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  • pharmacokinetics  (2,025)
  • stability  (680)
  • Springer  (2,703)
  • MDPI Publishing
  • 1
    Publication Date: 2020-11-12
    Description: Slope dynamics in volcanic environments comprise a wide spectrum of phenomena, from large lateral collapse to shallow debris remobilization, which may represent a major threat for human communities and infrastructures. Many volcanos built up from the ocean floor and large portions of the volcano edifice are submerged. In these settings, only the edifice’s summit can be investigated by terrestrial remote sensing and in-situ approaches. Growth and destruction, including tectonics and gravitational phenomena, affect entire volcano flanks and are not limited to the physical boundary of the sea level but could comprise their subaqueous parts.
    Description: Published
    Description: 2615–2618
    Description: 6V. Pericolosità vulcanica e contributi alla stima del rischio
    Description: JCR Journal
    Keywords: volcanoes ; flanks ; volcano-tectonics ; structure ; collapse ; stability ; 04.08. Volcanology ; 05.08. Risk
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
    Type: article
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  • 2
    ISSN: 1573-8221
    Keywords: acylprolyldipeptide ; GVS-111 ; pharmacokinetics ; blood-brain barrier permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an umodified state.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Mechanics of composite materials 36 (2000), S. 475-480 
    ISSN: 1573-8922
    Keywords: stability ; three-dimensional theory ; tribotechnics ; elastoplastic deformations ; viscoelasticity ; surface ; tracking and dead loads ; laminated coating ; piecewise-homogeneous model ; active loading
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract The problem of surface instability of laminated coatings with inelastic properties is considered within the framework of a model of piecewise-homogeneous media on the basis of the three-dimensional linearized theory of stability. A general statement of the problem is formulated and the basic characteristic equations are derived. The solutions of particular problems are obtained for elastoplastic and viscoelastic models of solids.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of dynamical and control systems 6 (2000), S. 503-510 
    ISSN: 1573-8698
    Keywords: nonconservative mechanical systems ; stability ; Lyapunov functions ; attraction domain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract Mechanical systems subjected to dissipative, gyroscopic, conservative, and also nonconservative positional forces are considered. The question of the effect of dissipative, gyroscopic, and conservative forces on the motion stability of a mechanical systems is determined by classical Kelvin–Chetaev theorems [1]. The presence of nonconservative positional forces considerably complicates the situation and excludes direct application of these theorems. Applying Lyapunov's functions method the condition of asymptotic stability of a mechanical system under the action of all listed above forces is obtained. Moreover, the estimation of the attraction domain in phase space is found. The precession system which is used in the solution of some problems in the applied theory of the gyroscopic systems is also examined. The connection between the stability of origin and precession systems is detected. Theoretical results are applied to the stabilization problem of stationary motion of the balanced gimbal suspension gyro by means of external moments.
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  • 5
    Electronic Resource
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    Springer
    Cybernetics and systems analysis 36 (2000), S. 699-721 
    ISSN: 1573-8337
    Keywords: stability ; stochastic functional differential equations ; previous history ; Poisson switchings ; "dangling spider" model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract To study the stability of the stochastic "dangling spider" model, the second Lyapunov method is substantiated for stochastic differential functional equations with the whole previous history.
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  • 6
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    Springer
    Pharmaceutical research 17 (2000), S. 1426-1431 
    ISSN: 1573-904X
    Keywords: eplerenone ; selective aldosterone receptor antagonist ; dog ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.
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  • 7
    ISSN: 1573-904X
    Keywords: allometric scaling ; interspecies scaling ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·Wbiv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent bivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · Wbiv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.
