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  • 1
    ISSN: 1439-0361
    Keywords: mate choice ; taxonomy ; phenotypic hybrids ; fitness ; decision rule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Die als Unterarten klassifizierten europäischen Formen der Aaskrähe, Rabenkrähe und Nebelkrähe, besiedeln verschiedene, aneinandergrenzende Verbreitungsgebiete und hybridisieren in der Kontaktzone. Die Nachkommen von Mischpaaren sind fruchtbar und können sowohl mit anderen Hybriden als auch mit Raben- und Nebelkrähen erfolgreich brüten. Trotzdem kommt es zu keiner völligen Vermischung der Formen und/oder Verlagerung der Verbreitungsgebiete. Vor diesem Hintergrund untersuchten wir die Partnerwahl von Aaskrähen in der Hybridisierungszone auf der nordfriesischen Insel Amrum und stellten fest, daß Partner gleichen Phänotyps häufiger miteinander verpaart waren, als stochastisch zu erwarten gewesen wäre. Unsere Daten bestätigen vergleichbare Studien aus Hybridisierungszonen in Italien und Sibirien. Wir schließen daraus, daß phänotypisch selektive Partnerwahl bei der Aaskrähe ein allgemeines Phänomen sein könnte und diskutieren, warum dieses Verhalten anfitness-relevante Parameter gekoppelt sein sollte. Um welche es sich dabei handeln könnte, wurde bisher nicht hinreichend untersucht und muß deshalb offen bleiben.
    Notes: Summary Carrion Crow and Hooded Crow are regarded as subspecies of the Crow. They show frequent hybridisation along the adjacent borders of their distribution. Mixed pairs produce fertile offspring which are able to breed successfully with both hybrids and mates of either phenotype. However, hybridisation does not lead to phenotypic changes of Carrion and Hooded Crows in general nor in their distinct distribution. We studied the mating behaviour of Crows in the hybrid zone on the Island of Amrum (Schleswig-Holstein, Germany) and found evidence that Crows may prefer mates of the same phenotype. Our data confirm previous studies which reported assortative mating with respect to plumage coloration from hybrid zones in Italy and Siberia. We discuss why this behaviour should be related tofitness traits which in our opinion have not yet been studied adequately nor identified.
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  • 2
    ISSN: 1573-0832
    Keywords: Africa ; Fusarium ; F. moniliforme ; grain ; Lesotho ; mating population ; Nigeria ; taxonomy ; Zimbabwe
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Several Fusarium species have been found associated with millet and sorghum in Nigeria, Lesotho and Zimbabwe. Amongst these, some isolates were originally identified as short- and long-chained types of F. nygamai. However, there was some question as to the correct identification of the long chained types. This study reclassified some of the isolates with long microconidial chains as F. moniliforme. Morphologically, these strains do not produce chlamydospores like F. nygamai, but produce swollen hyphal cells or resistant hyphae. The isolates in this study were crossed with the mating-type tester strains of Gibberella fujikuroi (F. moniliforme and G. nygamai (F. nygamai). Of the isolates with long chains of microconidia and other characteristics of F. moniliforme, 36% crossed with mating population ''A'' of G. fujikuroi. Of the isolates with characteristics of F. nygamai, 65% crossed with the testers used to produce the teleomorph of F. nygamai. Mating tests support the separation of the sample population into F. moniliforme and F. nygamai. The results of this study show that genetics can be an aid in resolving some problems in fungal taxonomy.
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  • 3
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    Antonie van Leeuwenhoek 71 (1997), S. 375-378 
    ISSN: 1572-9699
    Keywords: Candida novakii ; taxonomy ; yeasts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Two strains of an undescribed species of the genus Candida were isolated from decaying wood of Quercus sp. A description of the new species Candida novakii is given.
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  • 4
    ISSN: 1572-9699
    Keywords: phylogeny ; prosthecobacter ; taxonomy ; Verrucomicrobia ; Verrucomicrobiae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Four strains of nonmotile, prosthecate bacteria were isolated in the 1970s and assigned to the genus Prosthecobacter. These strains were compared genotypically by DNA/DNA reassociation and 16S rDNA based phylogenetic analyses. Genotypic comparisons were complemented with phenotypic characterizations. Together, these studies clearly indicate each Prosthecobacter strain represents a novel species of bacteria. We propose three new species of Prosthecobacter, P. dejongeii strain FC1, P. vanneervenii strain FC2, and P. debontii strain FC3; P. fusiformis is reserved for the type strain of the genus, strain FC4. Additionally, we propose the genera Prosthecobacter and Verrucomicrobium, currently members of the order Verrucomicrobiales, to comprise a novel higher order taxonomic group, the division Verrucomicrobia div. nov. and the class Verrumicrobiae class nov. Many novel members of the Verrucomicrobia, as revealed by molecular ecology studies, await isolation and description.
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  • 5
    ISSN: 1572-9699
    Keywords: keratinophilic fungi ; Neoarachnotheca ; Neoarachnotheca keratinophila ; Nannizziopsis tropicalis ; Onygenales ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Neoarachnotheca is proposed as a new genus of Onygenales. The outstanding generic characteristics are white, spherical ascomata with a wall formed by a network of hyphae and spherical, subhyaline ascospores with an irregular sheath. Nt. keratinophila, the type species, characterized by wavy peridial hyphae has been isolated from marine and river sediments and Myriodontium keratinophilum is its anamorph. Nannizziopsis tropicalis is proposed as a new species based on a strain isolated from soil in Burundi. RFLPs analysis of ITS and 5.8S rDNA support these proposals. The differences with related genera are discussed.
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  • 6
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    Antonie van Leeuwenhoek 74 (1998), S. 229-235 
    ISSN: 1572-9699
    Keywords: Dipodascus capitatus ; D.spicifer ; Geotrichum clavatum ; yeast ; taxonomy ; DNA heterogeneity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The G+C contents of 25 strains of Dipodascus capitatus, Dipodascus spicifer and Geotrichum clavatum were found to be heterogeneous on basis of derivative graphs of the melting profiles. Strains showing similar derivative graphs of the melting curve exhibited high levels of DNA homology (80-100%); strains showing dissimilar derivative graphs exhibited low levels of DNA homology (5 to 45%). Being considered separate taxa on basis of these parameters, D. capitatus, D. spicifer and G. clavatum could be identified by a combination of the key characteristics growth on xylose, cellobiose, salicin and arbutin.
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  • 7
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    Plant molecular biology reporter 16 (1998), S. 147-155 
    ISSN: 1572-9818
    Keywords: allele-specific PCR ; Beta ; ITS1 ; plant identification ; rDNA ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Sequence variation in the ITS1 locus of the nuclear ribosomal DNA in beets has previously been used to reconstruct phylogeny of the species in the genus Beta. We have developed protocols that allow the identification of Beta taxa by use of taxon-specific primers. Beta sections, species and subspecies can be identified. Differences within the ITS1 region of a single base can be exploited for species identification. The results from this study not only provide effective methods for wild beet identification, but also indicate the potential use of the techniques in other crops.
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  • 8
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    Journal of insect conservation 2 (1998), S. 151-159 
    ISSN: 1572-9753
    Keywords: Orthoptera ; biodiversity ; taxonomy ; conservation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Nature of Science, Research, Systems of Higher Education, Museum Science
    Notes: Abstract It is estimated that only 10–15% of the world's insect fauna has been described and named. Efforts to inventory insect biodiversity are hampered by this taxonomic impediment, which is compounded by the logistical problems of an insufficient taxonomic workforce and their remote location in museums thousands of miles from the areas of highest biodiversity. Compared to most other invertebrate groups however, the taxonomic impediment is relatively benign in the order Orthoptera. This is a small to medium-sized order (approximately 20 000 described species) which is well known taxonomically, owing to the group's agricultural importance worldwide. Furthermore, orthopteran taxonomists are now fortunate to have a published up-to-date catalogue of all known species, which has just become accessible as a regularly updated database on the World Wide Web. Whilst new information technology, in the form of e-mail networks, World Wide Web sites and CD-ROM information archives, is already enhancing communication between specialists and helping to reduce the logistical problems of documenting orthopteran biodiversity, a major reinvestment in basic taxonomic research is needed if we are to reduce the existing taxonomic impediment significantly. There is general agreement that an internationally coordinated approach will be necessary and priorities must be set to tackle the biodiversity/systematics crisis. In the future, the Orthoptera can make an important contribution to invertebrate faunal surveys and have potential as an indicator taxon. Furthermore, the Orthoptera Species File establishes a taxonomic framework which could be readily enlarged to include geographic data and phenology of species from existing museum specimens.
