bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations of the glucose metabolism in a triose phosphate isomerase‐negative Saccharomyces cerevisiae mutant
Authors: Compagno Concetta , Brambilla Luca , Capitanio Daniele , Boschi Francesco , Maria Ranzi Bianca , Porro Danilo 
Published: September 2002

AbstractThe absence of triose phosphate isomerase activity causes an accumulation of only one of the two trioses, dihydroxyacetone phosphate, and this produces a shift in the final product of glucose catabolism from ethanol to glycerol (Compagno et al., 1996). Alterations of glucose metabolism imposed by the deletion of the TPI1 gene in Saccharomyces cerevisiae were studied in batch and continuous cultures. The Δtpi1 null mutant was unable to grow on glucose as the sole carbon source. The addition of ethanol or acetate in media containing glucose, but also raffinose or galactose, relieved this effect in batch cultivation, suggesting that the Crabtree effect is not the primary cause for the mutant's impaired growth on glucose. The addition of an energy source like formic acid restored glucose utilization, suggesting that a NADH/energy shortage in the Δtpi1 mutant could be a cause of the impaired growth on glucose. The amount of glycerol production in the Δtpi1 mutant could represent a good indicator of the fraction of carbon source channelled through glycolysis. Data obtained in continuous cultures on mixed substrates indicated that different contributions of glycolysis and gluconeogenesis, as well as of the HMP pathway, to glucose utilization by the Δtpi1 mutant may occur in relation to the fraction of ethanol present in the media. Copyright © 2001 John Wiley & Sons, Ltd.
ON A GENERALIZED LORENZ CANONICAL FORM OF CHAOTIC SYSTEMS
Authors: ČELIKOVSKÝ SERGEJ , CHEN GUANRONG 
Published: September 2002

This paper shows that a large class of systems, introduced in [Čelikovský & Vaněček, 1994; Vaněček & Čelikovský, 1996] as the so-called generalized Lorenz system, are state-equivalent to a special canonical form that covers a broader class of chaotic systems. This canonical form, called generalized Lorenz canonical form hereafter, generalizes the one introduced and analyzed in [Čelikovský & Vaněček, 1994; Vaněček & Čelikovský, 1996], and also covers the so-called Chen system, recently introduced in [Chen & Ueta, 1999; Ueta & Chen, 2000].Thus, this new generalized Lorenz canonical form contains as special cases the original Lorenz system, the generalized Lorenz system, and the Chen system, so that a comparison of the structures between two essential types of chaotic systems becomes possible. The most important property of the new canonical form is the parametrization that has precisely a single scalar parameter useful for chaos tuning, which has promising potential in future engineering chaos design. Some other closely related topics are also studied and discussed in the paper.
Automatic Labeling of Semantic Roles
Authors: Gildea Daniel , Jurafsky Daniel 
Published: September 2002

We present a system for identifying the semantic relationships, or semantic roles, filled by constituents of a sentence within a semantic frame. Given an input sentence and a target word and frame, the system labels constituents with either abstract semantic roles, such as Agent or Patient, or more domain-specific semantic roles, such as Speaker, Message, and Topic. The system is based on statistical classifiers trained on roughly 50,000 sentences that were hand-annotated with semantic roles by the FrameNet semantic labeling project. We then parsed each training sentence into a syntactic tree and extracted various lexical and syntactic features, including the phrase type of each constituent, its grammatical function, and its position in the sentence. These features were combined with knowledge of the predicate verb, noun, or adjective, as well as information such as the prior probabilities of various combinations of semantic roles. We used various lexical clustering algorithms to generalize across possible fillers of roles. Test sentences were parsed, were annotated with these features, and were then passed through the classifiers. Our system achieves 82% accuracy in identifying the semantic role of presegmented constituents. At the more difficult task of simultaneously segmenting constituents and identifying their semantic role, the system achieved 65% precision and 61% recall. Our study also allowed us to compare the usefulness of different features and feature combination methods in the semantic role labeling task. We also explore the integration of role labeling with statistical syntactic parsing and attempt to generalize to predicates unseen in the training data.
Levodopa pharmacokinetic‐pharmacodynamic modeling and 6‐[18F]levodopa positron emission tomography in patients with Parkinson's disease
Authors: Dietz M. , Harder S. , Graff J. , Künig G. , Vontobel P. , Leenders K.L. , Baas H. 
Published: August 2002

