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  • pharmacokinetics  (52)
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  • 1
    Electronic Resource
    Electronic Resource
    Identity of Fusarium nygamai isolates with long and short microconidial chains from millet, sorghum and soil in Africa (1997)
    Springer
    Mycopathologia 140 (1997), S. 171-176 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006863825469
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  • 2
    Electronic Resource
    Electronic Resource
    Candida novakii, sp. nov. a new anamorphic yeast species of ascomycetous affinity (1997)
    Springer
    Antonie van Leeuwenhoek 71 (1997), S. 375-378 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1000238205640
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  • 3
    Electronic Resource
    Electronic Resource
    Verrucomicrobia div. nov., a new division of the Bacteria containing three new species of Prosthecobacter (1997)
    Springer
    Antonie van Leeuwenhoek 72 (1997), S. 29-38 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1000348616863
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  • 4
    Electronic Resource
    Electronic Resource
    Studies on keratinophilic fungi. Ix: Neoarachnotheca gen. nov. and a new species of Nannizziopsis (1997)
    Springer
    Antonie van Leeuwenhoek 72 (1997), S. 149-158 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1000394118040
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  • 5
    Electronic Resource
    Electronic Resource
    Biological control of pigweeds (Amaranthus retroflexus, L. A. Powellii, S. Watson and A. bouchonii Thell.) with phytophagous insects, fungal pathogens and crop management (1997)
    Springer
    Integrated pest management reviews 2 (1997), S. 51-59 
    Details
    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
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018480429706
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  • 6
    Electronic Resource
    Electronic Resource
    Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 235-237 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050280
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of nicardipine enantiomers in healthy young volunteers (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 289-292 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050292
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  • 8
    Electronic Resource
    Electronic Resource
    Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 379-381 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050304
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 441-449 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050317
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  • 10
    Electronic Resource
    Electronic Resource
    Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 359-366 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050214
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  • 11
    Electronic Resource
    Electronic Resource
    Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 415-419 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050223
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  • 12
    Electronic Resource
    Electronic Resource
    Lack of interaction between meloxicam and warfarin in healthy volunteers (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 421-425 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050224
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  • 13
    Electronic Resource
    Electronic Resource
    Genetic polymorphism of CYP2C19 and lansoprazole pharmacokinetics in Japanese subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 391-396 
    Details
    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).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050307
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  • 14
    Electronic Resource
    Electronic Resource
    Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 139-145 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050263
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  • 15
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of oral and intramuscular artemether (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 307-310 
    Details
    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).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050295
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  • 16
    Electronic Resource
    Electronic Resource
    Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 403-406 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050309
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    Population analysis of the non-linear red blood cell partitioning of draflazine following various infusion durations (1997)
    Springer
    European journal of clinical pharmacology 53 (1997), S. 57-63 
    Details
    ISSN: 1432-1041
    Keywords: Key wordsDraflazine ; Population analysis; nucleoside transport inhibitor ; non-linear red blood cell partition ing ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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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    Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 285-288 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050291
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    Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 229-234 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050279
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    Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 241-242 
    Details
    ISSN: 1432-1041
    Keywords: Key words Citalopram ; Cimetidine; drug ; drug interac‐tion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050282
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    Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form (1997)
    Springer
    European journal of clinical pharmacology 51 (1997), S. 473-480 
    Details
    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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    URL: http://dx.doi.org/10.1007/s002280050233
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    Characterization of Cyanobacteria by SDS-PAGE of whole-cell proteins and PCR/RFLP of the 16S rRNA gene (1997)
    Springer
    Archives of microbiology 168 (1997), S. 176-184 
    Details
    ISSN: 1432-072X
    Keywords: Key words Cyanobacteria ; Planktonic ; Total protein ; SDS-PAGE ; PCR ; RFLP ; 16S rRNA ; UPGMA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Planktonic, filamentous cyanobacterial strains from different genera, both toxic and nontoxic strains, were characterized by SDS-PAGE of whole-cell proteins and PCR/RFLP of the 16S rRNA gene. Total protein pattern analysis revealed the mutual relationships at the genus level. Restriction fragment length polymorphism (RFLP) of the 16S rRNA gene with reference strains proved to be a good method for the cyanobacterial taxonomy. The nonheterocystous strains outgrouped from the nitrogen-fixing ones. With both methods, Aphanizomenon clustered with Anabaena, and Nodularia with Nostoc. In the RFLP study of Anabaena, the neurotoxic strains were identical, but the hepatotoxic ones formed a heterogeneous group. Genetic distances found in the RFLP study were short, confirming that close genotypic relationships underlie considerable diversity among cyanobacterial genera.
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    Megaplasmids in Thermus oshimai isolates from two widely separated geographical areas: restriction fragment profiling and DNA homology (1997)
    Springer
    Archives of microbiology 168 (1997), S. 473-479 
    Details
    ISSN: 1432-072X
    Keywords: Key words Thermus oshimai ; Megaplasmids ; Pulsed-field gel electrophoresis ; RFLP ; Southern ; hybridization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Megaplasmid DNA was detected in ten isolates belonging to the recently described thermophilic eubacterial species Thermus oshimai and isolated from hot springs in Portugal (eight isolates) and Iceland (two isolates). The estimated size of the large plasmids purified from T. oshimai SPS-18 from S. Pedro do Sul, Portugal, and from isolate JK-91 from Hveragerdhi-Hengill, Iceland, was 214 and 275 kb, respectively. No sequence homologous to isolate SPS-18 megaplasmid is present in chromosomal DNA as indicated by Southern hybridization analysis. Overall examination of the HindIII fragment profiles of megaplasmid DNAs purified from isolates from the same geographical area gave similar but not always identical restriction profiles on agarose gels. Restriction fragment length polymorphism (RFLP) was higher for megaplasmids present in isolates purified from the Portuguese and Icelandic isolates than for megaplasmids from the same hot spring. Megaplasmid RFLP correlated with previous results obtained on the polymorphism of macrorestriction patterns of whole genomic DNA and with the RFLP of co-resident small plasmid DNA that was found in one half of the isolates examined. The 16-kb HindIII–HindIII fragment from isolate SPS-18 megaplasmid showed DNA–DNA homology with restriction fragments of similar size generated by the large plasmids present in all the other isolates, even in those from hot springs of widely separated geographical areas. This suggests a high degree of sequence conservation in T. oshimai megaplasmids.
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    Ribosomal DNA variation in foxtail millet, Setaria italica (L.) P. Beauv., and a survey of variation from Europe and Asia (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 751-756 
    Details
    ISSN: 1432-2242
    Keywords: Key words Foxtail millet ; rDNA ; RFLP ; Restriction mapping ; Geographical distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Restriction fragment length polymorphism (RFLP) and the structure of ribosomal RNA genes (rDNA) were investigated in 117 landraces of foxtail millet, Setaria italica (L.) P. Beauv. Five RFLP phenotypes were found when the genomic DNA was digested with BamHI; these were named types I–V. Of these types I, II and III were the most frequent. Type I was mainly distributed in the temperature zone, type II in the Taiwan-Philippines Islands and type III in South Asia. Restriction mapping of the cloned rDNA and comparison with RFLP phenotypes showed that the different types originated from a polymorphism in the length within the intergenic spacer (IGS) and BamHI site changes within the IGS.
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    URL: http://dx.doi.org/10.1007/s001220050621
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    Comparative molecular mapping of GA insensitive Rht loci on chromosomes 4B and 4D of common wheat (Triticum aestivum L.) (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 1133-1137 
    Details
    ISSN: 1432-2242
    Keywords: Key words Comparative genetic mapping ; Dwarfing genes ; GA insensitivity ; Microsatellites ; RFLP ; Wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The two GA-insensitive dwarfing gene loci Rht-B1 and Rht-D1 were mapped using three F2 populations, segregating for Rht-B1c (Rht3), Rht-D1b (Rht2) or Rht-D1c (Rht10). Rht-B1c was mapped on chromosome 4BS in the centromere region, distal and closely linked to the RFLP markers Xpsr144 (11.9 cM) and Xpsr584 (17.8 cM), but proximal to Xmwg634 (30 cM). Rht-D1c, however, was found to be closely linked to the distally located markers Xpsr921 (0.8 cM) and Xmwg634 (1.5 cM). The homoeologous relationships between the GA-insensitive dwarfing genes within the Triticeae are discussed.