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  • 8
    ISSN: 1573-904X
    Keywords: α1-acid glycoprotein ; protein binding ; dissociation rate ; species difference ; physiological model ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The extremely low clearance and small distribution volumeof UCN-01 in humans could be partly due to the high degree of bindingto hAGP (1,2). The quantitative effects of hAGP on the pharmacokineticsof UCN-01 at several levels of hAGP and UCN-01 were estimatedin rats given an infusion of hAGP to mimic the clinical situation anda physiological model for analysis was developed. Methods. The plasma concentrations of UCN-01 (72.5–7250 nmol/kgiv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, weremeasured by HPLC. Pharmacokinetic analysis under conditionsassuming rapid equilibrium of protein binding and incorporating thedissociation rate was conducted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in ratsgiven an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/700that in control rats. The Vdss and CLtot following 72.5–7250nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9–688ml/kg and 3.18–32.9 ml/h/kg, respectively, indicating non-linearitydue to saturation of UCN-01 binding. The CLtot estimated by thephysiological model assuming rapid equilibrium of UCN-01 bindingto hAGP, was six times higher than the observed value while the CLtotestimated by the model incorporating koff, measured using DCC, wascomparable with the observed value. Conclusions. These results suggest that the slow dissociation ofUCN-01 from hAGP limits its disposition and elimination.
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  • 9
    ISSN: 1573-904X
    Keywords: oral absorption ; humans ; dogs ; rats ; interspecies scale-up ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption. Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs. Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r2 = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r2 = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer Tmax values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory. Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.
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  • 10
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    Pharmaceutical research 17 (2000), S. 127-134 
    ISSN: 1573-904X
    Keywords: in-situ head perfusion ; pharmacokinetics ; red blood cells ; water
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a viable, single pass rat head perfusion modeluseful for pharmacokinetic studies. Methods. A viable rat head preparation, perfused with MOPS-bufferedRinger's solution, was developed. Radiolabelled markers (red bloodcells, water and sucrose) were injected in a bolus into the internalcarotid artery and collected from the posterior facial vein over 28minutes. The double inverse Gaussian function was used to estimatethe statistical moments of the markers. Results. The viability of the perfusion was up to one hour, with optimalperfusate being 2% bovine serum albumin at 37°C, pH 7.4. Thedistribution volumes for red blood cells, sucrose and water (from all studies,n = 18) were 1.0 ± 0.3ml, 6.4 ± 4.2ml and 18.3 ± 11.9ml, respectively.A high normalised variance for red blood cells (3.1 ± 2.0) suggestsa marked vascular heterogeneity. A higher normalised variance forwater (6.4 ± 3.3) is consistent with additional diffusive/permeabilitylimitations. Conclusions. Analysis of the physiological parameters derived fromthe moments suggested that the kinetics of the markers were consistentwith distribution throughout the head (weight 25g) rather than justthe brain (weight 2g). This model should assist in studying solutepharmacokinetics in the head.
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  • 11
    ISSN: 1573-904X
    Keywords: stealth and remote loading proliposome ; doxorubicin ; pharmacokinetics ; acute toxicity ; anticancer effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of the study was to prepare stealth and remoteloading proliposome (SRP-L) to carry doxorubicin (DXR) and evaluatethe pharmacokinetics, acute toxicity, and anticancer effect of DXRcarried with SRP-L. Methods. SRP-L was transparent solution. When SRP-L was injectedinto 0.9% NaCl aqueous solution containing DXR, liposomes formedand automatically loaded DXR (SRP-L-DXR). The long circulation ofSRP-L-DXR was evaluated using the pharmacokinetics ofSRP-L-DXR, cardiolipin liposomal DXR (CL-DXR) and free DXR (F-DXR).The acute toxicity and anticancer effect of SRP-L-DXR were evaluatedin C57BL/6 mice and murine hystocytoma M5076 tumor model. Results. The average diameter of SRP-L-DXR in pure water was112.9 ± 8.6 (nm) and the encapsulation efficiency of SRP-L-DXRwas 96.5 ± 0.2% in pure water, 95.5 ± 0.1% in 5% glucose and 98.01± 0.6% in 0.9% NaCl. The plasma concentration of SRP-L-DXR wasmuch higher than those of F-DXR and CL-DXR. Compared with thatof F-DXR, the SRP-L-DXR had lower acute toxicity and its anticancereffects depended upon the therapeutic treatment. Conclusions. A novel proliposome (SRP-L) was developed, whichcould automatically load DXR and form SRP-L-DXR with excellentcharacteristics. SRP-L-DXR had lower acute toxicity but was notalways more effective for the treatment of the ascitic M5076 thanF-DXR.