ObjectiveParameters of a pharmacokinetic‐pharmacodynamic (PK‐PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6‐fluorine 18, an established imaging method for striatal dopaminergic neurons.MethodsTwenty‐three patients in different disease stages (Hoehm and Yahr stage 2.5–5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427–42]; median duration, 12 years) were studied. PK‐PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSΣ) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal Emax model was applied to the PK‐PD analysis of plasma levodopa concentrations and corresponding CURSΣ. Thereafter 6‐[18F]levodopa PET was performed, and the influx rate constants (kc) for the putamen and the caudatus region were correlated with the median effective concentration (EC50) and the equilibrium half‐life (Teq) of the PK‐PD model.Results(1) A significant correlation was observed between PK‐PD parameters or with kc putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC50, 42% of the variability of Teq, and 36% of the variability of kc. (2) Significant correlations were observed between kc and either EC50 or Teq, yielding the closest correlation for the putamen region (r = −0.47, P < .05; and r = 0.55, P < .01; respectively).ConclusionsOur findings show that key parameters of a PK‐PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6‐[18F]levodopa PET. However, although PK‐PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.Clinical Pharmacology & Therapeutics (2001) 70, 33–41; doi: 10.1067/mcp.2001.116328
Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine
Authors: Dresser George K. , Bailey David G. , Leake Brenda F. , Schwarz Ute I. , Dawson Paul A. , Freeman David J. , Kim Richard B. 
Published: August 2002

ObjectivesOur objective was to examine the effect of different fruits and their constituents on P‐glycoprotein and organic anion transporting polypeptide (OATP) activities in vitro and on drug disposition in humans.MethodsP‐glycoprotein–mediated digoxin or vinblastine efflux was determined in polarized epithelial cell monolayers. OATP‐mediated fexofenadine uptake was measured in a transfected cell line. The oral pharmacokinetics of 120 mg fexofenadine was assessed with water, 25%‐strength grapefruit juice, or normal‐strength grapefruit, orange, or apple juices (1.2 L over 3 hours) in a randomized 5‐way crossover study in 10 healthy subjects.ResultsGrapefruit juice and segments and apple juice at 5% of normal strength did not alter P‐glycoprotein activity. Grapefruit extract reduced transport. 6′,7′‐Dihydroxybergamottin had modest inhibitory activity (50% inhibitory concentration [IC50], 33 μmol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP and rat oatp activity. 6′,7′‐Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC50, 0.28 μmol/L). Other furanocoumarins and bioflavonoids also reduced rat oatp3 activity. Grapefruit, orange, and apple juices decreased the fexofenadine area under the plasma concentration–time curve (AUC), the peak plasma drug concentration (Cmax), and the urinary excretion values to 30% to 40% of those with water, with no change in the time to reach Cmax, elimination half‐life, renal clearance, or urine volume in humans. Change in fexofenadine AUC with juice was variable among individuals and inversely dependent on value with water.ConclusionsFruit juices and constituents are more potent inhibitors of OATPs than P‐glycoprotein activities, which can reduce oral drug bioavailability. Results support a new model of intestinal drug absorption and mechanism of food‐drug interaction.Clinical Pharmacology & Therapeutics (2002) 71, 11–20; doi: 10.1067/mcp.2002.121152
Pharmacokinetics of losartan and its metabolite E‐3174 in relation to the CYP2C9 genotype
Authors: Yasar Ümit , Forslund‐Bergengren Cecilia , Tybring Gunnel , Dorado Pedro , LLerena Adrián , Sjöqvist Folke , Eliasson Erik , Dahl Marja‐Liisa 
Published: August 2002