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    URL: http://dx.doi.org/10.1007/s001220050673
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    A genetic linkage map of cowpea (Vigna unguiculata) developed from a cross between two inbred, domesticated lines (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 1210-1217 
    Details
    ISSN: 1432-2242
    Keywords: Key words Vigna unguiculata ; RFLP ; RAPD ; AFLP ; Linkage map
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  We have constructed a genetic linkage map within the cultivated gene pool of cowpea (2n=2x=22) from an F8 recombinant inbred population (94 individuals) derived from a cross between the inbreds IT84S-2049 and 524B. These breeding lines, developed in Nigeria and California, show contrasting reactions against several pests and diseases and differ in several morphological traits. Parental lines were screened with 332 random RAPD decamers, 74 RFLP probes (bean, cowpea and mung bean genomic DNA clones), and 17 AFLP primer combinations. RAPD primers were twice as efficient as AFLP primers and RFLP probes in detecting polymorphisms in this cross. The map consists of 181 loci, comprising 133 RAPDs, 19 RFLPs, 25 AFLPs, three morphological/classical markers, and a biochemical marker (dehydrin). These markers identified 12 linkage groups spanning 972 cM with an average distance of 6.4 cM between markers. Linkage groups ranged from 3 to 257 cM in length and included from 2 to 41 markers, respectively. A gene for earliness was mapped on linkage group 2. Seed weight showed a significant association with a RAPD marker on linkage group 5. This map should facilitate the identification of markers that “tag” genes for pest and disease resistance and other traits in the cultivated gene pool of cowpea.
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    URL: http://dx.doi.org/10.1007/s001220050683
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    Conservation of S-locus for self-incompatibility in Brassica napus (L.) and Brassica oleracea (L.) (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 73-82 
    Details
    ISSN: 1432-2242
    Keywords: Key words Self-incompatibility ; Brassica oleracea ; Brassica napus ; RFLP ; PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Self-incompatibility (SI) in Brassica is a sporophytic system, genetically determined by alleles at the S-locus, which prevents self-fertilization and encourages outbreeding. This system occurs naturally in diploid Brassica species but is introduced into amphidiploid Brassica species by interspecific breeding, so that in both cases there is a potential for yield increase due to heterosis and the combination of desirable characteristics from both parental lines. Using a polymerase chain reaction (PCR) based analysis specific for the alleles of the SLG (S-locus glycoprotein gene) located on the S-locus, we genetically mapped the S-locus of B. oleracea for SI using a F2 population from a cross between a rapid-cycling B. oleracea line (CrGC-85) and a cabbage line (86-16-5). The linkage map contained both RFLP (restriction fragment length polymorphism) and RAPD (random amplified polymorphic DNA) markers. Similarly, the S-loci were mapped in B. napus using two different crosses (91-SN-5263×87-DHS-002; 90-DHW-1855-4×87-DHS-002) where the common male parent was self-compatible, while the S-alleles introgressed in the two different SI female parents had not been characterized. The linkage group with the S-locus in B. oleracea showed remarkable homology to the corresponding linkage group in B. napus except that in the latter there was an additional locus present, which might have been introgressed from B. rapa. The S-allele in the rapid-cycling Brassica was identified as the S29 allele, the S-allele of the cabbage was the S 5 allele. These same alleles were present in our two B. napus SI lines, but there was evidence that it might not be the active or major SI allele that caused self-incompatibility in these two B. napus crosses.
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    RFLP-based mapping of three mutant loci in rye (Secale cereale L.) and their relation to homoeologous loci within the Gramineae (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 468-473 
    Details
    ISSN: 1432-2242
    Keywords: Key words Comparative mapping ; Absence of ligules ; Waxless plant ; Waxy endosperm ; RFLP ; Secale cereale L.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Three mutant loci of rye determining absence of ligules (al), waxless plant (wa1) and waxy endosperm (Wx) characters were mapped in a single F2 population, comprising 84 individual plants. The three loci could be clearly tagged in relation to 7 (al on chromosome 2R), 4 (wa1 on chromosome 7R) or 6 (Wx on chromosome 4R) RFLP markers. The mapping data are compared with existing data for homoeologous regions containing equivalent mutants of wheat, barley, rice and maize. It is shown that the loci analysed are highly conserved across the cereal species, including rye.
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    Relationship between seed yield heterosis and molecular marker heterozygosity in soybean (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 460-467 
    Details
    ISSN: 1432-2242
    Keywords: Key words Glycine max ; RFLP ; Isozyme ; Geographic origin ; Hybrid vigor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  In soybean [Glycine max (L.) Merr.] heterosis has been reported for seed yield. Molecular markers may be useful to select diverse parents for the expression of heterosis and yield improvement. The objective of this study was to determine if molecular markers could be used to predict yield heterosis in soybean. From each Maturity Group (MG) II and III, 21 genotypes were selected on the basis of high yield (HY), different geographic origin (GO), and isozyme loci (ISO) and for diversity in restriction fragment length polymorphisms (RFLP), and crosses were made within MGs and selection criteria groups to obtain 6 F1 hybrids per group. The 21 parents and the 24 F1 hybrids of each MG were evaluated for yield in replicated tests at two locations in 2 years, and midparent heterosis (MPH) and high-parent heterosis (HPH) estimates were calculated. On the basis of hybrid performance during the first year, 12 parents (3 per selection criteria group) were chosen in each MG to conduct a second RFLP analysis using 129 probes. Genetic distances (GDM) for pairs of the 12 genotypes were calculated with this RFLP information and correlated with MPH and HPH estimates. Significant MPH averages for seed yield were observed in the combined analysis of variance in each of the four selection criteria groups of MG II, and in the HY, ISO, and GO of MG III. Significant HPH averages were observed only in the ISO and GO groups of MG II. The greatest frequency of F1 hybrids with significant MPH was observed in the ISO and GO groups of both MGs. For HPH, the greatest frequency was observed in the ISO group of both MGs. In both MGs, the ISO group had the largest absolute MPH value; the RFLP group had generally the smallest. The observations indicated that the expression of heterosis in seed yield might be associated with diversity in the isozyme loci present in the parents. For the genotypes included in the second RFLP analysis, correlations of GDMs with MPH and HPH values on an entry-mean basis were low and not significant, indicating that heterosis in yield may not be associated with genetic diversity at the molecular level as determined by RFLPs. The results suggest that in soybean, parent selection on the basis of RFLPs and isozyme loci to exploit heterosis in seed yield may not be feasible. There was no association between genetic distance estimated by the RFLP analysis and seed yield heterosis, and in spite of the observed relationship between isozyme loci and heterosis for yield, the practicality of using the isozyme markers to select parents may be limited because of the reduced number of assayable isozyme loci in soybean.
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    Identification of molecular markers linked to the Yr15 stripe rust resistance gene of wheat originated in wild emmer wheat, Triticum dicoccoides (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 622-628 
    Details
    ISSN: 1432-2242
    Keywords: Key words Gene mapping ; RAPD ; RFLP ; Stripe rust ; Triticum dicoccoides ; Triticum durum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The Yr15 gene of wheat confers resistance to the stripe rust pathogen Puccinia striiformis West., which is one of the most devastating diseases of wheat throughout the world. In the present study, molecular markers flanking the Yr15 gene of wheat have been identified using the near-isogenic-lines approach. RFLP screening of 76 probe-enzyme combinations revealed one polymorphic marker (Nor/TaqI) between the susceptible and the resistant lines. In addition, out of 340 RAPD primers tested, six produced polymorphic RAPD bands between the susceptible and the resistant lines. The genetic linkage of the polymorphic markers was tested on segregating F2 population (123 plants) derived from crosses between stripe rust-susceptible Triticum durum wheat, cv D447, and a BC3F9 resistant line carrying Yr15 in a D447 background. A 2.8-kb fragment produced by the Nor RFLP probe and a 1420-bp PCR product generated by the RAPD primer OPB13 showed linkage, in coupling, with the Yr15 gene. Employing the standard maximum-likelihood technique it was found that the order OPB13 1420 –Yr15–Nor1 on chromosome 1B appeared to be no less than 1000-times more probable than the closest alternative. The map distances between OPB13 1420 –Yr15–Nor1 are 27.1 cM and 11.0 cM for the first and second intervals, respectively. The application of marker-assisted selection for the breeding of new wheat cultivars with the stripe rust resistance gene is discussed.
