.23, and K2=4.1×103 l·mol−1 and n2=3.77. The mean plasma concentration in rats after oral administration was 185 (37) μg·ml−1 (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K1=4.7×105 l·mol−1, n1=1.93, K2=4.3 l·mol−1 and n2=4.28. The plasma HTB concentration in man (n=8) was 35 μg·ml−1 (Cmax) after a single oral dose of triflusal 300 mg, 172.96 μg·ml−1 (Cmax·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 μg·ml−1 (Cmax·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.
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  • 29
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    European journal of clinical pharmacology 42 (1992), S. 181-185 
    ISSN: 1432-1041
    Keywords: Glycerol ; brain oedema ; serum ; cerebrospinal fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Glycerol 50 g infused i. v. over 2 to 6 h is widely used to treat cerebral oedema in patients with acute stroke. Its transit through the blood-cerebrospinal fluid barrier in subjects with uninflamed meninges has now been examined. In 7 patients with an external ventriculostomy for occlusive hydrocephalus, each of whom was given 500 ml of a 10% solution IV over 4 h, serum and CSF were repeatedly sampled during and after the infusion and glycerol was measured enzymatically. The highest serum glycerol level of 191–923 mg/l was observed at the end of the infusion. The maximum CSF glycerol of 18.7–110.8 mg/l was attained 0–1 h after the end of the infusion. Elimination both from serum and CSF approximated a single-exponential decay; the elimination half-life from serum was 0.29–0.56 h compared to 1.03–3.68 h from CSF. In six of the seven cases there was a temporary reversal of the serum/CSF concentration gradient during glycerol elimination. The ratios of the AUCs of CSF and serum, which describe the overall penetration of glycerol into CSF, ranged from 0.09–0.31. In conclusion, the serum level of glycerol produced by giving 50 g IV glycerol over 4 h may not be sufficiently high reliably dehydrate to brain tissue in many patients, and the slow elimination of glycerol from the CSF may be related to the so-called rebound phenomenon.
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  • 30
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    European journal of clinical pharmacology 42 (1992), S. 187-191 
    ISSN: 1432-1041
    Keywords: Dipyrone ; Acetylation phenotype ; metabolism ; pharmacokinetics ; urinary excretion ; metabolite clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml·min−1·kg−1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml·min−1·kg−1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.
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  • 31
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    European journal of clinical pharmacology 42 (1992), S. 197-201 
    ISSN: 1432-1041
    Keywords: Digoxin ; Salbutamol ; serum ; skeletal muscle digoxin ; pharmacokinetics ; drug interaction ; serum potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of the β2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a β2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man. Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 μg·kg−1·h−1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 μg·kg−1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a β2-adrenoceptor-mediated increase in Na-K-ATPase activity.
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  • 32
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    European journal of clinical pharmacology 42 (1992), S. 203-207 
    ISSN: 1432-1041
    Keywords: Nicorandil ; pharmacokinetics ; angina pectoris ; uraemia ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CLCr): GROUP I (n=6) 〉 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) 〈 20 ml/min. After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h−1 in Group I, 44 l·h−1 in Group II and 56 l·h−1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment. The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.
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  • 33
    ISSN: 1432-1041
    Keywords: Alprazolam ; benzodiazepines ; pharmacokinetics ; pharmacodynamics ; sublingual dosage
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P〈0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml−1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml−1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.
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  • 34
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    European journal of clinical pharmacology 42 (1992), S. 445-448 
    ISSN: 1432-1041
    Keywords: Ethanol ; whole blood ; plasma ; total body water ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ethanol in plasma and whole blood have been investigated and the results used to estimate the volume of total body water (TBW) by means of the dilution principle. Fifteen men (mean age 62 y) were given 0.6 g ethanol/kg body weight as an intravenous infusion over 1 h. The peak concentration of ethanol in plasma was 120 mg·dl−1 compared to 108 mg·dl−1 for whole blood. The disappearance rate of ethanol from plasma was 18.6 mg·dl−1·h−1 compared to 17.0 mg·dl−1·h−1 for the whole blood concentration-time data. The apparent volume of distribution of ethanol (Vz) was 0.54 l·kg−1 according to plasma kinetics compared to 0.59 l·kg−1 for the kinetics derived from whole blood. The mean area under the curve (AUC) was 294 mg·dl−1×h for plasma kinetics compared to 266 mg·dl−1×h for whole blood. The TBW was 40.9 l or 50.9% of body weight for the plasma concentration-time data. This agreed well with the 40.3 l or 50.1% of body weight obtained using whole blood.
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  • 35
    ISSN: 1432-1041
    Keywords: Methylprednisolone ; Rheumatoid arthritis ; bioavailability ; pharmacokinetics ; clinical response ; pulse steroid therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A commercially available 1.0 g intravenous (i.v.) dosage formulation of methylprednisolone, as the sodium hemisuccinate salt (Solu MedrolR, Upjohn) was administered both parenterally and orally (pulse steroid therapy) on separate occasions, to eight elderly (mean 65 y) patients with active rheumatoid arthritis. The relative oral bioavailability of the sterol was 69.2%. Elimination of methylprednisolone was prolonged when given orally; the mean residence times were 7.23 h and 3.94 h for oral and i.v. administrations, respectively. Clinical response to pulse steroid therapy was no different with respect to route of administration. There were no significant differences in standard clinical and laboratory assessments of disease activity when the two therapies were compared. Oral administration of methylprednisolone in patients requiring high-dose pulse steroid therapy is convenient and avoids the discomfort and inconvenience associated with i.v. administration.
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  • 36
    ISSN: 1432-1041
    Keywords: Acetyl-L-carnitine ; Senile Dementia of Alzheimer Type ; pharmacokinetics ; plasma concentration ; cerebrospinal fluid concentration ; carnitine metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type. The study design comprised a 3-day basal observation period, sham treatment with repeated blood sampling; treatment with 30 mg·kg−1 i.v. given twice for 10 days (plasma kinetics was studied on the 7th day), and 50 days of 2.0 g/day p.o. given in three daily doses. Total acid soluble L-carnitine, L-carnitine and acetyl-L-carnitine in plasma and CSF were evaluated using an enantioselective radioenzyme assay. Short chain L-carnitine esters were calculated as the difference between total and free-L-carnitine. The plasma concentrations of individual components of the L-carnitine family did not change during the three days of the basal period, nor were they affected during the sham therapy period. Following the i.v. bolus injections, the plasma concentrations showed a biphasic curve, with average t1/2 of 0.073 h and 1.73 h, respectively. At the end of oral treatment, plasma acetyl-L-carnitine and L-carnitine short chain esters were significantly higher than during the run-in phase. The CSF concentrations paralleled those in plasma, suggesting that ALC easily crosses the blood-brain barrier. It is concluded that i.v. and oral administration of multiple doses of ALC can increase its plasma and CSF concentration in patients suffering from Alzheimer's disease.
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  • 37
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    European journal of clinical pharmacology 42 (1992), S. 95-99 
    ISSN: 1432-1041
    Keywords: Ofloxacin ; Haemodialysis ; ofloxacin metabolites ; pharmacokinetics ; multiple doses ; dosage selection ; renal failure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 7 patients with end-stage renal disease on regular haemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 h for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC. Peak (3.1 mg·1−1) and trough levels (1.6 mg·1−1) and the AUC of ofloxacin were comparable to the values in healthy volunteers given 300 to 400 mg ofloxacin p.o. The mean half-life, determined in the dialysis-free interval (t1/2β) and during the haemodialysis session (t1/2HD), was 38.5 h and 9.9 h, respectively. Extrarenal clearance (32.7 ml·min−1) was unchanged as compared to that reported in healthy volunteers after a single dose of ofloxacin. The fractional removal by haemodialysis amounted to 21.5%. Two metabolites, ofloxacin-N-oxide and demethyl-ofloxacin, were detected in plasma. Despite prolonged t1/2β of both metabolites (66.1 and 50.9 h) and multiple doses of ofloxacin the peak concentrations of the metabolites reached only 14% and 5% of that of the parent drug, respectively. It is concluded that in patients on regular haemodialysis treatment the dosage adjustment employed resulted in safe and therapeutically favourable plasma concentrations. The observed accumulation of ofloxacin metabolites does not appear to have any toxic or therapeutic significance.