Background And AimLosartan is metabolized by polymorphic CYP2C9 to E‐3174. Our aim was to evaluate the pharmacokinetics of losartan and E‐3174 in relation to the CYP2C9 genotype.MethodsA 50‐mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E‐3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E‐3174 were analyzed in 8‐hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan.ResultsThe maximum plasma concentration of E‐3174 was significantly (P < .05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration–time curve (AUC) to the total E‐3174 AUC (AUClosartan/AUCE‐3174) was higher in the subject with the CYP2C9*3/*3 genotype (30‐fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2‐ and 3‐fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0‐ to 8‐hour urinary losartan/E‐3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P < .01) and approximately 40‐fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3).ConclusionThe CYP2C9*3 allele was shown to be associated with decreased formation of E‐3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E‐3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E‐3174 ratio in 0‐ to 8‐hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this.Clinical Pharmacology & Therapeutics (2002) 71, 89–98; doi: 10.1067/mcp.2002.121216
CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity
Authors: García‐Martín Elena , Martínez Carmen , Pizarro Rosa M. , García‐Gamito Francisco J. , Gullsten Harriet , Raunio Hannu , Agúndez José A. G. 
Published: August 2002

ObjectiveOur objective was to evaluate the presence of CYP3A4 gene variants in white individualswith low CYP3A4 enzyme activity.MethodsPersons with extremely low enzyme activity, either in vitro or in vivo, were selected in a panel of 97 healthy subjects. Genetic analyses for CYP3A4 variant alleles present in white subjects, including CYP3A4*1B, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, and CYP3A4*13, were performed on genomic deoxyribonucleic acid from these subjects by amplification‐restriction and sequencing.ResultsWith the exception of CYP3A4*1B, none of the variant alleles analyzed were present in30 genes from persons with extremely low enzyme activity. CYP3A4*1B was present in the population studied with an allele frequency of 5.5%. Nevertheless, the presence of CYP3A4*1B does not correlate with low enzyme activity, either in vivo or in vitro, in either heterozygosity or homozygosity. CYP3A4*2 was not identified in 290 genes from Spanish persons or in 70 genes from Finnish persons.ConclusionsAlthough the genetic component of the interindividual variability of CYP3A4 enzyme activity seems to be high, our findings do not support a key role for the variant alleles analyzed on the majority of white persons with low CYP3A4 activity. This suggests the occurrence of as yet unknown mutations that affect CYP3A4 orother functionally related genes.Clinical Pharmacology & Therapeutics (2002) 71, 196–204; doi: 10.1067/mcp.2002.121371
The value of plasma acetaminophen half‐life in antidote‐treated acetaminophen overdosage
Authors: Schiødt Frank Vinholt , Ott Peter , Christensen Erik , Bondesen Stig 
Published: August 2002

BackgroundA plasma acetaminophen (INN, paracetamol) half‐life of more than 4 hours has been correlated with hepatotoxicity in acetaminophen overdosing not treated with an antidote. Acetaminophen half‐life has not been studied in patients receiving the antidote N‐acetylcysteine.MethodsProspectively, 112 patients with acetaminophen overdosage all treated with intravenous N‐acetylcysteine were studied. A minimum of 2 plasma acetaminophen values >20 μmol/L were available for calculation of acetaminophen half‐life, assuming first‐order kinetics.ResultsOverall, the median acetaminophen half‐life was 5.4 hours (range, 0.8‐119.7 hours). Forty‐eight patients with no or little hepatotoxicity (ALT <1000 U/L), 43 patients with hepatotoxicity without encephalopathy, and 21 patients with hepatotoxicity and encephalopathy had acetaminophen half‐lives of 3.0 hours (range, 0.8‐10.0 hours), 6.4 hours (range, 1.3‐19.0 hours), and 18.4 hours (range, 4.6‐119.7 hours), respectively (P < .001). An acetaminophen half‐life >4 hours was observed in 71 patients, and 56 of those (79%) had hepatotoxicity(ALT >1000 U/L or coma). Thirty‐three of 41 patients (81%) with an acetaminophen half‐life <4 hours had no hepatotoxicity. A receiver operating characteristic curve analysis showed that an acetaminophen half‐life of 5.5 hours provided better discrimination; hepatotoxicity was therefore present in 49 of 54 patients with an acetaminophen half‐life >5.5 hours (positive predictive value, 91%) and in 15 of 58 patients with a half‐life below this limit (negative predictive value, 74%) despite treatment with N‐acetylcysteine.ConclusionsAcetaminophen half‐life correlates well with the degree of liver damage in patients treated with the antidote N‐acetylcysteine. Longer half‐lives reflect a greater toxic effect on the liver.Clinical Pharmacology & Therapeutics (2002) 71, 221–225; doi: 10.1067/mcp.2002.121857
Acute effect of L‐796568, a novel β3‐adrenergic receptor agonist, on energy expenditure in obese men
Authors: van Baak Marleen A. , Hul Gabby B. J. , Toubro Søren , Astrup Arne , Gottesdiener Keith M. , DeSmet Marina , Saris Wim H. M. 
Published: August 2002