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    URL: http://dx.doi.org/10.1007/s001220050604
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    Cytoplasmic-nuclear male sterility in pearl millet: comparative RFLP and transcript analyses of isonuclear male-sterile lines (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 961-968 
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    ISSN: 1432-2242
    Keywords: Key words Cytoplasmic-nuclear male sterility ; Pearl millet ; Pennisetum glaucum ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The identification of diagnostic cytoplasmic molecular markers is of prime interest to pearl millet breeders wishing to identify sources of cytoplasmic-nuclear male sterility (CMS) which can be used as an alternative to the single source currently used in the production of F1 hybrid seed. Here, we report the classification of five pearl millet CMS sources based on RFLP analysis of isonuclear lines carried out using mitochondrial gene-specific DNA probes in combination with eight restriction endonucleases. On the basis of RFLP data, the five CMS cytoplasms can be distinguished from each other and from the isonuclear fertile cytoplasm. In addition, based on cox1, cox3, atp6 and atp9 polymorphisms, these lines can be classified into two major groups: one corresponds to A5, Aegp, Av and A1 cytoplasms, and the other consists of the A4 cytoplasm. Our results suggest that a rearrangement involving the cox1 gene might be related to CMS in the first group (A5, Aegp, Av and A1), whereas a rearrangement within the atp6/cox3 cluster region might be related to CMS in the second group (A4).
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    URL: http://dx.doi.org/10.1007/s001220050648
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    Genetic diversity in Eastern U.S. soft winter wheat (Triticum aestivum L. em. Thell.) based on RFLPs and coefficients of parentage (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 472-479 
    Details
    ISSN: 1432-2242
    Keywords: Key words Genetic diversity ; RFLP ; Coefficient of parentage ; Triticum aestivum ; Gene pool
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Genetic diversity in a set of 11 red and 11 white wheat lines from the Eastern U.S. soft wheat germplasm pool was measured using restriction fragment length polymorphism (RFLP) assay and coefficients of parentage (COP) analysis. On average, 78% of all bands revealed by three enzymes with 48 RFLP clones were monomorphic. Average pairwise genetic similarity (GS) was 0.97 when data from all enzymes were pooled. Probe Polymorphic Information Content (PIC) indexes ranged from 0 to 0.73 with a mean of 0.2. Fewer than 55% of the probes revealed any polymorphism. The frequency of polymorphism in the Eastern U.S. soft white winter (SWW) wheat gene pool was much lower than that observed in the Eastern U.S. soft red winter (SRW) wheat gene pool. SWW lines formed a single group on a dendrogram based on cluster analysis of RFLP-derived GS estimates, while SRW lines did not form a single group. COP values for all pairs of the Eastern U.S. soft wheat lines ranged from 0.02 to 0.9 with a mean of 0.21. SWW wheat lines traced to 53 ancestral lines and had an average COP of 0.51. The SRW wheat gene pool had more complex parentages (mean COP=0.15 and a total of 65 ancestral lines). COPs were correlated with RFLP-based GS for all line pairs (r=0.73, P〈0.01). However, correlations between the two similarity measures were substantially lower when the SRW and SWW wheat gene pools were considered individually (r values of 0.23 and 0.28, respectively). The actual GS among unrelated lines in the U.S. Eastern soft wheat gene pool appears to be higher than that observed for unrelated landraces from Southwest Asia (0.96 vs. 0.905), suggesting that the ancestral landrace parents of this gene pool were themselves drawn from a base population where inbreeding, i.e., F, was greater than zero.
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    URL: http://dx.doi.org/10.1007/s001220050439
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    Sequence-tagged-sites (STSs) of cDNA clones in Cryptomeria japonica and their evaluation as molecular markers in conifers (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 764-772 
    Details
    ISSN: 1432-2242
    Keywords: Key words Linkage map ; RFLP ; STS ; Conifers ; Cryptomeria japonica ; cDNA ; Polymorphism ; Phylogeny ; Homology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  We have generated 66 sequence-tagged-site (STS) markers from cDNA clones of Cryptomeria japonica, and 60% of them have already been mapped into C. japonica linkage groups. All of the STS markers showed a single fragment following polymerase chain reaction (PCR) amplification. We investigated by polymorphism of these STS markers in a mapped F2 population and 15 plus trees by means of a restriction endonuclease analysis. Polymorphism levels were 10.6% and 22.7% in the F2 population and the 15 plus trees, respectively. PCR amplification levels of the 66 STS markers in 14 conifer species varied depending on their genetic relationship with C. japonica. Taxodium, which is closely related to C. japonica, had the most amplifications (31.82%), followed by Sequoiadendron giganteum, which is of the same family. The average proportion of PCR amplifications in each family gradually declined in the following order: from Taxodiaceae to Cuppresaceae, Sciadopityaceae, Pinaceae, and Taxaceae. These results are in general agreement with a molecular phylogenetic relationship based on chloroplast DNA. The 66 STS markers will be useful as on anchor point for genome mapping and population genetics, and some of them will also be useful when studying other conifers.
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    A RFLP-based linkage map of mustard [Brassica juncea (L.) Czern. and Coss.] (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 841-851 
    Details
    ISSN: 1432-2242
    Keywords: Key wordsBrassica juncea ; Mustard ; Linkage ; map ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  A genetic linkage map of Brassica juncea was constructed based on restriction fragment length polymorphism (RFLP) detected by anonymous cDNA markers from B. napus, using a segregating F1-derived doubled haploid (DH) progeny from a cross between a canola-quality mustard line (J90-4317) and a high-oil-content mustard line (J90-2733). The RFLP probes consisted of 229 cDNA probes from B. napus and a B. napus tandem repeat sequence, RDA2. The map consisted of 343 marker loci arranged in 18 major linkage groups plus five small segments with two to five marker loci, covering a total map distance of 2073 cM. Twenty-four percent of the markers were dominant in nature. Sixty-two percent of the marker loci were duplicated, and the majority were involved in inter-linkage group duplications, illustrating that complex duplications and subsequent rearrangements occurred after allopolyploidy. Deviation from the Mendelian segregation ratio for a DH population was observed for 27% of the markers. Two-thirds of these markers with a skewed segregation were clustered in 6 linkage groups and two unassigned segments. The overall average marker interval of the B. juncea map reported here was 6.6 cM, which would provide a marker density satisfactory for efficient use of the map in breeding applications, such as tagging of important agronomic traits and marker-assisted selection.
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    URL: http://dx.doi.org/10.1007/s001220050485
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    QTLs associated with chlorimuron ethyl sensitivity in soybean: Effects on seed yield and related traits (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 971-974 
    Details
    ISSN: 1432-2242
    Keywords: Key words Soybean ; Glycine max ; QTLs ; RFLP ; Chlorimuron ethyl ; Seed yield
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Soybean, Glycine max (L.) Merr., genotypes are known to differ in chlorimuron ethyl sensitivity (CS). Earlier we have reported two putatively independent marker loci linked to two quantitative trait loci (QTLs) controlling CS in a soybean population derived from a cross of PI97100 (sensitive to chlorimuron ethyl) and ‘Coker 237’ (tolerant to chlorimuron ethyl). The objective of the present study was to quantify the association of the two marker loci with seed yield and related traits in this soybean population following application of chlorimuron ethyl. Phenotypic data were collected for 111 F2-derived lines of the cross grown in replicated plots at Athens, G.A., in 1994 and 1995, and at Blackville, S.C., in 1995. The two CS marker loci explained as much as 50% of the genetic variation in seed yield and seed number m-2, but had no association with seed weight, plant height, lodging, seed protein, and seed oil. There were no epistatic interactions between the two marker loci for any of the traits. The marker locus (cr168-1 on USDA linkage group E) linked to the major CS QTL explained between 13 and 23% of the variation in seed yield. The Coker 237 allele at this locus was associated with decreased CS and increased seed yield. The marker locus (Blt015-2 on an unknown linkage group) linked to the minor CS QTL accounted for a maximum of 11% of the variation in seed yield. The Coker 237 allele at this locus was associated with an increase in CS and a decrease in seed yield. The association of the two marker loci with seed number m-2 strongly resembled their association with seed yield. Seed yield had a strong positive correlation (r=0.74 – 0.94) with seed number m-2, and the effect of chlorimuron ethyl on seed yield was due mainly to its effect on seed number m-2 rather than seed weight.