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  • 9
    ISSN: 1572-9745
    Keywords: Biological control ; insects ; pathogens ; germination ; taxonomy ; genetic variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Pigweeds (Amaranthus spp.) are of economic importance worldwide. In Europe, Amaranthus retroflexus is one of the ten weed species of greatest economic importance. It is a serious problem weed in several field crops (e.g. maize), as well as in vegetables, orchards and grape vines. It is an annual spreading by seeds which have a long viabilityand are dispersed principally by wind and water, but also by machinery. There is great variability in seed germination which renders control with post-emergence herbicides difficult. In addition, triazine herbicide-resistant populations occur in ten European countries. The aim of this subproject of COST action 816 is to investigate the possibilities of classical and inundative biological control of Amaranthus spp., to characterize potentialbiological control agents and to develop methods for their integration with current phytosanitary measures in the target crops. The project was initiated with an extended literaturesurvey followed by field surveys for insects and pathogens associated with Amaranthus spp. in several European countries. Promising isolates of fungal pathogens have been tested ondetached leaves and whole plants, and initial studies on the application of pathogens causing damping off in seedlings have been made. Further, the variability of different provenances ofAmaranthus spp. in response to fungal attack has been investigated
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  • 10
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    European journal of clinical pharmacology 52 (1997), S. 235-237 
    ISSN: 1432-1041
    Keywords: Key words Itraconazole ; Coca Cola; acidic beverage ; absorption ; pharmacokinetics ; drug concentration ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.
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  • 11
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    European journal of clinical pharmacology 52 (1997), S. 289-292 
    ISSN: 1432-1041
    Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.
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  • 12
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    European journal of clinical pharmacology 52 (1997), S. 379-381 
    ISSN: 1432-1041
    Keywords: Key words Nitroglycerin; transdermal nitrate ; pharmacokinetics ; patch renewal ; exercise test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. Results and conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.
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  • 13
    ISSN: 1432-1041
    Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
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  • 14
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    European journal of clinical pharmacology 51 (1997), S. 359-366 
    ISSN: 1432-1041
    Keywords: Key words Sufentanil ; pharmacokinetics ; haemo dynamics ; different infusion rates ; coronary surgery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract    Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg−1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg−1 · min−1, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min−1 · kg−1), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg−1) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean Cmax values of 421 (group I), 125 (group II), and 53 (group III) ng · ml−1 and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg−1 tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate.
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  • 15
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    European journal of clinical pharmacology 51 (1997), S. 415-419 
    ISSN: 1432-1041
    Keywords: Key words Midazolam ; Fluconazole ; CYP3A4 ; interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0–3, AUC0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0–3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
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  • 16
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    European journal of clinical pharmacology 51 (1997), S. 421-425 
    ISSN: 1432-1041
    Keywords: Key words Warfarin ; Meloxicam ; interaction ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.
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  • 17
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    European journal of clinical pharmacology 52 (1997), S. 391-396 
    ISSN: 1432-1041
    Keywords: Key words Lansoprazole ; CYP2C19; genotype ; hydroxy lation ; polymorphism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. Results: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1. Conclusion: The hydroxylation of lansoprazole to 5-hydroxylansoprazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/m2).
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  • 18
    ISSN: 1432-1041
    Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
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  • 19
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    European journal of clinical pharmacology 52 (1997), S. 307-310 
    ISSN: 1432-1041
    Keywords: Key words Artemether ; Thai males; malaria ; dihydroartemisinin ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).
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  • 20
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    European journal of clinical pharmacology 52 (1997), S. 403-406 
    ISSN: 1432-1041
    Keywords: Key words Oxybutynin ; Itraconazole; N-desethyloxy‐butynin; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.
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  • 21
    ISSN: 1432-1041
    Keywords: Key wordsDraflazine ; Population analysis; nucleoside transport inhibitor ; non-linear red blood cell partition ing ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant K d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1. Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.
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  • 22
    ISSN: 1432-1041
    Keywords: Key words Paracetamol ; Renal failure; polar conjugates ; non-insulin-dependent diabetes mellitus (NIDDM) ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A single oral dose of paracetamol (20 mg · kg−1) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min−1 · 1.73 m−2. The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur.
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  • 23
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    European journal of clinical pharmacology 52 (1997), S. 229-234 
    ISSN: 1432-1041
    Keywords: Key words Ranitidine ; Renal impairment; dose adjustment ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (CCr) ranging from 0 to 213 ml · min−1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min−1, correlated with CPAH (r 2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when CCr〈50 ml · min−1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when CCr〈10 ml · min−1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.
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  • 24
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    European journal of clinical pharmacology 52 (1997), S. 241-242 
    ISSN: 1432-1041
    Keywords: Key words Citalopram ; Cimetidine; drug ; drug interac‐tion ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
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  • 25
    ISSN: 1432-1041
    Keywords: Key words Nisoldipine ; Hypertension; Ca antagonist ; pharmacokinetics ; pharmacodynamics ; PK/PD modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.
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  • 26
    ISSN: 1573-3017
    Keywords: contamination risks ; fish ; Mississippi River ; ecological factors ; taxonomy
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    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract We compared contamination levels in fish from contaminated and uncontaminated floodplain swamps of the lower Mississippi River to assess differences in contamination risks between swamps, across different taxonomic and ecological groupings of fishes within and between swamps, and with seasonality in river stage. Fish tissue levels of inorganic contaminants were substantially lower than environmental levels in both swamps, suggesting either that fish were not uptaking these contaminants, or they were effectively eliminating the contaminants from their bodies. Tissue levels of organic contaminants were high relative to environmental levels, suggesting that these contaminants were bioaccumulating. Organic contaminants were significantly higher in fish from the contaminated swamp (Devil's Swamp) than in fish from a reference swamp up river (Tunica Swamp). Because the organic contaminants were largely confined to sediments, we expected bottom-oriented fishes to have higher concentrations than pelagic fishes. Assuming that uptake was primarily through the food chain, we expected top predators to exhibit higher concentrations than low-level consumers. We also expected year- round swamp residents to exhibit higher accumulations than more transitory users of backswamp habitat. However, organic contaminant levels did not differ in the directions expected for any of these groupings. We did observe differences in organic contaminant levels within and between swamps for different taxonomic groupings of fishes (species and genera). Some taxa occupying low to middle positions in the food web (e.g., gizzard shad, Lepomis spp.) exhibited higher concentrations than taxa near the top of the food web. Within Devil's Swamp, organic contaminant levels were significantly higher at low river stage, when fish were confined to the swamp, than at high river stage, when fish were free to move between the river and the swamp. We caught more species and more fish per unit effort in Devil's Swamp than in Tunica Swamp, contrary to expectations if contaminants in the former were negatively impacting population and community structure. Species richness differences between swamps were a consequence of catch differences, with higher catch corresponding to inclusion of more rare species. The lower catch in Tunica Swamp may have resulted from physical modifications of its waterways to support agriculture and hunting. The results of this study underscore the importance in factoring information on the taxonomy and ecology of organisms, and seasonal changes in environmental conditions, into assessments of contamination risks.
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  • 27
    ISSN: 1618-2545
    Keywords: Bruguiera gymnorrhiza ; ecology ; Lanceispora amphibia ; mangrove ; taxonomy
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    Topics: Biology
    Notes: Abstract Lanceispora amphibia gen. et sp. nov. in the Amphisphaeriaceae is described from senescent and fallen leaves ofBruguiera gymnorrhiza in mangrove forests in the Southwest Islands, Japan. The fungus produces immersed ascomata in leaf tissue, cylindrical asci with an apical ring staining blue with iodine, and oblanceolate ascospores with a septum above the middle. Studies on the fungal succession on the mangrove leaves revealed thatL. amphibia infects senescent leaves on the tree and inhabits intertidal fallen leaves, showing the highest frequency of occurrence at the late stage of decomposition. In culture the optimal conditions for hyphal growth were 20 ppt salinity and 30°C, and those for sexual reproduction were 10 ppt salinity and 25°C. Growth at 0 ppt (fresh water) was depressed. The fungus has amphibious habits, growing on the tree and in intertidal water; and it is adapted to the high osmotic conditions in leaf tissues of the mangrove tree and to the subtropical, brackish water environment of mangrove forests.
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  • 28
    ISSN: 1618-2545
    Keywords: Bauhinus ; Microbotryum ; taxonomy ; Ustilago ; ustomycetes
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    Topics: Biology
    Notes: Abstract A study of the type specimen ofUstilago jehudana resulted in the correction of the diagnosis. The sori are localized in the host gynoecium but not in the anthers. Morphological characters of the sori and ustospores of the later describedU. moenchiae-manticae are identical with these ofU. jehudana. Ustilago moenchiae-manticae is reduced here to a synonym ofU. jehudana. The smut is reported as new to Bulgaria on a new host, viz.,Moenchia erecta. A new combination,Bauhinus jehudanus, is proposed.