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  • 38
    ISSN: 1432-1041
    Keywords: Methotrexate ; non-steroidal anti-inflammatory drugs (NSAIDs) ; interaction ; disposition ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.
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  • 39
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    European journal of clinical pharmacology 43 (1992), S. 567-569 
    ISSN: 1432-1041
    Keywords: Mefloquine ; Tetracycline ; Thai subjects ; Thai subjects ; drug interaction ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with tetracycline has been studied in 20 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with tetracycline (1600 vs 1160 ng · ml−1), as well as a significantly reduced terminal half-life (14.4 vs 19.3 days), mean residence time (11.9 vs 16.0 days) and volume of distribution at steady state (13.3 vs 19.91 · kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 7 days was significantly increased by tetracycline (6.18 vs 4.76 μg · ml−1 · day). The changes in mefloquine disposition after tetracycline treatment are probably due to a reduction in enterohepatic recycling. The initial increase in mefloquine AUC without an apparent increase in side-effects suggests that this combination may have a place in the treatment of multi-drug resistant falciparum malaria.
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  • 40
    ISSN: 1432-1041
    Keywords: Cyclosporine ; Hyperlipidaemia ; heart transplantation ; fenofibrate ; fenofibric acid ; pharmacokinetics ; drug interaction ; nephrotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng·ml−1), Cmax (812 ng·ml−1 by RIA and 757 ng·ml−1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h). The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.
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  • 41
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    European journal of clinical pharmacology 42 (1992), S. 219-222 
    ISSN: 1432-1041
    Keywords: Thiamine ; pharmacokinetics ; analytical method ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel liquid chromatographic method for the determination of thiamine in plasma has been developed and has been used to study plasma thiamine concentrations after multiple dosage regimens for 11 days. The method involves purification, concentration and analytical separation of thiochrome on-line, using a switching column system. Ten healthy men were given 500 mg thiamine i.m. once a day (Group 1) and ten were given 250 mg p.o. every 12 h (Group 2). The times to reach steady state (7 and 5.6 days for Groups 1 and 2, respectively) were not different (P〉0.05). The mean elimination half-life was 1.8 days. The mean minimum steady-state concentration after the oral regimen (23 μg·l−1) was 78% of that after the intramuscular regime (29 μg·l−1).
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  • 42
    ISSN: 1432-1041
    Keywords: Ibopamine ; Isosorbide-5-mononitrate ; pharmacokinetics ; drug interaction ; healthy volunteers ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 μg·ml−1·h after 5-ISMN alone, 2.16 μg·ml−1·h after 5-ISMN + ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.
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  • 43
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    European journal of clinical pharmacology 42 (1992), S. 593-598 
    ISSN: 1432-1041
    Keywords: Metamizole ; Furosemide ; prostaglandins ; drug interaction ; adverse effects ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min−1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml−1 · h−1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F2α (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.
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  • 44
    ISSN: 1432-1041
    Keywords: 6-Mercaptopurine ; suppository ; bioavailability ; acute lymphoblastic leukaemia ; children ; interindividual variability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and the area under the plasma concentration-time curve (AUC) values of 6-mercaptopurine (6-MP) were determined in a balanced crossover study of oral (powder) and rectal (macrogol suppository) administration to 5 children with acute lymphoblastic leukaemia (ALL). The AUC (538.6 ng · h · ml−1) after the rectal dose of 30 mg/m2 was approximately 1.5-times of that (365.5 ng · h · ml−1) after the oral dose of 87.5 mg/m2. The coefficients of variation of interindividual variability of the AUCs were 21.5% and 32.3%, respectively. The relative bioavailability of the macrogol suppository compared to the powder was approximately 4.39. These findings indicate that rectal administration of 6-MP could avoid the first-pass effect of this drug in the alimentary canal and/or liver, resulting in a large AUC of 6-MP, and so could reduce interindividual variability in plasma 6-MP concentrations. Rectal administration of 6-MP may be more effective than empirical oral dosing for the treatment of children with ALL, especially for patients with nausea and/or vomiting.
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  • 45
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    European journal of clinical pharmacology 42 (1992), S. 635-639 
    ISSN: 1432-1041
    Keywords: Vancomycin ; Haemodialysis ; highflux membranes ; pharmacokinetics ; renal failure
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Vancomycin is usually given only once a week to haemodialysis (HD) patients. If highly permeable dialysis membranes are used, however, high clearance values have been reported, so the aim of the study was to determine whether high clearance of vancomycin resulted in sufficient drug elimination to induce subtherapeutic plasma levels after one week. In 18 chronic HD patients, treated with polysulfone dialyzers (1.2 m2), the pharmacokinetics of vancomycin were studied after administration of 1 g. Concentrations were determined by fluorescence polarisation immunoassay. At a blood flow of 219 ml·min−1, HD clearance of vancomycin was 62.3 ml·min−1. Immediately after dialysis plasma concentrations were 38% lower than predialysis levels. However, marked rebound in the vancomycin level was observed 5 h later, resulting in plasma levels only 16% lower than prior to dialysis. 3 HD treatments in 1 week removed about one third of the initial dose. After one week 15 of 18 patients still had a therapeutic plasma level (〉5 μg·ml−1). In conclusion, polysulfone membranes show high clearance of vancomycin. However, transfer of drug from blood to dialysate appears to be faster than from tissues to blood. Because of a marked rebound in plasma level after treatment, therapeutic drug concentrations will still be present in most patients after one week.
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  • 46
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    European journal of clinical pharmacology 43 (1992), S. 501-505 
    ISSN: 1432-1041
    Keywords: S-1452 ; thromboxane A2 receptor antagonist ; nocturnal dosage ; platelet aggregation ; circadian rhythm ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is well known that platelet aggregation shows a morning rise, which may contribute to the increase in the onset of ischaemic heart diseases during the morning period. The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane AZ receptor antagonist, would blunt the morning rise in platelet aggregability. S-1452 50 mg or placebo were given orally to 8 healthy subjects at 10.00 h (day trial) or 22.00 h (night trial) according to a cross-over design. Plasma concentrations of S-1452 and its metabolites, bisnor-( + )-S-145 and tetranor-(+ )-S-145, and platelet aggregation were determined during the 12-hour period following the dose. Mean plasma concentrations of S-1452, bisnor-( + )-S-145 and tetranor-(+ )-S-145 during the absorption phase were lower after the nocturnal dose than after the morning dose. The maximum plasma concentration and area under the plasma concentration-time curve of the compounds were also lower and the time to the maximum concentration were delayed after the treatment at night. A morning rise in platelet aggregation was observed following placebo treatment. The inhibitory effect of S-1452 on platelet aggregation was observed at 3 hours and persisted for up to 9 h in both trials. The results suggest that S-1452 is absorbed more slowly after the nocturnal dose than after the morning dose. However nocturnal treatment with 50 mg S-1452 may blunt the morning rise in platelet aggregability.
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  • 47
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    European journal of clinical pharmacology 43 (1992), S. 527-531 
    ISSN: 1432-1041
    Keywords: Calcitonin ; Colonic administration ; Bioavailability ; pharmacokinetics ; pharmacodynamics ; adverse effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentrationtime curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.