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    Evaluation of the extent of genetic variability among Theobroma cacao accessions using RAPD and RFLP markers (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 10-19 
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    ISSN: 1432-2242
    Keywords: Key words Theobroma cacao ; RFLP ; RAPD ; Genetic diversity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Random amplified polymorphic DNA (RAPD) and restriction fragment length polymorphism (RFLP) markers were used to evaluate genetic relationships within the Theobroma cacao species and to assess the organization of its genetic diversity. Genetic variability was estimated with 18 primers and 43 RFLP probes on 155 cocoa trees belonging to different morphological groups and coming from various geographic origins. The majority of the RFLP probes issued from low-copy DNA sequences. On the basis of on the genetic distance matrices, the two molecular methods gave related estimates of the genetic relationship between genotypes. Although an influence of cocoa morphological groups and geographical origins of trees was observed, a lack of gene differentiation characterized the T. cacao accessions studied. The continuous RFLP variability observed within the species may reflect the hybridization and introgressions between trees of different origins. Nevertheless, the Nacional type was detected to be genetically specific and different from well-known types such as Forastero, Criollo and Trinitario. Some of those genotypes were characterized by a low heterozygosity rate and may constitute the original Nacional pool. These results also provide information for the constitution of a cocoa tree core collection.
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    Analysis of RFLP mapping inaccuracy in Brassica napus L. (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 83-91 
    Details
    ISSN: 1432-2242
    Keywords: Key words Brassica napus ; Linkage map ; Mapping inaccuracy ; RFLP ; Segregation distortion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  We identified sources of mapping inaccuracy during the construction of RFLP linkage maps from one F2 population and two F1 microspore-derived populations from the same cross of oilseed Brassica napus. The genetic maps were compared using a total of 145 RFLP marker loci including 82 loci common to all three populations. In the process, we identified a series of mapping events that could lead to ambigous conclusions. Superimposed restriction fragments could be mistaken as a single dominant restriction fragment in a F2 population and, when analyzed as such, would yield inaccurate linkage information. Residual heterozygosity in parental lines resulted in complicated allelic assignment and yielded subsequent difficulties in linkage determination. Loose and spurious linkages occurred during mapping and were identified by comparing maps derived from different populations. LOD scores and χ2 test of independence were compared for their capacity to detect loose linkages or generate spurious ones. Extreme segregation distortions towards the same parental allele also contributed to an additional source of spurious linkage. Small but significant segregation distortions resulted in reduced estimates of the recombination fraction. The use of the same ‘probe× enzyme’ combinations in doubled haploid populations allowed the identification of the correct allele assignment as well as loose and spurious linkages. A translocation between two homoeologous linkage groups was observed. The consequences of such a chromosomal event as a source of error in mapping applications are discussed.
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    Chromosomal assignment of the nine linkage groups of sugar beet (Beta vulgaris L.) using primary trisomics (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 590-596 
    Details
    ISSN: 1432-2242
    Keywords: Key words Beta vulgaris ; Chromosomal assignment ; RFLP ; Primary trisomics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Twenty-four marker loci representing each of the nine linkage groups of sugar beet (Beta vulgaris) have been assigned to the nine primary trisomics of Butterfass (1964). Single-copy RFLP probes were hybridized with filter-bound DNA of the trisomics. The autoradiographs were scanned and analyzed by densitometric methods. Statistics on the integrated optical densities of the RFLP bands revealed a clear relationship of each linkage group to a distinct trisomic type. For the first time each of the linkage groups could unequivocally be assigned to one sugar beet chromosome. A standard nomenclature of the 9 chromosomes of sugar beet is suggested and discussed with respect to previous numbering systems.
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    The genetics of resistance to five races of downy mildew (Plasmopara halstedii) in sunflower (Helianthus annuus L.) (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 584-589 
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    ISSN: 1432-2242
    Keywords: Key words Linkage ; Major gene ; Race-specific resistance ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  These studies were undertaken to determine whether downy mildew resistance genes in sunflower were independent as first reported, or linked as suggested by more recent hypotheses. The segregations for downy mildew reaction of 111 F3 progenies from a cross between a susceptible line and a line with Pl2 were used to locate this gene on the sunflower consensus RFLP linkage map. It was shown that Pl2 was linked to the same RFLP markers on linkage group 1 as Pl1 and Pl6, mapped earlier, and at a very similar distance. The F3 progenies showed exactly the same segregation patterns when tested with race 1 and race D. One hundred and fifty four progenies from a cross between a susceptible line and HA335, containing Pl6 (considered as giving resistance to all Plasmopara halstedii races), were tested with the five French downy mildew races, 1, A, B, C and D. Two progenies were observed to show segregation for races 1 and D, while appearing homozygous-resistant to races A , B and C. Tests on F4 progenies confirmed this separation of resistances with fixation of susceptibility to races 1 and D and resistance to races A, B and C. It is concluded that the Pl6 gene is not a “strong” gene, giving resistance to all downy mildew races, but rather a cluster of genes, each providing resistance to one, or a few, downy mildew races. The genes giving resistance to races 1 and D, on one hand, and to races A, B and C, on the other hand, must be very closely linked, with about 0.6 cM between the two groups.
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    URL: http://dx.doi.org/10.1007/s001220050599
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    Chloroplast-DNA variation in the genus Lotus (Fabaceae) and further evidence regarding the maternal parentage of Lotus corniculatus L. (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 629-636 
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    ISSN: 1432-2242
    Keywords: Key words Lotus corniculatus ; Fabaceae ; cpDNA variation ; Maternal inheritance ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  To resolve the maternal parentage of the tetraploid Lotus corniculatus, restriction-site variation of chloroplast DNA (cpDNA) was studied in several accessions of that species, in the four putative parental diploid species, L. tenuis, L. alpinus, L. japonicus and L. uliginosus, and in four phylogenetically more distant diploid species, L. hispidus, L. edulis, L. ornithopodoides and Tetragonolobus maritimus var. siliquosus. Evidence of cpDNA maternal inheritance was obtained by using reciprocal controlled crosses between plants of L. corniculatus and natural tetraploid individuals of L. alpinus showing very distinct restriction patterns. Interspecific cpDNA variation in the eight Lotus species and T. siliquosus was analysed by comparing cpDNA fragment patterns produced by five restriction endonucleases and totalling 304 distinct fragments. Genetic differentiation in cpDNA was very high between the L. corniculatus group and L. hispidus on the one hand, and the three other species on the other hand. Sixteen restriction-site mutations and eight length polymorphisms were identified among the five species of the L. corniculatus group and L. hispidus, Lotus uliginosus, L. alpinus and L. japonicus showed at least six DNA changes with regard to the molecule of L. corniculatus. Accordingly, these species should be excluded as maternal progenitors of L. corniculatus. Conversely, the cpDNA of L. tenuis differed from that of L. corniculatus by only two small-length mutations. As also suggested previously from an analysis of several nuclear markers, the results reported here show decisively that L. tenuis may be considered as the most probable maternal ancestor of L. corniculatus.