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  • 29
    ISSN: 1618-2545
    Keywords: Aphyllophorales ; ribosomalDNA ; synnematous hyphomycete ; taxonomy ; Tretopileus sphaerophorus
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    Topics: Biology
    Notes: Abstract Tretopileus sphaerophorus, a synnematous hyphomycete with basidiomycetous affinities was newly isolated from the decaying petiole and peduncle ofCocos nucifera collected in Depok, Indonesia. The species produced first a bulbil as a propagule on the top of a synnema. After the bulbil had fallen, the synnema proliferated about seven times to produce new bulbils, each time making conspicuous nodes at the upper part. By careful morphological observation, clamp connections were confirmed on the hyphae in the specimens and culture. In culture, each hyphal cell with or without a clamp was found to be dikaryotic by DAPI nuclear staining. Germination of the bulbils occurred first from projecting hyphal tips on their upper surface, which have been treated as germ pores. The inner structure of the bulbils, the hyaline mucus of the bulbils, and conidium-like hyphal fragments were also examined. Phylogenetically,T. sphaerophorus was inferred to be related to the Aphyllophorales based on the nuclear encoded small subunit (18S) rDNA using the homology search system (FASTA) and the neighbour-joining method.
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  • 30
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    Mycoscience 39 (1998), S. 97-104 
    ISSN: 1618-2545
    Keywords: Loculoascomycetes ; phyllachoraceae ; phyllachorales ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The order Phyllachorales contains ascomycetous fungi of considerable economic importance. The group is represented mostly by foliar parasites which produce perithecia under a clypeus, inside a stroma, or do not produce any stromatic tissue. A major taxonomic problem with this order is the lack of reliable morphological characters that clearly delimit the entire group. The main purpose of this review is to provide a clear picture of the taxonomic relationships of the order Phyllachorales, along with a key to the most important genera in the family Phyllachoraceae.
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  • 31
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    Mycoscience 38 (1997), S. 55-69 
    ISSN: 1618-2545
    Keywords: discomycetes ; ITS rDNA phylogeny ; morphology ; taxonomy
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    Topics: Biology
    Notes: Abstract The systematics ofScleromitrula andVerpatinia of the family Sclerotiniaceae is reevaluated on the basis of morphological, cultural and molecular criteria.Scleromitrula shiraiana, Verpatinia species andCiborinia candolleana share gross morphological, microanatomical and cultural features which clearly distinguish them from the closely relatedCiborinia andRutstroemia species. Phylogenetic analyses of sequences from the internal transcribed spacer region (ITS1, ITS2, and the 5.8S gene) of nuclear ribosomal DNA demonstrate that the stipitate-capitate specimens ofScleromitrula andVerpatinia species plus the stipitate-cupulateCiborinia candolleana constitute a monophyletic clade separate from a clade including the type species ofCiborinia. Scleromitrula is emended to includeS. shiraiana, the new speciesS. rubicola, C. candolleana, and specimens formerly assigned toVerpatinia. A key to the accepted species ofScleromitrula is provided.
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  • 32
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    Mycoscience 38 (1997), S. 71-73 
    ISSN: 1618-2545
    Keywords: Ceratobasidiaceae ; Japan ; taxonomy ; Ypsilonidium bananisporum
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    Topics: Biology
    Notes: Abstract Ypsilonidium bananisporum sp. nov. belonging to Ceratobasidiales is described and illustrated. This fungus has all the characteristics of the genusYpsilonidium including reticulate-hypochnoid basidiomes, broad hyphae branching at right angles, broadly clavate basidia with two sterigmata, and basidiospores germinating by repetition. It differs from all hitherto known species in the genus by producing suballantoid to banana-shaped basidiospores, measuring 19.5–22×5.5–6 μm.
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  • 33
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    Mycoscience 38 (1997), S. 87-89 
    ISSN: 1618-2545
    Keywords: Israel ; Mycomycetes ; Physarales ; Stemonitales ; taxonomy
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    Topics: Biology
    Notes: Abstract Ten taxa of myxomycetes growing mainly withEucalyptus, oak and pine are described. They were found in Upper Galilee, Mt. Carmel and Central parts of the country and all are new to Israel.
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  • 34
    ISSN: 1618-2545
    Keywords: hyphomycetes ; identification ; taxonomy ; Tuberculariaceae ; Tuberculariales
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    Topics: Biology
    Notes: Abstract Mycoleptodiscus terrestris from black pepper roots in the Dominican Republic is described together with some notes and photomicrographs.
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  • 35
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    Mycoscience 38 (1997), S. 429-431 
    ISSN: 1618-2545
    Keywords: coelomycete ; Japan ; Microsphaeropsis rugospora ; soil fungus ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Abstract In an exploratory survey of soil-borne mitosporic fungi as producers of secondary metabolites useful to the pharmaceutical industry, a pale yellow pycnidial coelomycete was encountered and isolated on potato-dextrose agar. The fungus was characterized as follows: rapid growth on common media, conidiomata which are non-pulvinate, semi-immersed to immersed, nearly globose, glabrous, with a slightly papillate ostiole; pale yellowish brown, translucent, membranaceous peridium; discrete, ampulliform, monophialidic conidiogenous cells; and onecelled, dark brown, globose, thick-walled, rugose conidia which germinate very easily. In accordance with this profile, our isolate is included in the genusMicrosphaeropsis Höhnel. (Morgan-Jones, 1974a, b; Sutton, 1977, 1980; Morgan-Jones and White, 1987; Heiny et al., 1992; Katumoto, 1992). However, it proved to be sufficiently different from all described species ofMicrosphaeropsis to warrant its description as a new species.
    Notes: Abstract A new species ofMicrosphaeropsis (Sphaeropsidales, Coelomycetes),M. rugospora, is described and illustrated. This fungus is characterized by its rapid growth on common media such as oatmeal and potato-carrot agars; semi-immersed to immersed, nearly globose, papillate pycnidias; pale yellowish brown, translucent, membranaceous peridium; monophialidic, ampulliform conidiogenous cells; and one-celled, dark brown, globose conidia ornamented with distinct tubercles. The holotype was isolated from the cultivated soil in Tanegashima Island, southern Japan.
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  • 36
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    Mycoscience 39 (1998), S. 31-36 
    ISSN: 1618-2545
    Keywords: Mycogloea ; Platygloea ; Platygloeaceae ; Platygloeales ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Three new species ofMycogloea are described and illustrated; they are:M. amethystina from Canada,M. nipponica, from Japan, andM. bullata from Thailand.Mycogloea tahitiensis is reported from Japan and additional undescribed taxa in the genus are briefly noted. Some characteristics of the genus are discussed, and a key is provided for six species recognized at this time.
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  • 37
    ISSN: 1615-6110
    Keywords: Rosaceae ; Rosa sect.Caninae ; Systematics ; taxonomy ; genetic variation ; hemisexual ; apomixis
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    Topics: Biology
    Notes: Abstract Difficulties in delimiting well-defined entities in the dogroses (Rosa sect.Caninae) has resulted in very variable taxonomic treatments. The present study was undertaken to provide a background for taxonomy as well as plant breeding. Morphometric diversity was analysed on seedlings obtained from field collections in South Sweden of three species,Rosa dumalis, R. rubiginosa andR. villosa. A canonical variates analysis showed that the three species are relatively distinct whereas two subspecies ofR. dumalis were less well discriminated. Analyses of variance demonstrated that intraspecific variation is pronounced inR. dumalis and, to a lesser extent, inR. villosa.
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  • 38
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    Plant systematics and evolution 205 (1997), S. 241-264 
    ISSN: 1615-6110
    Keywords: Boraginaceae ; Boragineae ; Anchusella ; A. variegata ; A. cretica ; Lycopsis ; Anchusa ; Mediterranean flora ; macromorphology ; micromorphology ; karyology ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The two closely related speciesLycopsis variegata andAnchusa cretica, formerly placed inAnchusa subg.Rivinia, were compared with the type species ofLycopsis andAnchusa, on the basis of a set of macro and microcharacters. The presence of only two fertile stamens as well as other peculiar characters in flower structure, androecium, gynoecium, pollen and fruit, supports the institution of the new genusAnchusella, consisting ofA. variegata andA. cretica. Karyological and eco-chorological aspects are consistent with morphological data in pointing to the autonomy of this genus, which appears characterized by autapomorphic, advanced traits.