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  • 48
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    European journal of clinical pharmacology 43 (1992), S. 85-88 
    ISSN: 1432-1041
    Keywords: Hypertension ; Carvedilol ; chronic renal failure ; pharmacokinetics ; adverse effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and acute systemic haemodynamic effects of a single oral dose of 50 mg carvedilol has been studied in 24 hypertensive patients with chronic renal failure. The patients were stratified into 3 groups according to the creatinine clearance: I 51–90 ml · min−1; II 26–50 ml · min−1; III 4–25 ml · min−1. The area under plasma level time curve AUC, the elimination half-life t/12, the maximum plasma concentration Cmax, the time to peak concentration tmax were not significantly different between groups, whereas the amount of unchanged drug or metabolite excreted in urine Ae and the renal clearance CLR of carvedilol and its metabolites M2, M4, M5 were significantly decreased in Group III. Blood pressure and heart rate decreased in all 3 groups of patients after acute administration of 50 mg carvedilol. Mild adverse effects were reported in 6 patients. Despite a decrease in the renal clearance of carvedilol and of its metabolites with decreasing kidney function, its main pharmacokinetic parameters remained unchanged. The present results suggest that the dose of carvedilol need not be reduced in hypertensive patients with chronic renal failure.
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  • 49
    ISSN: 1432-1041
    Keywords: Tiopronin ; 2-mercaptopropionic acid ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tiopronin and its principal metabolite, 2-mercaptopropionic acid (2-MPA) in healthy volunteers after the oral administration of 500 mg (2 Acadione® tablets), followed by simultaneous assay of the two compounds in plasma over a period of 48 h using a new method (emission of fluorescence after HPLC and post-column derivatization by pyrene-maleimide). The absorption of tiopronin was slow (tmax between 4 and 6 h) and the plasma concentrations subsequently fell biexponentially. The principal metabolite 2-MPA appeared later in the plasma (tmax between 10 and 12 h after a lag-time of 3 h) then disappeared monoexponentially. About 15% of the tiopronin was metabolized to 2-MPA.
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  • 50
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    European journal of clinical pharmacology 42 (1992), S. 209-212 
    ISSN: 1432-1041
    Keywords: Ethanol ; gastric acid inhibition ; pharmacokinetics ; antisecretory drugs ; omeprazole ; ranitidine ; cimetidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of three gastric antisecretory drugs on the pharmacokinetics of ethanol have been studied in a randomized crossover experiment. Male medical students (n=12) took ethanol 0.8 g/kg body weight at 08.00 h after an overnight fast. On seven successive days before drinking ethanol they were given omeprazole 20 mg, cimetidine 800 mg, ranitidine 300 mg, or no drug, with a period of at least 7 days between treatments. The peak blood ethanol concentration of 21.9 to 22.8 mmol·l−1 occurred at 64 to 70 min after the end of drinking. The rate of disappearance of ethanol from the blood ranged from 3.0 to 3.3 mmol·l−1·h−1 and the rate of removal from the whole body ranged from 8.0 to 8.5 g·h−1. The apparent volume of distribution of ethanol was almost the same for all four treatments: mean 0.68 l·kg−1, corresponding to a mean total body water of 441 (59% body weight). Mean areas under the concentration-time profiles of ethanol ranged from 83 to 87 mmol·l−1·h for the four treatments. It is concluded that omeprazole, cimetidine and ranitidine do not alter the kinetics of a moderate dose of ethanol.
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  • 51
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    European journal of clinical pharmacology 42 (1992), S. 227-229 
    ISSN: 1432-1041
    Keywords: Tenoxicam ; Warfarin ; drug interaction ; pharmacokinetics ; anticoagulation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has been studied in healthy volunteers. Tenoxicam did not alter the plasma warfarin concentration versus time profile. Treatment with it for 14 days had no effect on the average dose of warfarin required to maintain the prothrombin time within a specified range. The coumarin dose index, an indicator of warfarin sensitivity, remained unchanged during tenoxicam administration. The results demonstrate the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation.
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  • 52
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    European journal of clinical pharmacology 43 (1992), S. 173-177 
    ISSN: 1432-1041
    Keywords: Enalapril ; Hydrochlorothiazide ; pharmacokinetics ; renal impairment ; old patients
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62–84 y, SBP 〉 160 mm Hg, DBP 〉 100 mm Hg, creatinine clearance 11–93 ml·min−1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0–24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol·l−1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.
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  • 53
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    European journal of clinical pharmacology 43 (1992), S. 179-184 
    ISSN: 1432-1041
    Keywords: Ebastine ; Ethanol interaction ; carebastine ; psychomotor performance ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g·kg−1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 µg·l−1 on Day 6 and 104 µg·l−1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g·l−1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol. We conclude that treatment with 20 mg ebastine once daily for one week provides steady concentrations of carebastine in plasma without impairment of skilled performance or important interactions with alcohol.
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  • 54
    ISSN: 1432-1041
    Keywords: β-Methyldigoxin ; Ranitidine ; pharmacokinetics ; drug interaction
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  • 55
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    European journal of clinical pharmacology 43 (1992), S. 197-199 
    ISSN: 1432-1041
    Keywords: Tenoxicam ; pharmacokinetics ; haemodialysis ; end-stage renal disease
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis. After a single dose, tenoxicam had a half-life (t1/2) of 33 h, an apparent clearance (CL·f−1) of 4.3 ml·min−1, and an apparent volume of distribution (Vz·f−1) of 11.8 l. The maximum tenoxicam concentration (Cmax) was 4.3 mg·l−1 at a median tmax of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples. Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate. Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.
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  • 56
    ISSN: 1432-1041
    Keywords: Noradrenaline ; Adrenaline ; catecholamines ; pharmacokinetics ; healthy volunteers ; IV infusion
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Noradrenaline and adrenaline were infused IV at 5 different rates (0.01–0.2 μg · kg · min− for 30 min to volunteers. The plasma catecholamine concentrations were determined by HPLC and electro-chemical detection. At the highest infusion rate, the arterial and venous plasma concentrations of noradrenaline increased from 1.18 to 44.1 nmol · l−1and from 1.14 to 31.9 nmol · l−1, respectively, and of adrenaline from 0.29 to 23.9 nmol · l−1 and from 0.28 to 19.3 nmol · l−1 respectively. The peripheral venous plasma concentration of noradrenaline averaged 76% of the arterial concentration, and of adrenaline it was 73%. There was a linear relationship between the peripheral venous and arterial plasma noradrenaline and adrenaline concentrations at therapeutic doses.
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  • 57
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    European journal of clinical pharmacology 43 (1992), S. 273-276 
    ISSN: 1432-1041
    Keywords: Molsidomine ; slow release ; pharmacokinetics ; in vitro/in vivo correlation ; pharmacokinetics ; healthy volunteers ; dissolution profile
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (〉 5 ng · ml−1 were not maintained over 24 h by this slow release formulation.
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  • 58
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    European journal of clinical pharmacology 43 (1992), S. 445-447 
    ISSN: 1432-1041
    Keywords: Captopril ; Digitoxin ; impedance cardiography ; drug interaction ; healthy volunteers ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: −7.9 to −1.6 beats · min−1), in mean diastolic blood pressure (95 % CI: −8.3 to −0.4 mm Hg), shortening of the QTc-interval (95 % CI: −42 to −19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: −16 to −1 ms) and electromechanical systole QS2c (95 % CI: −25 to −1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation. The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state. Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.