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    URL: http://dx.doi.org/10.1007/s001220050605
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    Direct comparison of levels of genetic variation among barley accessions detected by RFLPs, AFLPs, SSRs and RAPDs (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 714-722 
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    ISSN: 1432-2242
    Keywords: Key words Barley ; Genetic relationships ; Molecular analysis ; RFLP ; AFLP ; RAPD ; SSR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  RFLPs, AFLPs, RAPDs and SSRs were used to determine the genetic relationships among 18 cultivated barley accessions and the results compared to pedigree relationships where these were available. All of the approaches were able to uniquely fingerprint each of the accessions. The four assays differed in the amount of polymorphism detected. For example, all 13 SSR primers were polymorphic, with an average of 5.7 alleles per primer set, while nearly 54% of the fragments generated using AFLPs were monomorphic. The highest diversity index was observed for AFLPs (0.937) and the lowest for RFLP (0.322). Principal co-ordinate analysis (PCoA) clearly separated the spring types from the winter types using RFLP and AFLP data with the two-row winter types forming an intermediate group. Only a small group of spring types clustered together using SSR data with the two-row and six-row winter varieties more widely dispersed. Direct comparisons between genetic similarity (GS) estimates revealed by each of the assays were measured by a number of approaches. Spearman rank correlation ranked over 70% of the pairwise comparisons between AFLPs and RFLPs in the same order. SSRs had the lowest values when compared to the other three assays. These results are discussed in terms of the choice of appropriate technology for different aspects of germplasm evaluation.
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    Molecular genetic mapping of dwarfing genes in oat (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 783-790 
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    ISSN: 1432-2242
    Keywords: Key words Avena sativa ; Dwarfing genes ; RFLP ; RFLP mapping ; Bulked Segregant Analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Restriction fragment length polymorphism (RFLP) analysis provides a valuable tool for characterizing and understanding relationships among genes for useful traits in crop species, particularly in ones with complex genomes such as the hexaploid cultivated oat Avena sativa L. (2n=6x=42). Using Bulked Segregant Analysis (BSA) and F2 RFLP linkage data, we mapped three dominant oat dwarfing loci to different regions of the oat genome. Dw6, in oat line OT207, is 3.3±1.3 cM from the Xumn145B locus, which has not been placed on the hexaploid oat linkage map. Dw7, in line NC2469-3, is 4.3±2.3 cM from Xcdo1437B and 33±4.1 cM from Xcdo708B. This places Dw7 to linkage group 22. Dw8, in the Japanese lines AV17/3/10 and AV18/2/4, mapped 4.9±2.2 cM from Xcdo1319A in an AV17/3/10בKanota’ F2 population and 6.6±2.6 cM from it in an AV18/2/4בKanota’ population. This places Dw8 to linkage group 3. Aneuploid analysis of markers linked to the dwarfing genes located Dw6 on the smallest oat chromosome (chromosome 18) and Dw7 on the longest satellited chromosome (chromosome 19). The RFLP markers closely linked to the three dwarfing genes identify distinct regions of the oat genome that contribute to plant height and they should be useful in characterizing new genetic sources of dwarfness in oat.
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    Comparison of the genetic maps of Brassica napus and Brassica oleracea (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 569-582 
    Details
    ISSN: 1432-2242
    Keywords: Key words Brassica napus ; Brassica oleracea ; Genetic maps ; RFLP ; RAPD
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The genus Brassica consists of several hundreds of diploid and amphidiploid species. Most of the diploid species have eight, nine or ten pairs of chromosomes, known respectively as the B, C, and A genomes. Genetic maps were constructed for both B. napus and B. oleracea using mostly RFLP and RAPD markers. For the B. napus linkage map, 274 RFLPs, 66 RAPDs, and two STS loci were arranged in 19 major linkage groups and ten smaller unassigned segments, covering a genetic distance of 2125 cM. A genetic map of B. oleracea was constructed using the same set of RFLP probes and RAPD primers. The B. oleracea map consisted of 270 RFLPs, 31 RAPDs, one STS, three SCARs, one phenotypic and four isozyme marker loci, arranged into nine major linkage groups and four smaller unassigned segments, covering a genetic distance of 1606 cM. Comparison of the B. napus and B. oleracea linkage maps showed that eight out of nine B. oleracea linkage groups were conserved in the B. napus map. There were also regions in the B. oleracea map showing homoeologies with more than one linkage group in the B. napus map. These results provided molecular evidence for B. oleracea, or a closely related 2n=18 Brassica species, as the C-genome progenitor, and also reflected on the homoeology between the A and C genomes in B. napus.
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    RFLP-based estimates of parental contribution to F2- and BC1-derived maize inbreds (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 652-656 
    Details
    ISSN: 1432-2242
    Keywords: Key words Bootstrap ; Genetic drift ; Parental contribution ; RFLP ; Selection ; Zea mays L.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Selection and genetic drift during inbreeding may cause differences between the actual and expected proportions of the genome derived by an inbred from each of its parents. We used 70 RFLP loci to determine the frequency and magnitude of deviations from the expected parental contribution among F2- and BC1-derived maize (Zea mays L.) inbreds. Assuming inbreds i and j were the parents of inbred k, the parental contribution of i to k was estimated as p=(Sik−Sij)/ (1−Sij), where Sik and Sij were the average proportions, across the ten linkage groups in maize, of RFLP loci with alleles common to the inbreds in subscript. Bootstrap confidence intervals (CIs) were obtained for p by re-sampling RFLP similarity for each linkage group. Among 62 F2-derived inbreds, 13 had estimates of p that deviated significantly from the expected value of 0.5. One F2-derived inbred obtained p=0.801 of its genome from a parent. Among 34 BC1-derived inbreds, eight had estimates of p that deviated significantly from the expected contribution of 0.75 from the recurrent parent. Two inbreds, both from the same BC1 population, had an estimated p?0.94. The results suggested that selection during backcrossing generally favored the recurrent parent over the donor parent. Among the inbreds with significant deviations from the expected p, the width of 95% CIs with 70 RFLP loci was 〉0.20. Inbreds selfed from the same F2 or BC1 population varied in p, indicating that coefficients of co-ancestry calculated from pedigree records may give erroneous estimates of genetic relationship.
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    Genome organization of Magnaporthe grisea: integration of genetic maps, clustering of transposable elements and identification of genome duplications and rearrangements (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 20-32 
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    ISSN: 1432-2242
    Keywords: Key words Rice blast ; Linkage map ; Pyricularia grisea ; RFLP ; MAGGY ; Molecular map
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  A high-density genetic map of the rice blast fungus Magnaporthe grisea (Guy11×2539) was constructed by adding 87 cosmid-derived RFLP markers to previously generated maps. The new map consists of 203 markers representing 132 independently segregating loci and spans approximately 900 cM with an average resolution of 4.5 cM. Mapping of 33 cosmid probes from the genetic map generated by Sweigard et al. has allowed the integration of two M. grisea maps. The integrated map showed that the linear order of markers along all seven chromosomes in both maps is in good agreement. Thirty of eighty seven markers were derived from cosmid clones that contained the retrotransposon MAGGY (M. grisea gypsy element). Mapping of single-copy DNA sequences associated with the MAGGY cosmids indicated that MAGGY elements are scattered throughout the fungal genome. In eight cases, the probes associated with MAGGY elements showed abnormal segregation patterns. This suggests that MAGGY may be involved in genomic rearrangements. Two RFLP probes linked to MAGGY elements, and another flanking other repetitive DNA elements, identified sequences that were duplicated in the Guy11 genome. Most of the MAGGY cosmids also contained other classes of repetitive DNA suggesting that repetitive DNA sequences tend to cluster in the M. grisea genome.
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    Mapping and marker-assisted selection for a gene for extreme resistance to potato virus Y (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 192-197 
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    ISSN: 1432-2242
    Keywords: Key words Potato virus Y ; Resistance gene ; Solanum tuberosum subsp. andigena ; Potato ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The chromosomal location of the major gene Ry adg controlling extreme resistance to potato virus Y (PVY) in Solanum tuberosum subsp. andigena was identified by RFLP analysis of a diploid potato population. A total of 64 tomato and potato RFLP markers were screened with the bulked segregant analysis (BSA) on segregants extremely resistant, hypersensitive or susceptible to PVY. Four markers TG508, GP125, CD17 and CT168 at the proximal end of chromosome XI showed close linkage with extremely resistant phenotypes. TG508 was identified as the closest marker linked with the Ry adg locus with the maximum map distance estimated as 2.0 cM. The 4 markers linked with the Ry adg locus were tested on independent tetraploid and diploid potato clones and were subsequently found useful for marker-assisted selection for plants containing Ry adg .