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  • 39
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    Plant systematics and evolution 208 (1997), S. 1-9 
    ISSN: 1615-6110
    Keywords: Fabaceae ; Vicia faba ; V. kalakhensis ; Seed albumins ; HPLC ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Previously reported electrophoretic seed albumin data have shown an unexpected association ofVicia faba withV. kalakhensis. In the present work, seed albumins ofV. faba (subsp.paucijuga and subsp.faba) were compared with those ofV. kalakhensis using ionexchange (IE) and reversed-phase (RP) high-performance liquid chromatography (HPLC). Two subspecies ofV. faba displayed similar seed albumin profiles. On the other hand, seed albumin profiles ofV. faba andV. kalakhensis showed no major protein peak in common either in IE-HPLC or RP-HPLC chromatograms. The reported differences in seed albumin composition ofV. faba andV. kalakhensis are consistent with other taxonomical data showingV. faba to be genetically distant from the wild relatives.
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  • 40
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    Plant systematics and evolution 208 (1997), S. 239-248 
    ISSN: 1615-6110
    Keywords: Fabaceae ; Vicia ; sect.Hypechusa ; sect.Peregrinae ; Electrophoresis ; seed albumins ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract This work is a continuation of electrophoretic investigations aimed at revealing a wild relative ofVicia faba. Electrophoretic analysis (PAGE) of seed albumins covered 52 accessions representing eightVicia species of sect.Hypechusa and two species of sect.Peregrinae. Most of the examined species showed an intraspecific variation due to differences between accessions and/or individual variation within accessions. In spite of the intraspecific variation, marked interspecific differences were recorded. However, none of the investigated species displayed electrophoretic seed albumin patterns similar to those reported earlier forV. faba. Contribution of the obtained results to characterization of the examined taxa is discussed.
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  • 41
    ISSN: 1615-6110
    Keywords: Fabaceae ; Vicia faba ; trnL intron ; PCR-sequencing ; taxonomy
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    Topics: Biology
    Notes: Abstract The chloroplasttrnL intron from 46 differentVicia accessions, representing five of the nine sections of the genusVicia subg.Vicia sensuMaxted (1991a) were amplified by the Polymerase Chain Reaction (PCR) using oligonucleotide primers homologous to conserved regions intrnL. The products fell into two distinct groups; those of approximately 250 nt and those of around 450 nt in length. Of these, products from 17 differentVicia species were cloned and their nucleotide sequences determined. Multiple alignments were assembled and phylogenetic trees constructed by the weighted least-squares distance method. ALathyrus latifolius trnL intron sequence was used as an outgroup. The resulting trees clearly group and separate the sectt.Narbonensis, Bithynica andFaba species but were less able to distinguish species from sectt.Hypechusa andPeregrinae. Based on these sequence data,V. faba appears to be more distant from sect.Narbonensis than sectt.Hypechusa andPeregrinae. The results are in general agreement with a recent treatment ofVicia subg.Vicia (Maxted 1993) and lend further support to placingV. faba in the monospecific sect.Faba.
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  • 42
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    Plant systematics and evolution 213 (1998), S. 173-186 
    ISSN: 1615-6110
    Keywords: Fabaceae ; Vicia ; sect.Bithynicae ; sect.Narbonensis ; Allozymes ; genetic diversity ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Electrophoretic analysis of five enzyme systems, LAP, PGI, SKDH, SOD and 6-PGDH, among 102Vicia accessions representingV. bithynica and seven species of theV. narbonensis complex, namelyV. eristalioides, V. kalakhensis, V. johannis, V. galilaea, V. serratifolia, V. narbonensis andV. hyaeniscyamus, has been performed. The recorded variation was tentatively assigned to 41 allelic genes at eight loci; intraspecific variation was observed in all species except forV. eristalioides. The results obtained were compared with the corresponding data reported earlier forV. faba. Hierarchical grouping of the investigated taxa, includingV. faba, was based onNei's genetic identities calculated from the allozyme frequency data.Vicia faba andV. bithynica were shown to be most distantly related to one another and to the remaining species investigated.Vicia serratifolia appeared to be a peripheral member of theV. narbonensis complex. The results are discussed with reference to genetic diversity and taxonomic relationships of the species under study.
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  • 43
    ISSN: 1573-5176
    Keywords: Dunaliella ; ITS ; PCR ; RFLP ; strains ; taxonomy
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    Topics: Biology
    Notes: Abstract The genus Dunaliella comprises 28 species defined primarily by morphological and physiological criteria, which vary considerably depending on growth conditions. Concomitantly, the taxonomic status of various species is uncertain. To confirm the taxonomic identity and to better understand the relationship within Dunaliella, seven taxa ( D. salina, D. bardawil, D. tertiolecta, D. parva, D. viridis, D. lateralis, D. peircei) were compared using RFLP analysis of the nuclear rDNA repeats, specifically the internal transcribed spacer regions, including the 5.8S rRNA gene. Volvox aureus was used as an outgroup. A single ITS PCR amplification product was obtained for each taxon. An ITS fragment of ca. 640 bp was present in all the taxa within the subgenus Dunaliella, except for D. salina CCMP 1303 (ca. 540 bp) and D. lateralis (subgenus Pascheria) (ca. 600 bp). A cluster analysis based on the presence or absence of bands generated by digestion of the PCR product with 8 restriction endonucleases (DpnI, HhaI, EcoRI, PvuII, TaqI, HaeIII, MspI, StyI) revealed no correlation between the genetic relationship inferred from the ITS-RFLP data and the morpho-physiological attributes used for taxonomy. In addition, differences in morphology, physiology and in the length and restriction fragment patterns of the ITS region of D. salina CCMP 1303 suggest that this strain does not belong to Dunaliella.
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  • 44
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    Mycoscience 39 (1998), S. 333-335 
    ISSN: 1618-2545
    Keywords: Cortinarius prunicola ; Cortinarius Sect.Sericeocybe ; new species ; Rosaceae ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Cortinarius prunicola sp. nov., found in orchards and plantations ofPrunus mume, is described and illustrated. It is characterized by its dry and violet-white carpophores, unpleasant odor, and its close association withP. mume in spring and early summer. The differences betweenC. prunicola and similar species are briefly discussed.
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  • 45
    ISSN: 1573-0646
    Keywords: diethylnorspermine ; phase I ; pharmacokinetics ; CNS toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of ≥ 83 mg/m2/day.
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  • 46
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    Investigational new drugs 15 (1997), S. 195-206 
    ISSN: 1573-0646
    Keywords: depsipeptide ; electrospray LC/MS/MS ; pharmacokinetics ; oral absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Depsipeptide, a cyclic peptide (FR), isolated from Chrombacterium violaceum strain WB968 by Fujisawa Company during a screening program for anti-oncogene agents, possesses potent antitumor activity against human tumor cell lines and xenografts. This compound has been selected for preclinical and early clinical development by the National Cancer Institute. The pharmacokinetics and oral bioavailability of this depsipeptide in the rat were investigated in the present study. A sensitive and specific electrospray LC-tandem mass spectrometry method was first developed and validated for the analysis of this depsipeptide in plasma using t-boc-α-d-glutamic acid benzyl ester as the internal standard. The routine sensitivity limit was 1 or 10 ng/ml using 1.0 or 0.1 ml of plasma sample. The within-run CV values were 11.8, 17.9, 11.0, and 5.0% at 1, 10, 100, and 500 ng/ml levels, respectively, with corresponding accuracy of 94.4, 109, 95, and 97% (all n=6). A formulation based on ethanol, normal saline and PEG400 was then developed and Fischer rats were given this formulated drug separately by intravenous and oral route. Plasma drug concentrations were measured by this method and pharmacokinetics were analyzed by the standard techniques. Plasma concentration-time profiles were found to follow a biexponential decline with a mean terminal t1/2 of 97 min and mean total clearance (CLt) of 425.3 ml/min/kg following iv dosing at 10 mg/kg. Following oral dosing at 50 mg/kg, the peptide was absorbed but produced erratic drug levels also with a bioavailability of 15.6%. Thus, active plasma concentrations can be produced up to 3 hrs in the rat following a single dose at 10 mg/kg and the peptide represents one of the very few orally absorbed peptides reported.
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  • 47
    ISSN: 1573-0646
    Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
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  • 48
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.