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  • 59
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    European journal of clinical pharmacology 42 (1992), S. 237-256 
    ISSN: 1432-1041
    Keywords: Non-steroidal anti-inflammatory drugs ; Enantioselective ; Enantiomers ; pharmacodynamics ; pharmacokinetics ; stereoselective
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  • 60
    ISSN: 1432-1041
    Keywords: Dihydropyridine ; Felodipine ; availability ; flavonoids ; dietary interaction ; pharmacokinetics ; pharmacodynamics ; adverse effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol · l−1, and in the AUC from 23 to 65 nmol · h · l−1. The change in AUC corresponded to an increase in the systemic availability of felodipine from 15 to 45%, assuming no change in its clearance. This change was probably caused by inhibition of the oxidation of felodipine to the inactive dehydrofelodipine by flavonoids in grapefruit juice. The interaction with grapefruit juice is believed to be a class effect for the dihydropyridines, as oxidation of the dihydropyridine ring to the corresponding pyridine derivative is a major metabolic route for all these drugs. The higher plasma concentrations of felodipine taken with grapefruit juice resulted in a greater change in blood pressure measured in the morning 3 h after dosing (−9%) than did water (0%).
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  • 61
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    European journal of clinical pharmacology 42 (1992), S. 329-332 
    ISSN: 1432-1041
    Keywords: Midazolam ; Fentanyl ; Neonates ; pharmacokinetics ; sedation drug interaction ; hypotension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus (0.2 mg·kg−1) immediately followed by continuous infusion of 0.06 mg·kg−1·h−1 was administered to 15 critically ill neonates at a gestational age of 32.8 weeks, who required sedation for mechanical ventilation. Heart rate and blood pressure were closely monitored. Hypotension occurred in 4 patients after the bolus dose or during the continuous infusion. Three of them had also been given fentanyl. Individual pharmacokinetic parameters were calculated: plasma clearance was 3.9 ml·min−1, elimination half-life was 12.0 h. Because of its short half-life compared to diazepam, midazolam may be used during the neonatal period to achieve rapid, brief sedation. However, it should be administered cautiously to neonates, particularly in premature infants, or if fentanyl is also given.
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  • 62
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    European journal of clinical pharmacology 42 (1992), S. 343-345 
    ISSN: 1432-1041
    Keywords: Omeprazole ; Theophylline ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of omeprazole treatment on theophylline pharmacokinetics was studied in eight, non-smoking healthy male volunteers during repeated administration of a slow release formulation of theophylline. In a randomized double-blind cross-over study, the subjects received theophylline 5 mg·kg−1 per day with omeprazole 20 mg per day or identical placebo during two periods, each of 7 days, separated by a washout period of 7 days. The oral clearance of theophylline remained unchanged whether it was administered alone or with omeprazole (54.2 ml·min−1). The average urinary excretion of theophylline and its metabolites, 1,3 dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) amounted to 9%, 32%, 12% and 22% of the administered dose, respectively, and no significant change occured during concomitant treatment with omeprazole. Thus, the formation and clearance of the metabolites was not altered by omeprazole. Consequently, omeprazole in the recommended dose of 20 mg daily can safely be administered to patients on theophylline therapy.
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  • 63
    ISSN: 1432-1041
    Keywords: Metipranolol ; Liver cirrhosis ; pharmacokinetics ; pharmacodynamics ; beta-adrenoreceptor blockade
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics and heart rate reducing effect of deacetylmetipranolol (DMP), the active form of the β-adrenoreceptor blocking agent metipranolol (MP), administered as a single 40 mg oral dose have been compared in 6 patients with cirrhosis and 6 healthy volunteers. The mean maximal DMP concentration was significantly higher and the time to reach the peak level shorter in the patients compared to the healthy subjects. There was also a significantly higher AUC of DMP, a shorter half-life of the rapid phase of the decline in DMP concentrations, a smaller central compartment and lower apparent DMP clearance in patients. A correlation with the albumin level was observed in cirrhotics for individual values of apparent DMP clearance (r=0.92) and AUC (r=-0.89). The maximal reduction in heart rate was recorded in patients at plasma DMP levels which were already significantly lower than the peak levels. Median inhibitory concentrations (IC50) and maximum possible heart rate reductions (Δ HRmax), obtained by fitting individual plots of the plasma DMP concentration-effect relationship to the inhibitory Emax model in the postdistributional phase of DMP disposition were significantly higher in cirrhotics than in healthy subjects. It is conjectured that down-regulation of adrenoreceptors due to chronic sympathetic activation in hepatic cirrhosis contributes to decreased sensitivity to the reduction in heart rate following a single dose of the beta-blocker.
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  • 64
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    European journal of clinical pharmacology 42 (1992), S. 371-374 
    ISSN: 1432-1041
    Keywords: Ambenonium chloride ; Myasthenia gravis ; dietary effect ; serum concentration ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Influence of food on the serum concentration and kinetics ambenonium chloride (AMBC) has been examined in thirteen patients with myasthenia gravis (MG). Mean serum concentrations and Cmax during fasting were higher than those in the non-fasting state. The AUC (0–3 h) was also about four-times larger. The drug effects versus the serum concentration were observed to be anti-clockwise or clockwise. The effective range of the Cmax varied between patients. The unexpected increase in Cmax led to adverse muscarinic actions of AMBC, when the condition was changed from the non-fasting to the fasting state. It is recommended that the dose be changed during non-fasting treatment when adjusting the optimum regimen for patients myasthenia gravis. Patients must be advised to keep to the dosing and dietary schedule in order to avoid unexpected adverse actions to AMBC.
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  • 65
    ISSN: 1432-1041
    Keywords: Nitrendipine ; enantiomers ; stereoselectivity ; Renal failure ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the enantiomers of nitrendipine has been studied in seven elderly patients with chronic renal failure (CRF) and in six control subjects (mean creatinine clearance 30 and 97 ml·min−1 respectively). Racemic nitrendipine 20 mg was given once daily for seven days and the pharmacokinetics of the enantiomers over the last dosage interval were determined using a stereospecific assay. In both groups nitrendipine exhibited stereoselective pharmacokinetics (AUC, Cmax), but the half-lives of the enantiomers did not differ in individual subjects. As an index of stereoselectivity, the mean S/R ratio of AUCs in control subjects (2.07) was not significantly different from the ratio in patients with CRF (2.68). The mean AUCs of (S)- and (R)-nitrendipine during the last dosage interval were increased in CRF by 132% and 85%, respectively. The observed doubling of the half-lives and the increases in Cmax did not reach significance because of the large variability in each group. Thus, the pharmacokinetics of oral nitrendipine is altered in CRF, but there was no change in the stereoselectivity of its pharmacokinetics.
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  • 66
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    European journal of clinical pharmacology 42 (1992), S. 429-433 
    ISSN: 1432-1041
    Keywords: Chloroquine ; Rheumatoid arthritis ; desethylchloroquine ; bisdesethylchloroquine ; blood levels ; toxicity ; therapeutic activity ; dose-effect relationship ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood levels of racemic chloroquine and its main metabolites desethylchloroquine and bisdesethylchloroquine were measured in 29 patients treated chronically for rheumatoid arthritis. In six patients, the concentrations were followed during a one day dosage interval. There was considerable intersubject variability in the steady state blood concentrations of chloroquine (range 36.6 to 3895 ng·ml−1) and its two main biotransformation products; the latter represented, respectively, 47.7% and 12.9% of the concentration of chloroquine. This finding shows the need for further studies in view of the known toxic effects of chloroquine and the inevitable accumulation due to the exceptionally long residence time of the compound and its metabolites. The main requirement, which has not yet been met, for adding chloroquine to the list of drugs for which therapeutic drug monitoring is useful, is the lack of information about its mechanism of action, and consequently the dose-effect relationships of its therapeutic and toxic actions. Regular ophthalmic examination, in particular, is strongly recommended. The relatively high concentrations of desethylchloroquine and bisdesethylchloroquine found during chronic treatment show the need for more information about the therapeutic value and adverse effects of the metabolites.