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    Genetic variability of the wild diploid wheat Triticum urartu revealed by RFLP and RAPD markers (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 424-430 
    Details
    ISSN: 1432-2242
    Keywords: Key words Triticum urartu ; Wheat ; A genome ; RFLP ; RAPD ; Genetic variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Genetic variability among 49 accessions of Triticum urartu was estimated by RFLP and RAPD marker analyses, and the two data sets were compared. One T. timopheevii accession and two accessions of T. durum and T. aestivum, respectively, were included to identify T. urartu accessions closely related to these polyploid wheats. Twenty eight RFLP clones and 29 RAPD primers generated 451 and 155 polymorphic bands, respectively. The three accessions from Armenia clustered together and were well separated from all other accessions, which showed less pronounced geographical patterns. Genetic similarity and co-phenetic values calculated with RAPD markers were very similar to those calculated with RFLP markers for the intraspecific comparisons, but not for the interspecific comparisons. The identification of individual T. urartu accessions which are more related to polyploid wheats than others was not possible.
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    Genetic mapping of QTL controlling tissue-culture response on chromosome 2B of wheat (Triticum aestivum L.) in relation to major genes and RFLP markers (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 1047-1052 
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    ISSN: 1432-2242
    Keywords: Key words Tissue-culture response ; Wheat ; Genetic mapping ; RFLP ; QTL
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  Three quantitative trait loci (QTL) for tissue- culture response (Tcr) were mapped on chromosome 2B of hexaploid wheat (Triticum aestivum L.) using single-chromosome recombinant lines. Tcr-B1 and Tcr-B2, affecting both green spots initiation and shoot regeneration, were mapped in relation to RFLP markers in the centromere region and on the short arm of chromosome 2B, linked to the photoperiod-response gene Ppd2. A third QTL (Tcr-B3), influencing regeneration only, was closely related to the disease resistance locus Yr7/Sr9g on the long arm of chromosome 2B. The homoeologous relationships to the tissue-culture response loci Qsr, Qcg and Shd of barley are discussed. A possible influence of the earliness per se genes of wheat and barley is suggested.
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    RFLP mapping of the Ha 2 cereal cyst nematode resistance gene in barley (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 1060-1064 
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    ISSN: 1432-2242
    Keywords: Key wordsCCN ; RFLP ; Hordeum vulgare ; Heterodera avenae ; Genetic mapping
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The cereal cyst nematode (CCN), Heterodera avenae Woll., is an economically damaging pest of barley in many of the world’s cereal-growing areas. The development of CCN-resistant cultivars may be accelerated through the use of molecular markers. A number of resistance genes against the pest are well known; one of them, the single dominant Ha 2 resistance gene, has been shown to be effective against the Australian pathotype and maps to chromosome 2 of barley. Segregation analysis identified two restriction fragment length polymorphism (RFLP) markers flanking the resistance gene in two doubled-haploid populations of barley. AWBMA 21 and MWG 694 mapped 4.1 and 6.1 cM respectively from the Ha 2 locus in the Chebec×Harrington cross and 4.0 and 9.2 cM respectively in the Clipper×Sahara cross. Analysis of a further seven sources of CCN resistance in the form of near-isogenic lines (NILs) indicates that all available sources of resistance to the Australian pathotype of CCN in barley represent the Ha 2 locus.
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    Asymmetric fusion between wild and cultivated species of potato (Solanum spp.) –detection of asymmetric hybrids and genome elimination (1997)
    Springer
    Theoretical and applied genetics 94 (1997), S. 1104-1112 
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    ISSN: 1432-2242
    Keywords: Key words Asymmetric somatic hybrids ; Flowcytometry ; RFLP ; Solanum tuberosum ; Wild species
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The objective of this study was to evaluate the suitability of different techniques for a simple and rapid identification of asymmetric hybrids, without the use of selection markers and independent of the fusion partners used. Additionally, the degree of donor DNA elimination was determined. Among 473 viable plants obtained from asymmetric fusion experiments between three di-haploid breeding lines of potato (Solanum tuberosum) and diploid wild species (S. bulbocastanum, S. circaeifolium; X-ray treatment of the wild species) the most promising ones were investigated with three different methods: flow cytometry, RFLP analysis with an oligonucleotide probe (GATA)4, and with single-copy probes. Flow cytometry, which combines a high screening capacity with detailed information about the DNA content and allows a distinction between asymmetric hybrids and chimeras, detected 31 hypo-tetraploid and 42 hypo-hexaploid regenerates among 224 plants. With the oligonucleotide probe (GATA)4 only a few asymmetric hybrids were detected among all regenerates. More than 50% of these asymmetric regenerates were chimeras. Concerning the degree of DNA elimination, the results obtained by RFLP analysis with 17 single-copy probes were correlated with the results obtained by flow cytometry. The maximum DNA elimination of the donor genome was 52%. As a trend, an irradiation dosage of 210 Gy caused a higher DNA elimination in the wild species than a dosage of 70 Gy. No calli were obtained after irradiation of the wild species with 420 Gy.
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    High-resolution genetical and physical mapping of the Rx gene for extreme resistance to potato virus X in tetraploid potato (1997)
    Springer
    Theoretical and applied genetics 95 (1997), S. 153-162 
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    ISSN: 1432-2242
    Keywords: Key words PVX ; Resistance gene ; Mapping ; RFLP ; AFLP ; CAPS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  The Rx locus in potato confers extreme resistance to PVX. In the F1 progeny of crosses between the PVX-susceptible cultivar Huinkel and the cultivar Cara (Rx genotype) there was a 1 : 1 segregation of PVX resistance, indicating that Rx in Cara is present in the simplex condition. Using potato and tomato RFLP markers, we mapped Rx in Cara to the distal end of chromosome XII at a different position to the previously mapped Rx1 locus. To generate a high-resolution linkage map in the vicinity of Rx a total 728 AFLP primer combinations were screened using DNA of bulked resistant and susceptible segregants. We also screened segregating populations for chromosomal recombination events linked to the Rx locus and identified 82 plants with recombination events close to Rx. Using these recombinant plants we have identified AFLPs that flank Rx and span an interval of 0.23 cM in a region of the genome where 1 cM corresponds to approximately 400 kb.