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  • 49
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    Journal of applied phycology 10 (1998), S. 237-251 
    ISSN: 1573-5176
    Keywords: Gelidiales ; Gelidiella ; Gelidium ; Pterocladia ; Pterocladiella ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Segregating Pterocladiella from Pterocladia stimulated new taxonomic studies of the species originally assigned to Pterocladia. A total of 28 species are ascribed to the genus, one of them with doubts. Thirteen of the 27 names are synonyms. Three of the remaining 14 species belong with Gelidium, including G. americanum, G. mcnabbianum (Dawson) comb. nov. and G. musciformis. Seven other species belong with Pterocladiella, including P. bartlettii (Taylor) comb. nov., P. bulbosa, P. caerulescens, P. caespitosa (Kylin) comb. nov., P. caloglossoides (Howe) comb. nov., P. capillacea and P. melanoidea. Two species are retained in Pterocladia, the type P. lucida and P. rectangularis. Two others, P. heteroplatos and P. media are placed in incertae sedis as additional studies of fertile materials are needed to determine their generic status. The genus Pterocladia now appears to include two large-sized species restricted to Australia-New Zealand. Pterocladiella has 8 small-sized species (including P. minima), mainly inhabiting tropical and subtropical waters. Future research documenting sexual reproduction in Gelidiella and solving the presently recognized heterogeneity in Gelidium will help to trace the relationships between Pterocladiella and these two genera.
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  • 50
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 23-37 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; neuromuscular blocking agents ; doxacurium ; input rate ; intravenous ; bolus ; infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract One of the basic assumptions in pharmacokinetic–pharmacodynamic modeling (PK–PD) is that drug equilibration rate constant between plasma concentration and effect (Ke0 ) is not changed by input rate. To test this assumption in a clinical setting, a 25 μg/kg iv dose of doxacurium was administered either by bolus injection or 10-min infusion to 15 anesthetized patients. Neuromuscular function was monitored using train-of-four stimulation of the ulnar nerve. For the short infusion dose, arterial concentrations were measured at 1-min intervals during infusion and at frequent intervals thereafter. Following the iv bolus dose, the early PK profile of doxacurium was investigated by measuring doxacurium arterial concentrations every 10 sec during the first 2 min and at frequent intervals thereafter. PK–PD modeling was performed using nonparametric approach with and without including a finite receptor concentration (Rtot ) in the effect compartment. Kinetic parameters were unchanged. For the bolus and the infusion, Ke0 values were 0.053±0.006 and 0.056±0.009 min −1 , respectively. Using the Rtot model, corresponding Ke0 values were 0.148±0.016 and 0.150±0.024, respectively. The relatively faster Ke0 obtained with the Rtot model is compatible with the high potency of doxacurium. Our results show that PK–PD parameters derived with either a bolus or an infusion mode of administration are equally reliable.
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  • 51
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 107-123 
    ISSN: 1573-8744
    Keywords: pharmacodynamic responses ; pharmacokinetics ; differential equations ; drug ; indirect response models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Four basic models for characterizing indirect pharmacodynamic responses were proposed previously and applied using differential equations. These models consider inhibition or stimulation by drug of the production or loss of mediators or response variables. This report develops partially integrated solutions for these models which allow more detailed examination of the roles of model parameters and pharmacokinetic functions in affecting the time course of drug effects. Because of the nonlinear Hill function, the solutions are represented by means of definite integrals containing kinetic and dynamic functions. These solutions allow a qualitative examination, using calculus, of how response is controlled by Dose. IC50 or SC50, Imax or Smax, and kout for drugs exhibiting monotonic or biphasic disposition. Characteristics of the response curves that were identified include shape, maximum or minimum, and changes with the above parameters and time. These relationships, together with simulation studies, provide a fundamental basis for understanding the temporal aspects of the basic indirect response models.
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  • 52
    ISSN: 1573-8744
    Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
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  • 53
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 191-208 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; frequency response ; biophase models ; infusion pumps
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The presence of a biophase compartment in a pharmacokinetic model indicates that the response to an administered dose of drug is damped such that the time to peak effect occurs after the peak concentration in the bloodstream. This phenomenon, which is common to most intravenous anesthetic agents, can be exploited by a drug delivery method that administers minibolus doses of drug rather than a continuous infusion. Through analysis of the frequency response behavior of the biophase compartment, a bolus magnitude and dose frequency or interval (1/frequency) can be chosen such that the oscillation in drug effect is minimized even though the plasma concentration may be changing significantly with each supplemental dose. A pharmacokinetic and pharmacodynamic based method for calculating the bolus dose size and dosing interval is presented. The trade-off between dose interval and change in drug effect is exemplified through computer simulation of this strategy applied to delivery of the neuromuscular blocking agent pancuronium. The method provides a repetitive perturbation to the pharmacokinetic and pharmacodynamic system that can aid in model parameter identification during closed loop applications.
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  • 54
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 569-593 
    ISSN: 1573-8744
    Keywords: tracer method ; nonlinear kinetics ; Michaelis-Menten ; pharmacokinetics ; erythropoietin ; binding ; drug receptors ; receptor binding ; drug elimination ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.
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  • 55
    ISSN: 1573-8469
    Keywords: citrus bacterial canker ; detection ; epidemiology ; monoclonal antibodies ; variability ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Strains of Xanthomonas axonopodis pv. citri were isolated from Mexican lime (Citrus aurantifolia) trees in several countries in southwest Asia. These strains produced typical erumpent bacterial canker lesions on Mexican lime but not on grapefruit (C. paradisi). Lesions on grapefruit were watersoaked and blister-like in contrast to the typical erumpent lesions seen after artificial inoculation with all described pathotypes of X. axonopodis pv. citri. This group of strains hydrolysed gelatin and casein and grew in the presence of 3% NaCl as is typical of X. axonopodis pv. citri pathotype A. RFLP analyses and DNA probe hybridization assays also gave results consistent with X. axonopodis pv. citri pathotype A. Metabolic fingerprints prepared with the Biolog® system showed similarities as well as differences to X. axonopodis pv. citri pathotype A. In spite of the physiological and genetic similarities to pathotype A of X. axonopodis pv. citri, these strains had no or very little affinity for polyclonal antiserum prepared against any of the reference strains of X. axonopodis pv. citri and also did not react with monoclonal antibody A1, an antibody that detects all strains of pathotype A of X. axonopodis pv. citri. These strains were also insensitive to bacteriophage Cp3 like X. axonopodis pv. citri pathotype A and unlike X. axonopodis pv. citri pathotype B. We conclude that these strains, designated Xcc-A*, represent a variant of X. axonopodis pv. citri pathotype-A with pathogenicity limited to C. aurantifolia. The existence of extensive genotypic and phenotypic variation within pathotype A of X. axonopodis pv. citri was unexpected and further complicates the systematics of this species.
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  • 56
    ISSN: 1573-8744
    Keywords: sumatriptan ; interspecies allometric scaling ; brain weight ; metabolized drug ; pharmacokinetics ; mixed effect modeling ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%). and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg. 0.25 mg/kg, and 1 mg, kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species: 77 L/hr vs. 80 L/hr in man for total clearance, 137 L vs. 119 L for distribution volume at steady state. The value of the mixed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may emerge from more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.
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  • 57
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; physiologically based model ; homologous series ; barbiturates ; parameter optimization
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    Topics: Chemistry and Pharmacology
    Notes: Abstract As pan of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after iv bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration–time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration–time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration–time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.
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  • 58
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 313-348 
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; generalized models ; intraindividual variability ; verapamil ; norverapamil ; S-verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A new method and experimental design are presented to unambiguously estimate the transduction function (Φ) and the conduction function (ψ) of the generalized pharmacodynamic model: E = Φ(ψ*r), when measured pharmacokinetic response r is (i) drug plasma concentration and (ii) drug input rate into the systemic circulation. Φ relates the observed pharmacologic effect E to the concentration at the effect site: ce = (ψ*r), ψ defines transfer of drug from plasma site to effect site or from input site to effect site, and * represents the convolution integral. The model functions ψ and Φ were expressed as cubic splines giving a very flexible description of those processes which is not biased by the structured assumptions of more conventional models, e.g., effect compartment models. The experimental design proposed addresses the problem of ambiguous identification of the model functions typical of these models; that is, there is more than one pair of very different functions describing the effect data collected after a single drug administration. We tested the hypothesis that the simultaneous fitting of at least two administrations allows the unambiguous identification of the model functions without the need for unlikely or cumbersome constraints. The performance of the mathematical implementation and the robustness of the methods with respect to measurement noise and possible failure of some assumptions, such as intraindividual variability, were tested by computer simulations. The method was then applied to the results of a clinical study of verapamil pharmacodynamics in 6 healthy subjects. Results of these studies demonstrated that the mathematical implementation does not introduce bias or artifact into the estimated functions and that the models and the proposed methods are suitable for application to clinical research. Two drug administrations were sufficient to unambiguously describe verapamil pharmacodynamics in the 6 human subjects studied.