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  • 12
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    Pharmaceutical research 17 (2000), S. 903-905 
    ISSN: 1573-904X
    Keywords: P-glycoprotein ; hepatic metabolism ; pharmacokinetics ; first-pass metabolism ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 13
    ISSN: 1573-904X
    Keywords: bioequivalence ; dose proportionality ; mixed effects model ; pharmacokinetics ; power model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. Methods. Statistical estimation is used to derive a (1-α)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = β0 • Doseβ1; however, the logic holds for other functional forms. Results. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (ρ1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (ρ2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. Conclusion. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.
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  • 14
    ISSN: 1573-904X
    Keywords: glycyrrhizic acid ; modeling ; enterohepatic cycling ; PBPK ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.
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  • 15
    ISSN: 1573-904X
    Keywords: IVIVC ; racemate ; enantiomers ; metoprolol ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the ability of an IVIVC developedwith a racemate drug as well as each enantiomer in predicting the invivo enantiomer drug performance. Methods. Dissolution of metoprolol extended releasetablets with different release characteristics (e.g., fast (F),moderate (M), and slow (S)) was performed using USP ApparatusI, pH 1.2, 50 rpm. Metoprolol racemate tablets (S, M, and F, 100 mg) and 50mg oral solution were administered to healthy volunteers, blood samples werecollected over 24 (solution) and 48 (tablet) hours and assayed. IVIVC modelsdeveloped were: (1) Racemate-fraction of drug dissolved (FRD) vsRacemate-fraction of drug absorbed (FRA), (2) R-FRD vs R-FRA, and (3) S-FRDvs S-FRA for combinations of formulations (S/M/F, S/M, S/F, and M/F).Enantiomer Cmax and AUC prediction errors (PEs) were estimated for modelevaluation after convolution of in vivo release rates. Results. The R-IVIVC and S-IVIVC accurately predicted theR- and S-metoprolol pharmacokinetic profiles, respectively. The averagedprediciton errors (PE) for the enantiomer Cmax and AUC were less than10% for S/M/F, M/F, and S/F IVIVC models. Racemate-IVIVC (M/F) wasable to predict S-enantiomer with an average %PE of 2.52 for S-Cmaxand 4.3 for S-AUC. However, the racemate-IVIVC was unable to predict theR-enantiomer pharmacokinetic profile. Conclusions. Metoprolol racemate data cannot be used toaccurately predict R-enantiomer drug concentrations. However, the racematedata was predictive of the active stereoisomer.
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  • 16
    ISSN: 1573-904X
    Keywords: 1,4-dihydropyridine calcium channel antagonist ; (+)-[3H]PN 200-110 ; senescence-accelerated prone mouse ; brain concentration ; pharmacokinetics ; in vivo receptor binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the in vivo specific binding andpharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN200-110, in the senescent brain, using senescence-accelerated pronemice (SAMP8) and senescence-resistant mice (SAMR1). Methods. Blood, brain, and heart samples were taken periodically fromSAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN200-110, and the concentration of (+)-[3H]PN 200-110 in the plasmaand tissues was determined. In addition, the in vivo specific bindingof (+)-[3H]PN 200-110 in the brains of SAMR1 and SAMP8 wasmeasured periodically after intravenous injection of the radioligand. Results. There was very little significant difference between SAMR1and SAMP8 in terms of the half-life (t1/2), total body clearance (CLtot),steady-state volume of distribution (Vdss), and AUC for the plasmaconcentration of (+)-[3H]PN 200-110 after intravenous injection ofthe radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) weresignificantly lower in SAMP8 than in SAMR1, and the heartconcentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma)were similar in both strains. Also, the brain/plasma unbound AUCratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 wassignificantly lower in SAMP8 than in SAMR1. The in vivo specific binding(AUCspecific binding, maximal number of binding sites: Bmax) of(+)-[3H]PN 200-110 was significantly lower in brain particulate fractionsof SAMP8 than SAMR1. Conclusions. The concentration and in vivo specific binding of(+)-[3H]PN 200-110 was significantly reduced in the senescent brain. Thesimultaneous analysis of the concentrations of centrally acting drugsand the in vivo specific binding in the brain in relation to theirpharmacokinetics may be valuable in evaluating their CNS effects.