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  • 67
    ISSN: 1432-1041
    Keywords: Calcium channel blocker ; Nilvadipine ; blood pressure ; liver disease ; pharmacokinetics ; pharmacodynamics ; cirrhosis ; hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen normotensive patients with liver disease (6 with cirrhosis and 8 with chronic hepatitis) and 7 healthy volunteers were given a single oral dose of nilvadipine 2 mg. In addition, nilvadipine 4 mg was administered orally twice daily for several months to 6 hypertensive patients with mild liver dysfunction and 18 hypertensives with normal liver function. A significant increase in plasma nilvadipine was found in the patients with cirrhosis as compared both to the normal and chronic hepatitis subjects; the time to peak concentration was similar among the three groups. The peak plasma nilvadipine concentration was closely correlated both with the serum albumin level and the retention of indocyanine green. Changes in blood pressure, pulse rate and various vasoactive hormones following a single oral dose of nilvadipine did not differ between the groups. Thus, an increase in plasma nilvadipine relative to the level in normal subjects was demonstrated in patients with cirrhosis following a single oral dose, as well as in patients with slight liver dysfunction following long-term oral administration.
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    European journal of clinical pharmacology 42 (1992), S. 481-485 
    ISSN: 1432-1041
    Keywords: Digoxin ; Spironolactone ; drug interaction ; biliary clearance ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of an inhibitory effect of spironolactone on the biliary clearance of digoxin has been investigated in 6 healthy subjects. Plasma clearance and the renal and biliary clearance of digoxin were determined twice at steady state (digoxin 0.5 to 1 mg·d−1 p.o. for 6 days), alone or in combination with spironolactone 200 mg daily, after an intravenous dose of digoxin (0.7 × oral dose) on Day 7. Plasma and urine were collected for 48 h. Biliary clearance of digoxin was determined on Day 8 by a duodenal perfusion technique. During spironolactone treatment plasma digoxin clearance tended to be lower (255 vs 224 ml/min; P=0.057) and renal clearance significantly lower (166 vs 144 ml/min), while the biliary clearance of digoxin remained unchanged (106 vs 103 ml/min). Thus, spironolactone reduced the renal clearance of digoxin by an average of 13%, without affecting its biliary clearance.
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    European journal of clinical pharmacology 42 (1992), S. 545-547 
    ISSN: 1432-1041
    Keywords: Vinorelbine ; anti-neoplastic agents ; vinca alkaloids ; pharmacokinetics ; lung neoplasms ; HPLC ; assay method
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of vinorelbine has been investigated by a new HPLC method in 8 cancer patients receiving 8 weekly doses (30 mg·m−2) administered by brief infusion (15 min). The plasma concentration-time curves showed a tri-exponential decay with a long terminal half-life (44.7 h) and a high volume of distribution (Vz=75.61·kg−1). The concentrations after the 8th infusion were significantly lower than after the 1st infusion, but without significant modification of CL (1.28 l·h−1·kg−1) or AUC (0.80 mg·l−1·h). The pharmacokinetic parameters exhibited wide inter-individual variations. The results are consistent with those of previous RIA studies, although the HPLC method appears to be more specific and more precise.
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    European journal of clinical pharmacology 42 (1992), S. 663-666 
    ISSN: 1432-1041
    Keywords: Morphine ; Codeine ; drug metabolism ; pharmacokinetics ; systemic availability ; individual variability ; post-operative state
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolism and systemic availability of codeine have been studied in 12 patients after cholecystectomy. They were given 20 mg codeine as an IV bolus dose on the first day after surgery and 50 mg codeine as a single oral on the fourth day after surgery. Codeine had a medium to high extraction ratio and a total plasma clearance of 10.8 (4.3) ml·min−1·kg−1. The clearance varied fourfold between subjects. All the patients were extensive metabolizers with regard to the debrisoquine/sparteine polymorphism, as tested using dextromethorphan as the probe drug. Nevertheless, the formation of morphine from codeine was very small and plasma morphine concentrations were below the detection limit of 3.3 nmol·1−1 (1 ng·ml−1). As a corollary, the morphine/codeine ratio in the the concentration-time curves was less than 3% in all the patients. The systemic availability of codeine varied extensively between subjects (range 12–84%). This might partly explain differences in the dose of codeine required as an analgesic.
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    European journal of clinical pharmacology 42 (1992), S. 671-673 
    ISSN: 1432-1041
    Keywords: Nifurtimox ; Changas' disease ; renal failure ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of nifurtimox, a drug used in the treatment of Trypanosoma cruzi infections, has been studied in seven patients with chronic renal failure undergoing haemodialysis, and in seven healthy subjects. Each subject took nifurtimox 15 mg·kg−1 orally and blood samples were obtained for 10 h after administration. Nifurtimox in serum was analyzed by HPLC. The patients with chronic renal failure had a higher Cmax than the control subjects due to a change in systemic availability. An alternative explanation would be that both the distribution volume and the clearance had changed. The mean half-life in the patients with chronic renal failure was similar to that in the healthy subjects.
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    European journal of clinical pharmacology 43 (1992), S. 209-210 
    ISSN: 1432-1041
    Keywords: Moxonidine ; Hydrochlorothiazide ; pharmacokinetics ; drug interaction ; steady-state ; healthy volunteers ; adverse effects
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  • 73
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    European journal of clinical pharmacology 43 (1992), S. 269-271 
    ISSN: 1432-1041
    Keywords: Lignocaine ; diabetes mellitus ; pharmacokinetics ; epidural anaesthesia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lignocaine has been compared after epidural anaesthesia in diabetics and nondiabetic patients. Epidural lignocaine 8 mg · kg−1 was given to 8 well controlled Type II diabetic and 8 nondiabetic patients and the plasma drug concentration in serial blood samples were measured by HPLC. The plasma level of lignocaine was lower in diabetics compared to non-diabetics. The peak level was attained at 20 min in both groups. The clearance of the drug was significantly higher, (39,9 vs 16,7 ml · min− · kg−) associated with a decreased elimination half-life and mean residence time. The study suggests that the rate of absorption of lignocaine is not altered after epidural administration and that its hepatic metabolism is increased in diabetics compared to non-diabetics.
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  • 74
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    European journal of clinical pharmacology 43 (1992), S. 289-294 
    ISSN: 1432-1041
    Keywords: Microdialysis ; Drug concentration ; parameter estimation ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Microdialysis has recently been adapted for sampling the extracellular fluid of various organs in order to measure drug concentrations, and the first clinical application has been published. My aim here is to provide simple rules about how to analyse pharmacokinetic data from such studies. The plotting of data on a time scale and the estimation of C (0) and slopes is not a trivial problem when multicompartmental models are assumed or sampling intervals are unequal. I have developed formulae and algorithms to solve the problem. A simple rule of thumb is given, suggesting when these formulae need to be applied. It is shown that the calculations of half-life and slopes is similar to standard methods for equal sample intervals and that calculation of AUC and clearance may be even more accurate for microdialysis data than for ordinary blood sampling, because of the time-integral character of the dialysis method. I have dealt with both zero-order and first-order kinetics.
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  • 75
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    European journal of clinical pharmacology 43 (1992), S. 437-439 
    ISSN: 1432-1041
    Keywords: Pirmenol ; pharmacokinetics ; elderly subjects ; age effect ; adverse effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of pirmenol was compared in twelve healthy young (aged 18 to 45 y) and 11 elderly subjects (over 65 y) subjects given pirmenol HCl 100 mg every 12 h for a total of 14 doses. In addition, the single-dose pharmacokinetics of pirmenol was determined following a 100 mg oral dose in the young subject group for comparison with the results of repeated administration. In the young subjects, the mean single-dose and steady-state CLR of pirmenol were similar; however, Ae was 29 % higher and CL/f was 22 % lower at steady state than after the single dose. Steady-state (fourteenth dose) Cmin, Cmax, tmax, λz, Ae, CL/f, CLR and V values were similar in the young and elderly subjects. Based on pharmacokinetic considerations, the dosage of pirmenol is unlikely to differ in young and elderly subjects.