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  • 59
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 471-476 
    ISSN: 1573-8744
    Keywords: steady-state volume of distribution ; statistical moment analysis ; pharmacokinetics ; infusion study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A recent study by Heatherington and Rowland showing discrepancies in steady-state volume of distribution (Vss) estimation of two barbiturates between bolus and infusion studies in rat hindlimb preparations was reviewed. Their rationale is that increasing the duration of administration may increase the accessibility for tissue distribution and thus increase Vss for compounds showing slow tissue uptake. Such a dosing-duration-dependent distribution concept is, however, inconsistent with the principle in linear kinetics that the fate or disposition function of any drug molecules is independent of time of administration and presence of other molecules. When their well-designed bolus studies were reanalyzed by including extrapolated outflow data from the last sampling time to infinity, the Vss values for the two barbiturates were found to be very similar to those obtained by the infusion method. Our analysis seems to validate a theoretical concept that parameter estimation is independent of the duration of administration in linear kinetics. A potential complication of using the bolus method to study Vss is presented.
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  • 60
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.
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  • 61
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    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 349-362 
    ISSN: 1573-8744
    Keywords: bioavailability ; pharmacologic data ; pharmacodynamics ; pharmacokinetics ; computer simulation ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A novel method is described for assessing drug bioavailability from pharmacologic data. The method is based upon a generalized model for the relationship between the observed effect (E) and the input rate (f): E = Φ(ceδ * f), where * denotes convolution, ceδ is effect site unit impulse response (“amount” of drug at the effect site resulting from the instantaneous input of a unit amount of drug) and Φ is transduction function (relates “amount” of drug at the effect site to E). The functions Φ and ceδ are expressed as cubic splines for maximum versatility. Pharmacologic data collected after the administration of two different doses by iv infusion are analyzed simultaneously to estimate the function parameters. This experimental design addresses the fact that Φ and ceδ cannot be uniquely estimated from the results of a single dose experiment. The unknown f from a test treatment is then estimated by applying an implicit deconvolution method to the pharmacologic data collected during that treatment. The method was tested with simulated data. The method and the model were further evaluated by application to a clinical study of verapamil (V) pharmacodynamics in 6 healthy volunteers. Simulations showed that the method is accurate and precise in the presence of a high degree of measurement error, but large intrasubject variability in the model functions can result in biased estimates of the amount absorbed. The method produced reasonably accurate estimates of the V input rate and systemic availability (F) in the 6 human volunteers though there was a trend towards underestimation (estimated total F%=93.6±14 vs. the true F% of 100).
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  • 62
    ISSN: 1573-8744
    Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions
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    Topics: Chemistry and Pharmacology
    Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
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  • 63
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328 
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
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    Topics: Chemistry and Pharmacology
    Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.
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  • 64
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling
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    Topics: Chemistry and Pharmacology
    Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
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  • 65
    ISSN: 1573-5117
    Keywords: taxonomy ; Ostracoda ; China ; ancient lakes ; saline lakes ; biogeography ; checklist ; Fabaeformiscandona danielopoli n.sp.
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    Topics: Biology
    Notes: Abstract Fabaeformiscandona danielopoli n.sp. isdescribed from the Chinese Lake Erhai, a freshwaterlagoon of the ancient saline lake Qinghai. The speciesbelongs to the acuminata-group of the genus andis characterized by the shape of both male and femalevalves and by the morphology of the female genitallobe and of lobe ‘a’ in the hemipenis. The new speciesis quite rare in its type locality and might beendemic to the ancient Qinghai basin. A checklist ofRecent non-marine Chinese ostracods is offered inappendix.
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  • 66
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    Hydrobiologia 365 (1997), S. 33-46 
    ISSN: 1573-5117
    Keywords: Phylogeny ; cladistics ; taxonomy ; systematics ; classification ; evolution ; history ; chronicle ; Nemertea ; Hoplonemertea
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    Topics: Biology
    Notes: Abstract I review how some influential nemertean systematistshave perceived and illustrated phylogenetic trees andargue that the nineteenth century nemerteantaxonomists still influence many contemporarynemertean taxonomists to a high degree. By showing hownineteenth century systematics differs from moremodern views on trees, I hope to convey the advantagesof a cladistic approach to tree-thinking and nemerteansystematics. Furthermore I propose a systematizationof the Eureptantia that illustrates the cladisticapproach to tree-thinking but, more importantly, isalso a better representation of eureptantic phylogenythan previous classifications.
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  • 67
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    Hydrobiologia 356 (1997), S. 157-163 
    ISSN: 1573-5117
    Keywords: Lecanidae ; N.E. India ; Tripura ; taxonomy ; distribution
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    Topics: Biology
    Notes: Abstract Thirty-five species of the family Lecanidae are examined from Tripura state in North-Eastern India. Of these, Lecane levistyla and L. scutata are interesting cold-water forms; L. batillifer is an Australasian element; L. acanthinula and L. sinuata are Oriental endemics and L. braumi, L. lateralis and L. simonneae are palaeotropical species. The lecanid fauna also includes the pantropical L. thienemanni and L. sola while the remainder are cosmopolitan and tropicopolitan elements.
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  • 68
    ISSN: 1573-5117
    Keywords: Branchiopoda ; Branchinella ; taxonomy ; morphology ; India
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    Topics: Biology
    Notes: Abstract The fairy shrimp Branchinella kugenumaensis (Ishikawa) was long considered a widely, though disjunctly, distributed species occurring from Japan through eastern Asia to southern India. Attempts by Raj (1951, 1961) to make the Indian populations a new variety (B. k. var. madurai) on the basis of antennal and frontal appendage morphology and on its distribution pattern, were considered unconvincing by later authors. Our new comparison of Japanese and Indian specimens has revealed several differences. The resting egg shells of B. kugenumaensis from Japan have irregular polygonal fields; whereas, the shells of the Indian taxon have lip-like units covered with spinules. Furthermore, there are lobes lateral to the basal penes in the Indian specimens that are lacking in the Japanese taxon. As well as differences in antennal and frontal appendage morphology. These differences correspond with previous illustrations of populations from both geographic regions and lead us to consider Raj's proposed subspecies as a valid species. This brings the number of accepted species in the genus Branchinella to 34. More specimens will need to be evaluated from the area between India and Japan to determine if B. maduraiensis is endemic to the Indian subcontinent or is more broadly distributed on the Asian mainland.
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  • 69
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    Hydrobiologia 360 (1997), S. 47-54 
    ISSN: 1573-5117
    Keywords: taxonomy ; ecology ; caves ; Chydoridae ; Slovenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Alona stochi n.sp., a third blind cave-dwellingcladoceran from the Dinaric region, was found onseveral occasions in a small cave 30 km south-east ofLjubljana (Slovenia). It is related to Alonahercegovinae Brancelj, 1990 and A. sketiBrancelj, 1992. Several characters suggest that itbelongs to a primitive group within the genus Alona.A. stochi was found in a 'semi-cave' environment, accompanied by a cave-associated fauna(Amphibia: Proteus anguinus, Decapoda: cf. Troglocaris schmidti, Copepoda: Troglodiaptomussketi, Diacyclops tantalus, charon,Elaphoidella stammeri).
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  • 70
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    Hydrobiologia 360 (1997), S. 55-61 
    ISSN: 1573-5117
    Keywords: Crustacea ; Anomopoda ; Moinidae ; Moina ephemeralis ; taxonomy ; cladocerans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Moina ephemeralis n.sp. is described from SouthSlovakia. It belongs to the Moinagouldeni-lipini group. Together with Moinamacrocopa (Straus, 1820) it is the second specieswith a 2-egged ephippium from Central Europe. Thespecies was recorded in the plankton of a highlyeutrophic fish pond.
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  • 71
    ISSN: 1573-5117
    Keywords: Cladocera ; chydoridae ; taxonomy ; Mexico ; aloninae
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    Topics: Biology
    Notes: Abstract Spinalona anophtalma n. gen. n. sp. is describedon parthenogenetic and ephippial females andmales from material collected in a temporary lagoonlocated in the Neovolcanic Province from Mexico at analtitude of 2507 m above sea level. It ischaracterized by a strong armature of the antenna,postabdomen and postabdominal claw, no compound eyeor ocellus, the exopod of thoracic limb IIIwith only four setae and that of P5 with only three setae.This new taxon has no relationwith blind Alona from hypogean habitats.
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  • 72
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    Hydrobiologia 369-370 (1998), S. 363-372 
    ISSN: 1573-5117
    Keywords: Euglenophyta ; South America ; geographical distribution ; taxonomy
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    Topics: Biology
    Notes: Abstract A taxonomic revision of the Euglenophyta found exclusively in South America is presented. The taxonomy, geographical distribution and critical analysis of the synonyms are given. More than two hundred species and infraspecific entities from South America are described, many of them recorded several times in different regions. The genus Trachelomonas comprises the highest number of new taxa, reaching more than 100 entities. It is followed by Phacus (48 taxa), Strombomonas (33 taxa), Euglena (15 taxa) Lepocinclis (14 taxa), and Distigma, Entosiphon and Sphenomonas with one new taxon each.