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  • 17
    ISSN: 1573-904X
    Keywords: morphine ; nociceptive effect ; electrical stimulation vocalisation method ; microdialysis ; retrodialysis by drug ; pharmacokinetics ; pharmacodynamics ; modelling ; blood-brain barrier transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p 〈 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 ± 0.09 and 0.22 ± 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.
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  • 18
    ISSN: 1573-904X
    Keywords: aspergillosis ; pharmacokinetics ; amphotericin B ; biodistribution ; liposomes ; cholesterol hemisuccinate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study compared the biodistribution of two amphotericin B formulations in normal and Aspergillus infected mice. Amphotericin B cholesterol hemisuccinate vesicles (ABCV) which reduces the toxicity of amphotericin B and thereby enhances its therapeutic efficacy in a murine model of aspergillosis was compared with conventional amphotericin B deoxycholate suspension (AmBDOC). Methods. ABCV (12 mg/kg wt) and AmBDOC (2 mg/kg wt) were intravenously administered to normal and A.fumigatus infected mice. The concentration of amphotericin B in plasma and other organs was determined at different time points. Results. It was observed that ABCV had a significantly different pharmacokinetic profile compared to conventional amphotericin B. In comparison to AmBDOC significantly lower levels of amphotericin B were observed in kidneys and plasma, the major target organs of toxicity. Animals receiving ABCV demonstrated high levels of amphotericin B in liver (38% retention till 48 h) and spleen (2.6% retention till 48 h) in comparison to AmBDOC (7.3% and 0.21% retention in liver and spleen respectively till 48 h). Biodistribution studies of ABCV in infected mice demonstrated that there was a moderate enhancement in levels of amphotericin B in liver, spleen, lungs and kidneys as compared to normal mice and the plasma levels were reduced. However, such observations were not made after AmBDOC administration to infected mice except for kidneys in which there was a marked increase in uptake as compared to normal mice. Conclusions. Our results suggest that prolonged retention of high concentrations of ABCV in reticuloendothelial system organs is the reason for its reduced toxicity. Enhanced localization of the drug at the infected site may lead to improvement in therapeutic efficacy.
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  • 19
    ISSN: 1573-904X
    Keywords: particle size ; PLG microspheres ; protein delivery ; spray-freeze drying ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein. Methods. Atomization variables were explored for excipient-free (no zinc added) and zinc-complexed bovine serum albumin (BSA). Particle size was measured by laser diffraction light scattering following sonication in organic solvent containing poly(lactide-co-glycolide) (PLG). Powder surface area was determined from the N2 vapor sorption isotherm. Size-exclusion chromatography (SEC) was used to assess decrease in percent protein monomer. Fourier-transform infrared (FTIR) spectroscopy was employed to estimate protein secondary structure. PLG microspheres were made using a non-aqueous, cryogenic process and release of spray-freeze dried BSA was assessed in vitro. Results. The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N2 relative to that for liquid feed). Particle size was inversely related to specific surface area and the amount of protein aggregates formed. Zinc-complexation reduced the specific surface area and stabilized the protein against aggregation. FTIR data indicated perturbations in secondary structure upon spray-freeze drying for both excipient-free and zinc-complexed protein. Conclusions. Upon sonication, spray-freeze dried protein powders exhibited friability, or susceptibility towards disintegration. For excipient-free protein, conditions where the mass flow ratio was 〉 ∼0.3 yielded sub-micron powders with relatively large specific surface areas. Reduced particle size was also linked to a decrease in the percentage of protein monomer upon drying. This effect was ameliorated by zinc-complexation, via a mechanism involving reduction in specific surface area of the powder rather than stabilization of secondary structure. Reduction of protein particle size was beneficial in reducing the initial release (burst) of the protein encapsulated in PLG microspheres.