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    European journal of clinical pharmacology 43 (1992), S. 441-443 
    ISSN: 1432-1041
    Keywords: Flecainide ; quinidine ; pharmacokinetics ; metabolism inhibition ; drug interaction ; renal transport
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min. Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg−1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min−1·kg−1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min−1·kg−1). The excretion of the metabolites of flecainide over 48 h was significantly reduced. These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min−1·kg−1). The effects of flecainide on ECG intervals were not altered by quinidine. Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.
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    Behavior genetics 22 (1992), S. 469-487 
    ISSN: 1573-3297
    Keywords: courtship ; pheromones ; Drosophila ; apterous ; juvenile hormone ; reproductive development ; sexual behavior
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    Topics: Biology , Psychology
    Notes: Abstract Theapterous (ap) gene ofDrosophila melanogaster exhibits extreme pleiotrophy: its functioning is essential for life, normal wing structure, juvenile hormone production, female fertility, and normal development of female sexual receptivity. Four mutantap alleles (ap 4,ap 56f,ap c, andap blt) were characterized for three additional phenotypes: male mating success, courtship behavior, and immature male sex appeal (the ability of males to stimulate homosexual cortship). Mating success with mature wild-type virgin females is reduced in males mutant for theap gene, the extreme case beingap 4/ap 4 males, which are behaviorally sterile. Inap mutants, nonwing courtship elements are qualitatively like those ofap +/ap + males. However, the mean rate of nonwing courtship directed toward virgin wild-type females (i.e., the mean temporal frequency of these displays) is reduced in males homozygous forap 4,ap 56f, orap c alleles. In contrast, theap blt allele makes for wild-type rates of nonwing courtship. Immature male sex appeal persists for at least 3 days in males homozygous forap c and, to a lesser extent, inap 56f orap 4 homozygotes;ap blt/ap blt and wild-type males lose immature male sex appeal after 1 day. All three male phenotypes map to theap locus, which is therefore essential for the development of normal levels of male courtship and male mating success and for the timely loss of immature male sex appeal. For each phenotype,ap + is dominant toap alleles making for behavioral abnormalities, with a single exception (for rate of nonwing courtship,ap +/ap c was low). For mating success and frequency of nonwing courtship, each allele pair exhibits at least partial complementation, except forap 4 andap 56f, which fail to complement. For immature male sex appeal,ap c,ap 4, andap 56f fall into the same complementation group. Juvenile hormone production is not correlated with effects on male reproductive behavior.
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    Behavior genetics 22 (1992), S. 557-573 
    ISSN: 1573-3297
    Keywords: Drosophila ; biometrical analysis ; behavior genetics ; genetic analysis ; ss a ; deletion mapping
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    Topics: Biology , Psychology
    Notes: Abstract The homeotic mutationspineless-aristapedia (ss a ) transforms the aristae into second tarsi. Flies with aSS a phenotype also show extremely positive geotaxis as measured in a Hirsch-type geotaxis maze. Other antennal mutants and flies with their aristae amputated do not show such extreme positive geotaxis. Deletion analysis has comapped the geotaxis effect withSS a in band 89C on the third chromosome. Finally, a biometrical analysis has detected additional genes on the X chromosome that also affects geotaxis.
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    Biochemical genetics 30 (1992), S. 159-168 
    ISSN: 1573-4927
    Keywords: Drosophila ; indirect flight muscle ; tropomyosin ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We describe polymorphism in aDrosophila indirect flight muscle-specific tropomyosin isozyme, named TnH-34. Three variants of this protein differ in their mobilities as determined by 1-D and 2-D SDS-PAGE. Meiotic mapping places the polymorphism close to, if not within, the structural gene encoding this tropomyosin isozyme. The most likely site of the mutations is within a single C-terminal exon. Flight-testing of different genotypes reveals that this variation in TnH-34 does not affect flight ability. These results suggest that some sequence variation may be tolerated in this section of the protein and correlate with the variability of this protein in different insect species.
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    Biochemical genetics 30 (1992), S. 305-315 
    ISSN: 1573-4927
    Keywords: Drosophila ; diaphorase ; purification ; kinetics ; immunochemical characteristics
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Diaphorase-1 and diaphorase-2 were isolated from twoDrosophila species,D. virilis andD. melanogaster, and purified by gel filtration, affinity chromatography, immunoaffinity chromatography, and ion-exchange chromatography. The molecular weights of both enzymes were the same in each species. The molecular weight of diaphorase-1 was the same under both denaturating and nondenaturating conditions, close to 60,000, indicating a monomeric structure. Sodium dodecyl sulfate (SDS) electrophoresis of the purified diaphorase-2 revealed the presence of a single protein band of 55,000 Da, while the molecular weight of the native enzyme was found to be 67,000. The two diaphorases were further characterized by their pH optima, isoelectric points, and kinetic parameters, and antibodies were raised in rabbits against the purified enzymes fromD. virilis. The antibodies showed no cross-reactions but recognized the corresponding diaphorases inD. melanogaster andD. novamexicana as well asD. virilis. The data obtained confirmed the hypothesis of an independent genetic control of diaphorase-1 and diaphorase-2 inDrosophila.
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    Biochemical genetics 30 (1992), S. 305-315 
    ISSN: 1573-4927
    Keywords: Drosophila ; diaphorase ; purification ; kinetics ; immunochemical characteristics
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Diaphorase-1 and diaphorase-2 were isolated from twoDrosophila species,D. virilis andD. melanogaster, and purified by gel filtration, affinity chromatography, immunoaffinity chromatography, and ion-exchange chromatography. The molecular weights of both enzymes were the same in each species. The molecular weight of diaphorase-1 was the same under both denaturating and nondenaturating conditions, close to 60,000, indicating a monomeric structure. Sodium dodecyl sulfate (SDS) electrophoresis of the purified diaphorase-2 revealed the presence of a single protein band of 55,000 Da, while the molecular weight of the native enzyme was found to be 67,000. The two diaphorases were further characterized by their pH optima, isoelectric points, and kinetic parameters, and antibodies were raised in rabbits against the purified enzymes fromD. virilis. The antibodies showed no cross-reactions but recognized the corresponding diaphorases inD. melanogaster andD. novamexicana as well asD. virilis. The data obtained confirmed the hypothesis of an independent genetic control of diaphorase-1 and diaphorase-2 inDrosophila.
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    Biochemical genetics 30 (1992), S. 77-83 
    ISSN: 1573-4927
    Keywords: acetylcholinesterase ; insecticide ; resistance ; Drosophila
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Selection of field populations originating from several countries allowed us to isolate 13 strains ofDrosophila melanogaster resistant to parathion.In vitro studies of acetylcholinesterase inhibition by paraoxon have been carried out on purified enzymes: most of the resistant strains harbor an altered acetylcholinesterase. Enzymes with higher resistance levels have been characterized with respect to their cross-resistance toward several insecticides. The patterns obtained have permitted us to group them and to delineate four categories. The existence of four distinct types of protein suggests that several mutations of acetylcholinesterase are responsible for insecticide resistance inDrosophila.