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  • 73
    ISSN: 1573-5117
    Keywords: Neocervinia itoi ; Copepoda ; Harpacticoida ; taxonomy ; cold-seep ; Japan
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    Topics: Biology
    Notes: Abstract A new species of harpacticoid copepod, Neocervinia itoi (Cerviniidae), is described on the basis of females and copepodids collected from the Hatsushima cold-seep site in Sagami Bay, Japan. It is morphologically very close to its deep-sea congeners N. tenuicauda (Brotskaya, 1963) and N. unisetosa (Montagna, 1981). The new species differs primarily in the segmentation of the antennule and the endopod of both mandible and maxilliped, and in form and shape of the setae on leg 5. The presence of sensillar structures on the proximal part of the antennule is discussed. A key to the species of Neocervinia is presented.
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  • 74
    ISSN: 1573-5117
    Keywords: marine nematodes ; Draconematidae ; Bathychaetosoma ; taxonomy ; revision ; phylogeny
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    Topics: Biology
    Notes: Abstract The family Draconematidae is reviewed. Diagnoses of all taxa are updated or emended, basedupon an evaluation of diagnostic features. Aphylogenetic analysis at the genus level based onparsimony suggested that Tenuidraconema belongsto the Draconematinae. A new genus Bathychaetosoma is erected to accomodate B.uchidai (Kito, 1983). It is characterized by acephalic region with a smooth, non-thickened cuticleand numerous cephalic adhesion tubes located posteriorto the head region and extending over more than twohead diameters along the cervical region.
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  • 75
    ISSN: 1573-5117
    Keywords: Diaptomidae ; Copepoda ; Calanoida ; taxonomy ; Allodiaptomus rarus n.sp. ; Thailand
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A brief taxonomic review is made of the diaptomid copepods of Thailand. The updated list contains 21 species; the records of some species, however, are unreliable. Neodiaptomus botulifer Kiefer, N. yangtsekiangensis Mashiko, and Allodiaptomus calcarus Shen & Tai are redescribed. The extensive morphologic variability observed in N. botulifer casts serious doubt on the validity of Neodiaptomus malaindosinensis Lai & Fernando; hence the synonymy of these two species is discussed. It is clarified that Lai & Fernando (1981) and others had erroneously identified and/or described N. yangtsekiangensis and A. calcarus as Arctodiaptomus bacillifer (Koelbel) and Neodiaptomus mephistopheles Brehm, respectively, and that the occurrence of the latter two species in Thailand is hardly likely. Mongolodiaptomus uenoi (Kikuchi) and Heliodiaptomus elegan Kiefer are reported for the first time from Thailand. Also included in this paper is an illustrated description of a new species, Allodiaptomus rarus n.sp., which is closely related to A. calcarus Shen & Tai.
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  • 76
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    Hydrobiologia 365 (1997), S. 149-156 
    ISSN: 1573-5117
    Keywords: Nemertea ; North America ; taxonomy ; Micrura leidyi ; Fragilonemertes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract An elongate, pencil-shaped, burrowing heteronemerteanthat fragments readily is commonly encountered in clamflats and sometimes in sandy beaches of the NewEngland states. It is usually a reddish color, bearsa caudal cirrus, and has been routinely recorded asMicrura leidyi. Histological examination ofdeep red to reddish purple individuals proved them tobe intertidal specimens of the normally deep waterTarrhomyos luridus. Living pink to redindividuals could be divided into two groups on thebasis of color pattern, but were indistinguishablehistologically. Comparison with Micrurafasciolata, the type species of the genus,showed morphological differences that do not representinterspecific variation, but indicate a separategeneric placement.
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  • 77
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615 
    ISSN: 1573-8744
    Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.
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    International journal of primatology 19 (1998), S. 879-905 
    ISSN: 1573-8604
    Keywords: Alouatta seniculus ; taxonomy ; geographic distribution ; Guianas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Cytogenetic and morphological studies have begun to reexamine the taxonomy of the red howlers Alouatta seniculus which live throughout the northern and western Amazon basin, in the Guianas, and from northern Colombia and Venezuela, south to Bolivia. We briefly review the current state of knowledge of the taxonomy and distributions of red howlers, in particular, that of the Guianan subspecies. Recently, two names have been applied to populations from this region, Simia straminea Humboldt, 1812, and Alouatta macconnelli Elliot, 1910. Allen (1911, 1916) unquestioningly accepted the validity of A. macconnelli from the Guyana coast, but most subsequent taxonomic revisions (Cruz Lima, 1945; Cabrera, 1957; Husson, 1978) have synonymized it with S. straminea. Tate (1939) and Hill (1962) listed Alouatta seniculus macconnelli, but both doubted its validity. Nevertheless, recent cytogenetic and morphological studies, without due consideration of the taxonomic history of the two scientific names, have led to the resurrection of A. macconnelli, as distinct from S. straminea. The use of the name Alouatta macconnelli has evidently arisen from a cursory reading of Hill (1962) or an uncritical interpretation of his provisional subspecific distribution map or both. There are also contradictory interpretations of a reciprocal translocation as indicating that Simia straminea and Alouatta macconnelli are separate species (Bonvicino et al., 1995) or the same subspecies (Sampaio et al., 1996). Doubts about the type locality of Simia straminea Humboldt, 1812, as given by Hill (1962), led us to research its original description and to conclude that Simia straminea is a synonym of Alouatta caraya and therefore unavailable for Alouatta seniculus. Before A. macconnelli is accepted as the next available name for the Guianan red howlers, however, we advocate a thorough review of Guianan, Venezuelan, and Colombian red howler subspeciation, with due consideration for the taxonomic status of Mycetes auratus and Mycetes laniger Gray, 1845. We note that Alouatta guariba (Humboldt, 1812) is a senior synonym of Alouatta fusca (Saint-Hilaire, 1812).
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85 
    ISSN: 1573-8744
    Keywords: rifapentine ; pharmacokinetics ; gender differences ; female
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.
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  • 80
    ISSN: 1573-8744
    Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 385-408 
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; indirect response models ; infusions ; inhibition ; stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 559-579 
    ISSN: 1573-8744
    Keywords: acetaminophen ; age ; antipyretic ; fever ; ibuprofen ; pediatrics ; pharmacokinetics ; pharmacodynamics ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
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  • 83
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect pharmacodynamic response models ; glucocorticoid receptor ; Northern hybridization ; mRNA ; down-regulation ; tyrosine aminotransferase ; dose dependence ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
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  • 84
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    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 409-436 
    ISSN: 1573-8744
    Keywords: pharmacodynamic recession slope ; Hill function ; k · m product ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).
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  • 85
    ISSN: 1573-904X
    Keywords: poly(glycolide-co-D,L-lactide) ; poly(D,L-lactide) ; granulocyte-macrophage colony-stimulating factor (GM-CSF) ; biodegradable microspheres ; pharmacokinetics ; resorbable polymer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study describes the preparation and characterization of a controlled release formulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) encapsulated in poly(glycolide-co-D,L-lactide) (PLGA) and poly(D,L-lactide) (PLA) microspheres. Methods. GM-CSF was encapsulated in PLGA/PLA microspheres by a novel silicone oil based phase separation process. Several different blends of PLGA and low molecular weight PLA were used to prepare the microspheres. The microspheres and the encapsulated GM-CSF were extensively characterized both in vitroand in vivo. Results. Steady release of GM-CSF was achieved over a period of about one week without significant 'burst' of protein from the microspheres. Analysis of microsphere degradation kinetics by gel permeation chromatography (GPC) indicated that low molecular weight PLA enhanced the degradation of the PLGA and thereby affected release kinetics. GM-CSF released from the microspheres was found to be biologically active and physically intact by bioassay and chromato-graphic analysis. Analysis of serum from mice receiving huGM-CSF indicated that the GM-CSF was biologically active and that a concentration of greater than 10 ng/mL was maintained for a period lasting at least nine days. MuGM-CSF was not detected followingin vivo administration of muGM-CSF microspheres. The tissues of mice receiving muGM-CSF microspheres were characterized by infiltration of neutrophils, and macrophages which were in significant excess of those found in mice administered with placebo controls (i.e. microspheres without GM-CSF). Conclusions. This study demonstrates the influence of formulation parameters on the encapsulation of GM-CSF in PLGA/PLA microspheres and its controlled release in biologically active form. The intense local tissue reaction in mice to muGM-CSF microspheres demonstrates the importance of the mode of delivery on the pharmacologic activity of GM-CSF.