ObjectiveOur objective was to investigate the thermogenic efficacy of single oral doses of the novel β3‐adrenergic receptor agonist L‐796568 [(R)‐N‐[4‐[2‐[[2‐hydroxy‐2‐(3‐pyridinyl)ethyl]amino]ethyl]‐phenyl]‐4‐[4‐[4‐(trifluoromethyl)phenyl]thiazol‐2‐yl]‐benzenesulfonamide, dihydrochloride] inhumans.MethodsTwelve healthy overweight to obese men participated in this 2‐center, 3‐period, randomized, placebo‐controlled, crossover trial. In each period subjects received 250 mg L‐796568, 1000 mg L‐796568, or placebo. Energy expenditure and respiratory quotient were determined by indirect calorimetry; blood samples were taken; and ear temperature, heart rate, and blood pressure were measured at baseline and during the 4‐hour period after administration.ResultsEnergy expenditure increased significantly after the 1000‐mg dose (about 8%) and this was accompanied by an increase in plasma glycerol and free fatty acid concentrations. Systolic blood pressure also increased significantly. No changes in heart rate, diastolic blood pressure, ear temperature, plasma catecholamine, potassium, orleptin were found.ConclusionsSingle‐dose administration of 1000 mg of the novel β3‐adrenergic receptor agonist L‐796568 increased lipolysis and energy expenditure in overweight men. This is the first study to show such an effect of β3‐adrenergic receptor agonists in humans without significant evidence for β2‐adrenergic receptor involvement.Clinical Pharmacology & Therapeutics (2002) 71, 272–279; doi: 10.1067/mcp.2002.122527
Raised Visual Detection Thresholds Depend on the Level of Complexity of Cognitive Foveal Loading
Authors: Plainis Sotiris , Murray Ian J , Chauhan Kamlesh 
Published: August 2002

The objective of the study was to measure the interactions between visual thresholds for a simple light (the secondary task) presented peripherally and a simultaneously performed cognitive task (the primary task) presented foveally. The primary task was highly visible but varied according to its cognitive complexity. Interactions between the tasks were determined by measuring detection thresholds for the peripheral task and accuracy of performance of the foveal task. Effects were measured for 5, 10, 20, and 30 deg eccentricity of the peripherally presented light and for three levels of cognitive complexity. Mesopic conditions (0.5 lx) were used. As expected, the concurrent presentation of the foveal cognitive task reduced peripheral sensitivity. Moreover, performance of the foveal task was adversely affected when conducting the peripheral task. Performance on both tasks was reduced as the level of complexity of the cognitive task increased. There were qualitative differences in task interactions between the central 10 deg and at greater eccentricities. Within 10 deg there was a disproportionate effect of eccentricity, previously interpreted as the ‘tunnel-vision’ model of visual field narrowing. Interactions outside 10 deg were less affected by eccentricity. These results are discussed in terms of the known neurophysiological characteristics of the primary visual pathway.
Braided Inflatable Tubular Structure Technology in Crash Safety
Authors: Mowry Greg , Head Andrew 
Published: August 2002