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  • 83
    ISSN: 1573-4927
    Keywords: Drosophila ; glycerol-3-phosphate dehydrogenase ; restriction map ; duplication ; enzyme activity
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Restriction site variation in a 25-kb region including thesn-glycerol-3-phosphate dehydrogenase (Gpdh) locus has been assessed in 29 single femaleD. melanogaster lines from the Cardwell (Australia, QLD) population. TheGpdh locus was duplicated in about one-third of the lines, although the duplication was incomplete and lacked exons 1 and 2. There was no restriction site variation in the duplicated region. Three insertions were found in the gene region but only one affected GPDH activity. The lines with the duplication had higher levels of GPDH activity and protein amount than did nonduplicated lines. This effect was also observed in lines extracted from two other Australian populations. The duplication is shown to have a similar structure in each population investigated and is also present in populations from China and Africa. It is suggested that the effect of the duplication on GPDH activity, which might be due to structural factors affecting transcription at theGpdh locus, could account for the worldwide distribution of the duplication.
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    Biochemical genetics 30 (1992), S. 515-527 
    ISSN: 1573-4927
    Keywords: glutathioneS-transferase ; Drosophila ; cellular detoxification ; pesticide resistance ; insect metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We have isolated aDrosophila gene,DmGST-2, that encodes glutathioneS-transferase, a homo- or heterodimeric enzyme thought to be involved in detoxification of xenobiotics, including known carcinogens. The encoded protein has a primary sequence that is more similar to mammalian placental and nematode GSTs than that of a previously describedDrosophila GST gene, herein referred to asDmGST-1. We provide a physical map of the gene and show that it specifies at least two mRNAs, measuring 1.9 and 1.6 kb, which differ only in the lengths of their 3′ untranslated regions. Both of the mRNAs are present during all developmental stages.In situ hybridization of theDmGST-2 gene to larval polytene chromosomes places it within the 53F subdivision of chromosome 2, and Southern blotting to chromosomal DNA indicates that the gene has no close relatives within theDrosophila genome. Our results make possible molecular genetic approaches for further elaborating the function of glutathioneS-transferases in insect development and physiology, in the metabolism of plant toxins, and in conferring insecticide resistance.
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    Theoretical and applied genetics 83 (1992), S. 821-826 
    ISSN: 1432-2242
    Keywords: Drosophila ; Balancers ; Inversions ; Translocations ; Meiosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We used a screen for maternally generated late embryonic lethals as a new method for the isolation of inversions that are suitable for the balancing of mutations in Drosophila hydei. The recovery of several inversions by this method demonstrates that female meiosis in D. hydei apparently differs from meiosis in female D. melanogaster, since in D. hydei the defective chromosomes which are generated by a single crossing-over within a paracentric inversion can be recovered via the egg nucleus. In addition, the classic method of crossingover suppression was used in order to isolate more inversions and to improve the balancing capacities of inversions. We succeeded in constructing chromosomes that allow the balancing of mutations on nearly the whole genome of D. hydei. We discuss here whether or not this method is suited for application to other organisms.
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  • 86
    ISSN: 1573-0646
    Keywords: pharmacokinetics ; cytotoxicity ; molecular combination ; fluorouracil ; nitrosourea
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary B.3839 is the prototype compound in a series of novel molecular combinations of chloroethylnitrosoureas and 5-fluorouracil(5-FU) and has been tested against MAC tumours in mice. Previous studies have shown it is moderately active against MAC15A and highly active against MAC13 though this activity is dependent on route of administration. The aim of this study was to determine whether bioavailability could explain this difference in anti-tumour activity. Plasma levels of B.3839 and 5-FU after i.p. and oral administration were measured using HPLC. Non tumour-bearing and MAC26 bearing mice gave almost identical plasma profiles after i.p. administration with the Cmax being 29.8 and 30.4μ gml−1 and t1/2 16 and 15 min. The AUCs were 15.3 and 13.9μg h ml−1 suggesting tumour load had no influence over plasma levels. Oral administration gave a much lower Cmax of 8.0μg ml−1 but an AUC of 15.2μg h ml−1 due to a longer terminal t1/2 (94 min) giving 99% bioavailability. Levels of 5-FU release from B.3839 by either route were considered too small to influence anti-tumour activity. Cytotoxicity assaysin vitro against the MAC lines gave IC70 values of 5.3, 13.8 and 8.6μg ml−1 for MAC 26,13 and 15A respectively after a one hour exposure. Bone marrow toxicity was shown to be less severe than that of TCNU which is currently in clinical trials. The results show bioavailability alone is not enough to explain tumour response. There appears to be a need for a threshold concentration (C) to be maintained for a period of time (t).
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 95-99 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; physiological model ; cisplatin ; DDP ; cis-dichlorodiammineplatinum(II)
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    Topics: Chemistry and Pharmacology
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  • 88
    ISSN: 1573-8744
    Keywords: prednisolone ; pharmacokinetics ; pharmacodynamics ; corticosteroids ; protein binding
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4−and 49.2−mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CLand Vss increasing with dose. Free prednisolone exhibited slight capacitylimited elimination and distribution as CLand Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity-in particular IC50-and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration-time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.
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    Evolutionary ecology 6 (1992), S. 342-351 
    ISSN: 1573-8477
    Keywords: Drosophila ; polymorphism ; aggregation ; ephemeral patches ; soft selection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Many models have been proposed in which environmental heterogeneity promotes genetic diversity. Such models describe the situation where different phenotypes have different fitness values in different types of patch and are the genetic equivalent of the traditional resource partitioning models in ecology which allow the coexistence of species. Here we construct a different type of cellular model in which polymorphisms in populations ofDrosophila can be maintained without traditional resource partitioning. Parameter values taken from laboratory and field observations represent fungal breedingDrosophila. Some stochasticity is used in the description of the migration between patches. In the model space is divided into a uniform matrix of cells each of which has the potential to contain an ephemeral resource item (fungal fruiting body). Square arenas of up to 400 cells were used. Genotypes arrive at a fresh site, breed (Hardy-Weinberg equilibrium) and lay eggs. The eggs hatch and the larvae compete using the Hassell-Comins competition equations, as if they were three different species. Adult emergents all migrate to an adjacent cell. The aggregation patterns observed in nature are produced using an ‘attraction probability’ where each fly has a chance of moving to the currently most densely populated adjacent patch. This ‘black box’ description of migration produces distribution patterns which are indistinguishable from those seen in wild populations of fungal breedingDrosophila. Results show that the ‘attraction probability’ is the key factor in the maintenance of polymorphism and that even when the competitive advantage of the superior genotype is very great, polymorphisms can be maintained.
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 147-169 
    ISSN: 1573-8744
    Keywords: computers ; pharmacokinetics ; pharmacodynamics ; infusions ; drug delivery ; computer driven ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 611-635 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; plasma concentration-effect relation-ship ; anesthesia ; analgesic ; narcotic ; opioids ; alfentanil ; brain ; electroencephalograph ; spectral edge ; semilinear canonical correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To examine the relationship between the electroencephalograph (EEG) and plasma opioid concentration, one would like to collapse the high-dimensional EEG signal into a univariate quantity. Such a simplification of the EEG is desirable because a univariate quantity can be modeled using standard nonlinear regression techniques, and because most of the information in the EEG is redundant or unrelated to drug concentration. In previous studies of the EEG response to opioids, the manner in which a univariate component was extracted from the EEG was ad hoc.In this paper, this extraction was performed optimally using a new statistical technique, semilinear canonical correlation. Data from 15 patients who received an intravenous infusion of the semisynthetic opioid alfentanil were analyzed. The components of the EEG that were nearly maximally correlated with plasma drug concentration were found, based on a standard pharmacokinetic-pharmacodynamic model. Two new EEG components were produced from the powers in the frequency spectrum of the EEG: a weighted sum of the logarithms of the powers, and a weighted sum of the powers expressed as percentages of the total power. These components both had a median R2 of 0.84, compared to median R2sranging from 0.37 to 0.83 for five commonly used ad hocEEG components. The new components also had less variability in R2 between subjects.