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  • 86
    ISSN: 1573-904X
    Keywords: recombinant human erythropoietin ; liposome ; intravenous administration ; subcutaneous administration ; pharmacokinetics ; pharmacological effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Recombinant human erythropoietin (Epo) is used frequently through intravenous (i.v.) and subcutaneous (s.c.) administration for the clinical treatment of the last stage of renal anemia. We encapsulated Epo in liposomes to develop an alternative administration route. The purpose of our study was to evaluate the pharmacokinetics and the pharmacological effects of liposomal Epo in comparison with the Epo after i.v. and s.c. administration to rats. Methods. Epo was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterol mixture (SS) prepared by the reversed-phase evaporation vesicle method. After filtration through a 0.1 μm polycarbonate membrane, liposomes were gel filtered (Epo/liposomes). Results. Epo/liposomes showed higher pharmacological activity than Epo/liposomes before gel filtration after i.v. administration to rats. Non-encapsulated Epo lost its activity, whereas encapsulated Epo in liposomes retained it. The pharmacological effects of Epo/liposomes were greater than those of Epo after i.v. administration. Epo/liposomes afforded 3−9 times higher AUC, lower clearance and lower steady-state volume of distribution than Epo after both i.v. and s.c. administrations. Epo/liposomes had an improved pharmacokinetic profile compared with Epo. S.c. administration of Epo/liposomes at 7 h may penetrate primarily (40% of dose) through the blood as a liposome and partly (7% of dose) in lymph. Conclusions. Epo/liposomes may reduce the frequency of injections required for a certain reticulocyte effect in comparison to Epo. The lower clearance of Epo/liposomes may increase the plasma concentrations of Epo, which increases the efficacy.
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  • 87
    ISSN: 1573-904X
    Keywords: ascorbic acid ; pharmacokinetics ; human ; models— theoretical ; models—nonlinear ; bioavailability ; ascorbic acid deficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. Methods. A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. Results. The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. Conclusions. The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.
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  • 88
    ISSN: 1573-904X
    Keywords: Avonex™ ; Rebif® ; interferon-beta-la ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 89
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    Pharmaceutical research 14 (1997), S. 556-567 
    ISSN: 1573-904X
    Keywords: cyclodextrins ; drug formulation ; drug delivery ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug releasedin vivo? Does the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.
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  • 90
    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
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  • 91
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    Pharmaceutical research 14 (1997), S. 1287-1297 
    ISSN: 1573-904X
    Keywords: pharmacometrics ; pharmacokinetics ; simulate ; predict ; validate ; clinical trial ; population ; decision support ; informatics ; bootstrap ; clinical outcomes ; algorithm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Single dose pharmacokinetic data from several individuals can be used to predict the fraction of the population that is expected to be within a therapeutic range. Without having some measure of its reliability, however, that prediction is only likely to marginally influence critical drug development decision making. The system (Forecaster) described generates an approximate prediction interval that contains the original prediction and where, for example, the probability is approximately 85% that a similar prediction from a new set of data will also be within the range. The goal is to validate that the system functions as designed. Methods. The strategy requires having a Surrogate Population (SP), which is a large number (≥1500) of hypothetical individuals each represented by set of model parameter values having unique attributes. The SP is generated so that a sample taken from it will give data that is statistically indistinguishable from the available experimental data. The automated method for building the SP is described. Results. Validation studies using 300 independent samples document that for this example the SP can be used to make useful predictions, and that the approximate prediction interval functions as designed. Conclusions. For the boundary conditions and assumptions specified, the Forecaster can make valid predictions of pharmacokinetic-based population targets that without a SP would not be possible. Finally, the approximate prediction interval does provide a useful measure of prediction reliability.
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  • 92
    ISSN: 1573-904X
    Keywords: remifentanil ; esmolol ; pharmacokinetics ; pharmacodynamics ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective β-blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. Methods. Sprague-Dawley rats (N = 8, Wt. = 325 ± 15g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 μg/ kg/min), and REMI & ES (15 μg/kg/min and 600 μg/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1−50 Hz) for spectral edge (97%). Results. No significant differences (p 〈 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 ± 148 ml/ min kg) or Vd (REMI = 286 ± 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid Emax PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean Emax and EC50 after REMI were 18.0 ± 6.0 Hz and 32 ± 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. Conclusions. At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.
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  • 93
    ISSN: 1573-904X
    Keywords: microdialysis ; blood-brain barrier transport ; pharmacokinetics ; drug equilibration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. Methods. Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. Results. Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. Conclusions. Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.
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  • 94
    ISSN: 1573-904X
    Keywords: human hepatocytes ; extraction ratio ; pharmacokinetics ; clearance ; in vitro models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The present investigation retrospectively evaluates the use of human hepatocytes to classify compounds into low, intermediate or high hepatic extraction ratio in man. Methods. A simple approach was used to correlate the in vivo hepatic extraction ratio of a number of compounds in man (literature and in-house data) with the corresponding in vitro clearance which was determined in human hepatocytes. The present approach assumes that, for compounds eliminated mainly through liver metabolism, intrinsic clearance is the major determinant for their in vivo hepatic extraction ratio and subsequently their bioavailability in man. The test compounds were selected to represent a broad range of extraction ratios and a variety of metabolic pathways. Results. The present data show that in vitro clearances in human hepatocytes are predictive for the hepatic extraction ratios in vivo in man. Most of the test compounds (n = 19) were successfully classified based upon human hepatocyte data into low, intermediate or high hepatic extraction compounds, i.e. compounds with potential for high, intermediate or low bioavailabilities in humans. Conclusions. The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.
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  • 95
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    Pharmaceutical research 14 (1997), S. 213-217 
    ISSN: 1573-904X
    Keywords: valproic acid ; valproyl hydroxamic acid derivatives ; pharmacokinetics ; antiepileptic activity ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anti-convulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid—VPA-HA, N-(l-hydroxyethyl)-valpromide—HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(l-methoxyethyl) valpromide and N-( 1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.
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  • 96
    ISSN: 1573-904X
    Keywords: CTLA4Ig ; intravenous ; subcutaneous ; pharmacokinetics ; immunogenicity ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. Methods. A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. Results. After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1−4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. Conclusions. The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.
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  • 97
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamic modeling ; NONMEM ; model validation ; cisatracurium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. Methods. Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I−III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. Results. The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p 〈 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. Conclusions. The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.
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  • 98
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    Pharmaceutical research 14 (1997), S. 98-102 
    ISSN: 1573-904X
    Keywords: Remeron ; mirtazapine ; Org 3770 ; antidepressant ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare, in a clinical study of a special design, the pharmacokinetic profile of mirtazapine in 20 young healthy male volunteers on two treatment regimens with homothetic oral tablets at steady state: NOCTE (1 × 30 mg at 21.00 h) and BID (15 mg at 21.00 h and 15 mg at 09.00 h). Methods. Pharmacokinetic parameters were calculated from mirtazapine plasma levels assayed by gas chromatography with nitrogen-sensitive detection. A special analysis of variance allowed interesting interactions to be distinguished. Results. The steady state was reached after 4 and 6 days for NOCTE and BID respectively; the difference was presumably due to intersubject variability. In accordance with pharmacokinetic theory, the peak-to-trough ratio at steady state was significantly lower (twofold) for BID than for NOCTE. Within BID, a small difference (approx. 10%) was found in the extent of absorption between evening and morning administration. Although statistically significant, this difference meets strict bioequivalence requirements. The regimens NOCTE and BID were found to be bioequivalent for the steady-state area-under-the-curve-curve and the peak time. Bioequivalence testing for the peak level was not meaningful due to the difference in dosing regimens. The observed elimination half-lives of 19.7 ± 3.0 h and 20.8 ± 2.7 h (n = 20) for NOCTE and BID, respectively are in agreement with previous results. Conclusions. Differences (if any) were found to meet strict bioequivalence requirements and were so small that they are of no clinical consequence.
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  • 99
    ISSN: 1573-904X
    Keywords: intravenous microdialysis ; blood sampling ; fluconazole ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. Methods. An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. Results. There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p 〉 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. Conclusions. These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.
    Type of Medium: Electronic Resource
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  • 100
    ISSN: 1573-904X
    Keywords: topotecan ; pharmacokinetics ; topoisomerase I inhibitor ; reversible metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs. Methods. The pharmacokinetics of topotecan and SK&F 105992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs. Results. When administered intravenously to dogs, SK&F 105992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105992 appeared to decline multi-exponentially following IV infusion of either compound. A 2-compartment model was found to adequately characterize the data. Conclusions. The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105992, whereas the clearance of SK&F 105992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105992 data, was approximately 50%.
    Type of Medium: Electronic Resource
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