Most innovations may account for the use of non-conventional tools in current situations or the use of current tools in non-conventional situations. This paper describes the relationship of braided structure technology to the implementation of air bags in crash safety technology. The first introduction of the Inflatable Tubular Structure (ITS®) to the crash safety community was in March 1995. Then, in early 1997, (ITS®) was implemented in the automotive industry as a side-impacted head protection device. In several real-world side-impact crashes of vehicles equipped with the ITS, it reportedly “saved the lives of the vehicle passengers.” The same principle of the ITS in side-impact head protection devices has been extended to several other restraint devices, as well as new environments. This paper briefly describes design parameters of braid technology and various applications of braid structures for the development of inflatable restraints for enhanced vehicle occupant protection.
Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers
Authors: Robertson Philmore , Hellriegel Edward T. , Arora Sanjay , Nelson Michael 
Published: August 2002

BackgroundModafinil has been reported to produce a concentration‐related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes.ObjectiveOur objective was to determine whether the pharmacokinetics of steady‐state ethinyl estradiol (INN, ethinylestradiol) and single‐dose triazolam were altered after 4 weeks of modafinil treatment in volunteers.MethodsThis was a placebo‐controlled, single‐blind, single‐period study in 41 female subjects who were receiving long‐term treatment with an oral contraceptive that contained ethinyl estradiol (0.035 mg) and norgestimate (0.180–0.250 mg). Pharmacokinetic profiles for ethinyl estradiol and for a single oral dose of triazolam (0.125 mg) were obtained the day before initiation of treatment with modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo (28 days). A second dose of triazolam was administered with the final dose of modafinil, and pharmacokinetic profiling was repeated.ResultsThe modafinil treatment group had a marked decrease in maximum observed plasma concentrations and areas under the plasma concentration–time curve for triazolam relative to placebo, with a much smaller decrease in these parameters for ethinyl estradiol. The half‐life of triazolam was also decreased, but the half‐life of ethinyl estradiol did not appear to be affected by treatment with modafinil.ConclusionModafinil induced CYP3A4/5 activity in humans in vivo, suggesting that there is potential for metabolic drug‐drug interactions between modafinil and substrates of CYP3A4/5. However, the induction appeared to be more gastrointestinal than hepatic in nature. Therefore significant metabolic drug‐drug interactions are most likely to occur with compounds (such as triazolam) that undergo significant gastrointestinal CYP3A4/5‐mediated first‐pass metabolism.Clinical Pharmacology & Therapeutics (2002) 71, 46–56; doi: 10.1067/mcp.2002.121217
Pharmacokinetic and pharmacodynamic modeling of humanized anti–factor IX antibody (SB 249417) in humans
Authors: Chow Fung‐Sing , Benincosa Lisa J. , Sheth Sunita B. , Wilson Douglas , Davis Charles B. , Minthorn Elisabeth A. , Jusko William J. 
Published: August 2002

BackgroundSB 249417 is a humanized anti‐factor IX/IXa antibody that, on administration to rats and monkeys, produces an immediate suppression of factor IX activity and prolongation of activated partial thromboplastin times (aPTT).ObjectiveOur objective was to establish the pharmacokinetics of SB 249417 and to explore its effects on factor IX activity levels and aPTT in humans.MethodsIn this phase I, single‐blind, randomized, placebo‐controlled, parallel‐group, single intravenous infusion study, individual and mean data from a total of 26 healthy volunteers at 5 dosing levels were analyzed. A 2‐compartment pharmacokinetic model was used in the analysis of total SB 249417 concentration‐time profiles. A modified indirect‐response model was used, with the total concentration indirectly serving as the driving force for the suppression of free factor IX concentration (as assessed by factor IX activity). The aPTT was related to factor IX activity with a biexponential equation, and a population approach was used to generate posterior parameter estimates for the individual fittings.ResultsMean parameter estimates from individual fittings are 0.092 L/kg for volume of distribution, 0.15 L/kg for steady‐state volume of distribution, and 0.0021 L/kg per hour for systemic clearance. The model described well the factor IX activity and aPTT time course in response to SB 249417 at 5 dose levels. The estimated half‐life of factor IX in blood was 21 hours.ConclusionsThis model was stable and robust in fitting both mean and individual data. Endogenous factor IX baseline levels and dose were the major determinants of the decline in factor IX activity during the infusion period. Thereafter the recovery of factor IX activity was governed solely by the endogenous factor IX turnover rate.Clinical Pharmacology & Therapeutics (2002) 71, 235–245; doi: 10.1067/mcp.2002.122276