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    Biochemical genetics 30 (1992), S. 159-168 
    ISSN: 1573-4927
    Keywords: Drosophila ; indirect flight muscle ; tropomyosin ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We describe polymorphism in aDrosophila indirect flight muscle-specific tropomyosin isozyme, named TnH-34. Three variants of this protein differ in their mobilities as determined by 1-D and 2-D SDS-PAGE. Meiotic mapping places the polymorphism close to, if not within, the structural gene encoding this tropomyosin isozyme. The most likely site of the mutations is within a single C-terminal exon. Flight-testing of different genotypes reveals that this variation in TnH-34 does not affect flight ability. These results suggest that some sequence variation may be tolerated in this section of the protein and correlate with the variability of this protein in different insect species.
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  • 93
    ISSN: 1573-4927
    Keywords: Drosophila ; glycerol-3-phosphate dehydrogenase ; restriction map ; duplication ; enzyme activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Restriction site variation in a 25-kb region including thesn-glycerol-3-phosphate dehydrogenase (Gpdh) locus has been assessed in 29 single femaleD. melanogaster lines from the Cardwell (Australia, QLD) population. TheGpdh locus was duplicated in about one-third of the lines, although the duplication was incomplete and lacked exons 1 and 2. There was no restriction site variation in the duplicated region. Three insertions were found in the gene region but only one affected GPDH activity. The lines with the duplication had higher levels of GPDH activity and protein amount than did nonduplicated lines. This effect was also observed in lines extracted from two other Australian populations. The duplication is shown to have a similar structure in each population investigated and is also present in populations from China and Africa. It is suggested that the effect of the duplication on GPDH activity, which might be due to structural factors affecting transcription at theGpdh locus, could account for the worldwide distribution of the duplication.
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  • 94
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 511-528 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; population analysis ; model building ; generalized additive models ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract One major task in clinical pharmacology is to determine the pharmacokinetic-pharmacodynamic (PK-PD) parameters of a drug in a patient population. NONMEM is a program commonly used to build population PK-PD models, that is, models that characterize the relationship between a patient's PK-PD parameters and other patient specific covariates such as the patient's (patho)physiological condition, concomitant drug therapy, etc. This paper extends a previously described approach to efficiently find the relationships between the PK-PD parameters and covariates. In a first step, individual estimates of the PK-PD parameters are obtained as empirical Bayes estimates, based on a prior NONMEM fit using no covariates. In a second step, the individual PK-PD parameter estimates are regressed on the covariates using a generalized additive model. In a third and final step, NONMEM is used to optimize and finalize the population model. Four real-data examples are used to demonstrate the effectiveness of the approach. The examples show that the generalized additive model for the individual parameter estimates is a good initial guess for the NONMEM population model. In all four examples, the approach successfully selects the most important covariates and their functional representation. The great advantage of this approach is speed. The time required to derive a population model is markedly reduced because the number of necessary NONMEM runs is reduced. Furthermore, the approach provides a nice graphical representation of the relationships between the PK-PD parameters and covariates.
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  • 95
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 591-609 
    ISSN: 1573-8744
    Keywords: nicotine ; cotinine ; pharmacokinetics ; physiologically-based pharmacokinetic model ; interindividual variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided;chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.
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  • 96
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    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 397-412 
    ISSN: 1573-8744
    Keywords: neural networks ; pharmacodynamics ; pharmacokinetics ; modeling ; drug effect prediction ; alfentanil ; model testing ; system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and selforganization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive,logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30–180 min) was excellent and its predictive extrapolation capability (180–300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behaviorof the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.
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  • 97
    ISSN: 1617-4623
    Keywords: Drosophila ; Muscle proteins ; Paramyosin ; Leucine zippers ; Differential polyadenylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Several cDNA clones encoding the complete Drosophila paramyosin sequence, including two potential polyadenylation sites, have been obtained. Southern analysis and in situ hybridization to polytene chromosomes indicate that in Drosophila the paramyosin gene is single copy, located on the left arm of the third chromosome at region 66D14. Northern analyses show predominantly two different RNAs which are the products of the choice between the two alternative polyadenylation sites. The two species begin to be synthesized around 10 h of development when embryonic muscles are formed, expression peaking at the end of embryogenesis. The protein is first expressed at germ band shortening in association with muscle precursor cells. A second maximum of paramyosin RNA expression occurs at late pupal stages when the higher molecular weight form becomes more abundant. In young adults this species becomes the main transcript detected. The 102 kDa polypeptide sequence is highly similar to that of Caenorhabditis elegans paramyosin. The protein has a central α-helical coiled-coil rod, organized in 29 groups of four typical seven-residue repeats and flanked by two short non-α-helical regions. Several leucine zippers are located on the hydrophobic face of the α-helix in paramyosin which, together with disulfide bonds between cysteines, are probably involved in the stabilization of the dimer. The structural and functional properties of Drosophila paramyosin deduced from the sequence are compared with those of known invertebrate myosins and paramyosins.
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  • 98
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    Molecular genetics and genomics 235 (1992), S. 441-449 
    ISSN: 1617-4623
    Keywords: Drosophila ; Gene regulation ; Transcription ; Transposable element
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Two spontaneous mutations of rudimentary, the gene encoding the first steps of de novo pyrimidine biosynthesis in Drosophila, are suppressed by mutant alleles of the suppressor of Hairy-wing locus. This interaction differs from typical su(Hw) suppression in that neither rudimentary allele is associated with an insertion of the gypsy retrotransposon. One allele, r sP1, appears to be a point mutation. Adult r sP1 homozygous females accumulate substantially less 7.3 kb rudimentary transcript than do wild-type females. The other allele, r sP2, is an insertion of an mdg3 retrotransposon in the sixth exon of rudimentary and in the opposite transcriptional orientation. This insertion divides the rudimentary locus into two separate, yet functional, transcription units by truncating transcription from the rudimentary promoter and promoting transcription of downstream rudimentary sequences. Phenotypic suppression of both r sP1 and r sP2 by mutant alleles of the suppressor of Hairy-wing locus correlates with enhanced levels of the r sP1 and r sP2 transcripts.
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  • 99
    ISSN: 1617-4623
    Keywords: Phosphoglycerate kinase ; Drosophila ; Nucleotide sequence ; Glycolysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The gene that encodes phosphoglycerate kinase in Drosophila melanogaster (Pgk) has been isolated and characterized. There is a single copy of Pgk in the Drosophila genome located at cytogenetic position 23A1-2. Transcripts of Pgk are 1.6 kb long and are found during development with a profile similar to the expression pattern of other genes of the glycolytic pathway. There are substantial amounts of maternal transcript in early embryos which decline in abundance until mid-embryogenesis when transcript levels increase; levels remain high, during larval stages, fall during pupariation and rise again at emergence. The nucleotide sequence of the Pgk gene reveals two small introns, one of which is at a position identical to the site of an intron found in Pgk genes from other organisms. The Pgk gene has no TATA box in the region of transcription initiation and has multiple transcription initiation sites that are closely spaced within 110 nucleotides of the translation start site.
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  • 100
    ISSN: 1617-4623
    Keywords: Dosage compensation ; LSPI-α ; L12 ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The X-linked geneLSPI-α ofDrosophila melanogaster, expressed in the third larval instar, does not exhibit dosage compensation at its normal locus but does compensate when it is relocated to ectopic sites on the X chromosome. A transcription unit designatedL12, which is active in the second larval instar and capable of encoding a putative protein of 28.5 kDa, lies immediately downstream fromLSPI-α. We have determined thatL12 is dosage compensated by measuring the steady-state level of its transcript in male and female larvae. The difference in response of these two adjacent genes should be taken into consideration when models of the mechanism of dosage compensation are formulated.
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