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    Lanceispora amphibia gen. et sp. nov., a new amphisphaeriaceous ascomycete inhabiting senescent and fallen leaves of mangrove (1997)
    Springer
    Mycoscience 38 (1997), S. 207-213 
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    ISSN: 1618-2545
    Keywords: Bruguiera gymnorrhiza ; ecology ; Lanceispora amphibia ; mangrove ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    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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    Taxonomical studies on ovariicolous ustomycetes on caryophyllaceae I.Ustilago jehudana andUstilago moenchiae-manticae (1997)
    Springer
    Mycoscience 38 (1997), S. 323-328 
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    ISSN: 1618-2545
    Keywords: Bauhinus ; Microbotryum ; taxonomy ; Ustilago ; ustomycetes
    Source: Springer Online Journal Archives 1860-2000
    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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    A synopsis of the genusScleromitrula (=Verpatinia) (Ascomycotina: Helotiales: Sclerotiniaceae) (1997)
    Springer
    Mycoscience 38 (1997), S. 55-69 
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    ISSN: 1618-2545
    Keywords: discomycetes ; ITS rDNA phylogeny ; morphology ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    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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    Ypsilonidium bananisporum sp. nov. (Ceratobasidiales) from Iriomote Island, Japan (1997)
    Springer
    Mycoscience 38 (1997), S. 71-73 
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    ISSN: 1618-2545
    Keywords: Ceratobasidiaceae ; Japan ; taxonomy ; Ypsilonidium bananisporum
    Source: Springer Online Journal Archives 1860-2000
    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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    Myxomycetes from Israel IV (1997)
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    Mycoscience 38 (1997), S. 87-89 
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    ISSN: 1618-2545
    Keywords: Israel ; Mycomycetes ; Physarales ; Stemonitales ; taxonomy
    Source: Springer Online Journal Archives 1860-2000
    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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    Mycoleptodiscus terrestris from black pepper roots in the Dominican Republic (1997)
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    Mycoscience 38 (1997), S. 91-94 
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    ISSN: 1618-2545
    Keywords: hyphomycetes ; identification ; taxonomy ; Tuberculariaceae ; Tuberculariales
    Source: Springer Online Journal Archives 1860-2000
    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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    Microsphaeropsis rugospora, a new species from Japanese soil (1997)
    Springer
    Mycoscience 38 (1997), S. 429-431 
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    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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    Different levels of morphometric variation in three heterogamous dogrose species (Rosa sect.Caninae, Rosaceae) (1997)
    Springer
    Plant systematics and evolution 204 (1997), S. 207-224 
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    ISSN: 1615-6110
    Keywords: Rosaceae ; Rosa sect.Caninae ; Systematics ; taxonomy ; genetic variation ; hemisexual ; apomixis
    Source: Springer Online Journal Archives 1860-2000
    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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    Anchusella, a new genus ofBoraginaceae from the Central-Eastern Mediterranean (1997)
    Springer
    Plant systematics and evolution 205 (1997), S. 241-264 
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    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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    Genetic analysis of aMicroseris douglasii (Asteraceae) population polymorphic for an alien chloroplast type (1997)
    Springer
    Plant systematics and evolution 206 (1997), S. 273-284 
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    ISSN: 1615-6110
    Keywords: Asteraceae ; Microseris ; Chloroplast introgression ; reticulate evolution ; RAPD ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Recent evidence suggests chloroplast introgression fromMicroseris bigelovii intoM. douglasii. We have examined 23 plants from a population ofM. douglasii polymorphic forM. douglasii andM. bigelovii chloroplast types. All 23 plants were completely homozygous for morphological and RAPD markers, and inbred lines derived by selfing have been used for DNA analysis. Chloroplast RFLP analysis identified 16 plants withM. bigelovii chloroplasts and seven withM. douglasii chloroplasts. The nuclear genomes of the 16 plants withM. bigelovii chloroplasts were examined with 22 primers for RAPD amplification products shared exclusively withM. bigelovii. Five of 268 markers appeared to be shared betweenM. bigelovii and one or more of these 16 plants on the basis of their position in gels. Detailed examination of these five amplification products showed that none of them are nuclear DNA fromM. bigelovii. Very little, if any, nuclear DNA fromM. bigelovii can be present inM. douglasii plants with chloroplasts typical ofM. bigelovii. The study demonstrates the usefulness of the RAPD technique for screening large numbers of markers to select a few potentially informative ones for rigorous examination.
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    Comparative HPLC analysis of seed albumins fromVicia faba andV. kalakhensis (Fabaceae) (1997)
    Springer
    Plant systematics and evolution 208 (1997), S. 1-9 
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    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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    Electrophoretic seed albumin patterns inVicia species of sectt.Hypechusa andPeregrinae (Fabaceae) (1997)
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    Plant systematics and evolution 208 (1997), S. 239-248 
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    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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    Distribution of photo-induced and non-photo-induced sporulator physiotypes ofBipolaris oryzae in Japan (1997)
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    Mycoscience 38 (1997), S. 147-153 
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    ISSN: 1618-2545
    Keywords: Bipolaris oryzae ; mycochrome ; photo-control of conidiation ; RAPD ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The distribution of three sporulator physiotypes ofBipolaris oryzae, namely, photo-induced, and non-photo-induced (I) and (II), was investigated. Of 407 isolates, 99% belonged to the photo-induced type, in which conidial development was under photo-control of the antagonistic action of blue/UV-A and near-UV radiation mediated through the ‘mycochrome’ system at conidiophore induction and conidiophore maturation stages. Of the remainder, 1 isolate belonged to the non-photo-induced (I) type, and 4 isolates belonged to the non-photo-induced (II) type. Conidial development in the former of these was photo-controlled by the ‘mycochrome’ system at conidiophore maturation stage alone, while in the latter it was not affected by light conditions. No difference was found between the three physiotypes in restriction fragment length polymorphisms (RFLPs) of rDNA. However, random amplified polymorphic DNA (RAPD) revealed polymorphisms between photo-induced and non-photo-induced isolates and showed that non-photo-induced (I) and (II) strains were clustered in the same group, suggesting that they are genetically close. Photo-induced sporulators ofB. oryzae were confirmed to be widely distributed in paddy fields in Japan.
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    Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy (1997)
    Springer
    Investigational new drugs 15 (1997), S. 227-234 
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    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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    Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS (1997)
    Springer
    Investigational new drugs 15 (1997), S. 195-206 
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    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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    Marker-assisted transfer of acylsugar-mediated pest resistance from the wild tomato, Lycopersicon pennellii, to the cultivated tomato, Lycopersicon esculentum (1997)
    Springer
    Molecular breeding 3 (1997), S. 307-317 
    Details
    ISSN: 1572-9788
    Keywords: insect resistance ; marker-assisted selection ; PCR ; quantitative trait loci ; RAPD ; RFLP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Acylsugars exuded from type IV trichomes mediate the multiple pest resistance found in the wild tomato species, Lycopersicon pennellii. A marker-assisted selection breeding program was used to attempt the transfer of the ability to accumulate acylsugars to cultivated tomato. RFLP and PCR-based markers were used through three backcross generations to select plants containing 5 target regions associated by QTL analysis with acylsugar accumulation. The BC1F1 plant selected possessed all 5 target regions and accumulated acylsugars at a moderate level similar to that of the interspecific F1 control. The BC2F1 and BC3F1 selections contained complementary subsets of the 5 target regions and did not accumulate acylsugars. BC3F1 plants with complementary subsets of the 5 target regions were intermated to produce populations segregating for the 5 target regions. From 1000 BC3F1-intermated plants, three plants were found which accumulated acylsugars at low levels and contained 3 to 5 of the target regions. The recovery of acylsugar accumulation in progeny of the intermated BC3F1 plants supports the involvement of at least some of the 5 target regions in acylsugar biosynthesis. However, since the levels of acylsugars accumulated by these plants were lower than that of the interspecific F1, it is likely that another, as of yet unidentified, region is necessary for accumulation of higher levels of acylsugars.
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    Genetic dissection of herbicide tolerance in maize by molecular markers (1997)
    Springer
    Molecular breeding 3 (1997), S. 481-493 
    Details
    ISSN: 1572-9788
    Keywords: Alachlor ; herbicide tolerance ; maize ; RFLP ; SSR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract In order to detect the genetic architecture of maize tolerance to Alachlor, a widely used chloroacetanilide, linkage analysis between the expression of the trait and allelic composition of molecular markers was performed. The experiment was carried out on a population of 142 recombinant inbred lines, developed starting from the F1 between two lines with different reactivity to the herbicide, and self-fertilized for 10 generations; the lines were typed by 48 RFLP markers and 66 microsatellites (SSR). Besides seedling tolerance, evaluated as proportion of normal (non-injured) plants after herbicide treatment, other minor components of tolerance were studied: seed germination ability, pollen germination and tube growth in the presence of the herbicide. The analysis, performed by three statistical methods, revealed the presence of factors controlling seedling tolerance on seven chromosomal regions. Five QTLs appeared to be involved in seed germination ability in the presence of Alachlor, four QTLs in pollen tolerance in terms of germination and four in tube growth under stress were detected. Three loci, on chromosomes 1, 7 and 10, explained most of the variation of seedling tolerance, thus being interesting candidate for marker-assisted selection.
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    Pharmacokinetic–Pharmacodynamic Modeling of Doxacurium: Effect of Input Rate (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 23-37 
    Details
    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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    Mathematical Formalism for the Properties of Four Basic Models of Indirect Pharmacodynamic Responses (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 107-123 
    Details
    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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    Pharmacokinetic-Based Minibolus Delivery as an Alternative to Continuous Infusion for Drugs That Exhibit a Biophase Lag (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 191-208 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1025732129798
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    A Tracer Interaction Method for Nonlinear Pharmacokinetics Analysis: Application to Evaluation of Nonlinear Elimination (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 569-593 
    Details
    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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    Molecular records of micro-evolution within the Algerian population of Fusarium oxysporum f. sp. albedinis during its spread to new oases (1997)
    Springer
    European journal of plant pathology 103 (1997), S. 485-490 
    Details
    ISSN: 1573-8469
    Keywords: bayoud disease ; date palm ; population genetics ; RAPD ; RFLP ; VCG
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The genetic diversity of the date palm wilt pathogen Fusarium oxysporum f. sp. albedinis in Algeria was assessed using vegetative compatibility, restriction fragment length polymorphism (RFLP) of mitochondrial DNA (mtDNA), and random amplified polymorphic DNA (RAPD). Ninety-eight isolates were collected from the main infested regions, Touat, Gourara and Mzab, and 6 isolates from Morocco were added for comparison. All isolates were vegetatively compatible and belonged to VCG 0170. No variation was detected in the mtDNA of a subset of 73 isolates and the RAPD analysis indicated that they were genetically very closely related. However, some geographic substructuring was apparent, suggesting that local diversification of the pathogen might have occurred. These results provide evidence that the Algerian isolates of F. oxysporum f. sp. albedinis belong to a same clonal lineage and support the hypothesis that they were probably founded by a single virulent clone that originated from the Moroccan oases where the date palm wilt (Bayoud disease) was first detected. Based on similarity of RAPD patterns occurring in different oases, and on historical records of the Bayoud disease in Algeria, spread of the pathogen in the different regions is discussed.
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    Mixed Effect Modeling of Sumatriptan Pharmacokinetics During Drug Development. I: Interspecies Allometric Scaling (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 149-167 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1025728028890
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    Quantitative Structure-Pharmacokinetics Relationships: I. Development of a Whole-Body Physiologically Based Model to Characterize Changes in Pharmacokinetics Across a Homologous Series of Barbiturates in the Rat (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 277-312 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; physiologically based model ; homologous series ; barbiturates ; parameter optimization
    Source: Springer Online Journal Archives 1860-2000
    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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    New Mathematical Implementation of Generalized Pharmacodynamic Models: Method and Clinical Evaluation (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 313-348 
    Details
    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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    Similarity or Discrepancy in Pharmacokinetic Parameter Estimation Between Bolus and Infusion Studies (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 471-476 
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    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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    Bioavailability Assessment from Pharmacologic Data: Method and Clinical Evaluation (1997)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 349-362 
    Details
    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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    On a new species of Fabaeformiscandona KRSTIC, 1972 (Crustacea, Ostracoda) from China, with a preliminary checklist of Recent Chinese non-marine ostracods (1997)
    Springer
    Hydrobiologia 357 (1997), S. 117-128 
    Details
    ISSN: 1573-5117
    Keywords: taxonomy ; Ostracoda ; China ; ancient lakes ; saline lakes ; biogeography ; checklist ; Fabaeformiscandona danielopoli n.sp.
    Source: Springer Online Journal Archives 1860-2000
    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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    Tree-thinking and nemertean systematics, with a systematization of the Eureptantia (1997)
    Springer
    Hydrobiologia 365 (1997), S. 33-46 
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    ISSN: 1573-5117
    Keywords: Phylogeny ; cladistics ; taxonomy ; systematics ; classification ; evolution ; history ; chronicle ; Nemertea ; Hoplonemertea
    Source: Springer Online Journal Archives 1860-2000
    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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    Lecanid rotifers (Rotifera: Monogononta: Lecanidae) from North-Eastern India (1997)
    Springer
    Hydrobiologia 356 (1997), S. 157-163 
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    ISSN: 1573-5117
    Keywords: Lecanidae ; N.E. India ; Tripura ; taxonomy ; distribution
    Source: Springer Online Journal Archives 1860-2000
    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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    Branchinella maduraiensis Raj (Crustacea, Branchiopoda, Anostraca) shown by new evidence to be a valid species (1997)
    Springer
    Hydrobiologia 359 (1997), S. 93-99 
    Details
    ISSN: 1573-5117
    Keywords: Branchiopoda ; Branchinella ; taxonomy ; morphology ; India
    Source: Springer Online Journal Archives 1860-2000
    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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    Alona stochi n.sp. – the third cave-dwelling cladoceran (Crustacea: Cladocera) from the Dinaric region (1997)
    Springer
    Hydrobiologia 360 (1997), S. 47-54 
    Details
    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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    Moina ephemeralis n.sp. from Central Europe (1997)
    Springer
    Hydrobiologia 360 (1997), S. 55-61 
    Details
    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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    Spinalona anophtalma, n. gen. n. sp. (Anomopoda, Chydoridae) a blind epigean cladoceran from the Neovolcanic Province of Mexico (1997)
    Springer
    Hydrobiologia 353 (1997), S. 19-28 
    Details
    ISSN: 1573-5117
    Keywords: Cladocera ; chydoridae ; taxonomy ; Mexico ; aloninae
    Source: Springer Online Journal Archives 1860-2000
    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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    URL: http://dx.doi.org/10.1023/A:1003053332275
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    Marine nematodes of the family Draconematidae (Nemata): a synthesis with phylogenetic relationships (1997)
    Springer
    Hydrobiologia 357 (1997), S. 185-202 
    Details
    ISSN: 1573-5117
    Keywords: marine nematodes ; Draconematidae ; Bathychaetosoma ; taxonomy ; revision ; phylogeny
    Source: Springer Online Journal Archives 1860-2000
    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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    URL: http://dx.doi.org/10.1023/A:1003155424665
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    A note on the Diaptomidae of Thailand, including redescription of three species and description of a new species (Copepoda, Calanoida) (1997)
    Springer
    Hydrobiologia 361 (1997), S. 201-223 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1003135200559
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    The morphology of Micrura leidyi (Verrill, 1892) with consequent systematic revaluation (1997)
    Springer
    Hydrobiologia 365 (1997), S. 149-156 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1003147029909
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    Characterization of Poly(glycolide-co-D,L-lactide)/Poly(D,L-lactide) Microspheres for Controlled Release of GM-CSF (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1422-1430 
    Details
    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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    Pharmacokinetic and Pharmacological Profiles of Free and Liposomal Recombinant Human Erythropoietin After Intravenous and Subcutaneous Administrations in Rats (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1621-1628 
    Details
    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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    Pharmacokinetic Model of Ascorbic Acid in Healthy Male Volunteers During Depletion and Repletion (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1133-1139 
    Details
    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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    Comparative Pharmacokinetics and Pharmacodynamics of Two Recomhinant Human Interferon Beta-la (IFNβ-la) Products Administered Intramuscularly in Healthy Male and Female Volunteers (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 546-549 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1012128406432
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    Cyclodextrins: Their Future in Drug Formulation and Delivery (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 556-567 
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    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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    URL: http://dx.doi.org/10.1023/A:1012136608249
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    Validation of a Decision Support System for Use in Drug Development: Pharmacokinetic Data (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1287-1297 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1012191831815
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    The Pharmacokinetics and Electroencephalogram Response of Remifentanil Alone and in Combination with Esmolol in the Rat (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1817-1823 
    Details
    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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    Drug Equilibration Across the Blood—Brain Barrier-Pharmacokinetic Considerations Based on the Microdialysis Method (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 128-134 
    Details
    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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    The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 152-155 
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    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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    Pharmacokinetics and Antiepileptic Activity of Valproyl Hydroxamic Acid Derivatives (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 213-217 
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    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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    Assessment of Dose Proportionality, Absolute Bioavailability, and Immunogenicity Response of CTLA4Ig (BMS-188667), a Novel Immunosuppressive Agent, Following Subcutaneous and Intravenous Administration to Rats (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 911-916 
    Details
    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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    Prospective Use of Population Pharmacokinetics/ Pharmacodynamics in the Development of Cisatracurium (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 91-97 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012015719694
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