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  • 20
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; toxicokinetics ; tissue distribution ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels 〉200 μg/ml and tissue levels 〉3000 μg/g.
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  • 21
    ISSN: 1573-904X
    Keywords: paclitaxel ; emulsions ; filter-sterization ; particle size ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Paclitaxel is currently administered i.v. as a slow infusion of asolution of the drug in an ethanol:surfactant:saline admixture. However,poor solubilization and toxicity are associated with this drug therapy.Alternative drug delivery systems, including parenteral emulsions, areunder development in recent years to reduce drug toxicity, improveefficacy and eliminate premedication. Methods. Paclitaxel emulsions were prepared by high-shearhomogenization. The particle size of the emulsions was measured by dynamiclight scattering. Drug concentration was quantified by HPLC and invitro drug release was monitored by membrane dialysis. The physicalstability of emulsions was monitored by particle size changes in boththe mean droplet diameter and 99% cumulative distribution. Paclitaxelpotency and changes in the concentration of known degradants wereused as chemical stability indicators. Single dose acute toxicity studieswere conducted in healthy mice and efficacy studies in B16 melanomatumor-bearing mice. Results. QW8184, a physically and chemically stable sub-micronoil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drugloading (8-10 mg/mL) having a mean droplet diameter of 〈100 nmand 99% cumulative particle size distribution of 〈200 nm. In vitro release studies demonstrated low and sustained drug release both inthe presence and absence of human serum albumin. Based on singledose acute toxicity studies, QW8184 is well tolerated both in miceand rats with about a 3-fold increase in the maximum-tolerated-dose(MTD) over the current marketed drug formulation. Using the B16mouse melanoma model, a significant improvement in drug efficacywas observed with QW8184 over Taxol®. Conclusions. QW8184, a stable sub-micron o/w emulsion of paclitaxelhas been developed that can be filter-sterilized and administered i.v.as a bolus dose. When compared to Taxol®, this emulsion exhibitedreduced toxicity and improved efficacy most likely due to thecomposition and dependent physicochemical characteristics of the emulsion.
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  • 22
    ISSN: 1573-904X
    Keywords: (R,S)-Ifosfamide ; R2-, R3-, S2-, S3-DCE-IFF ; iterative-two stage analysis ; pharmacokinetics
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe the pharmacokinetics of R- andS-Ifosfamide (IFF), and their respective 2 and 3 N-dechloroethylated (DCE)metabolites (R2-, R3-, S2, S3-DCE-IFF) in cancer patients. Methods. (R,S)-IFF was administered (1.5 g/m2)daily for 5 days in 13 cancer patients. Plasma and urine samples were collectedand analyzed using an enantioselective GC-MS method. An average of 97observations per patient were simultaneously fitted using apharmacokinetic-metabolism (PK-MB) model. A population PK analysis was performedusing an iterative 2-stage method (IT2S). Results. Auto-induction of IFF metabolism was observed over the 5day period. Increases were seen in IFF clearance (R: 4 vs 7 L/h; S: 5vs 10 L/h), and in the formation of DCE (R: 7 vs 9%; S: 14 vs 19%)and active metabolites (4-OHM-IFF; R: 71 vs 77%; S: 67 vs 71%). Anovel finding of this analysis was that the renal excretion of the DCEmetabolites was also induced. Conclusions. This population PK-MB model for (R,S)-IFF may beuseful in the optimization of patient care, and gives new insight intothe metabolism of (R,S)-IFF.
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    Archive of applied mechanics 70 (2000), S. 17-29 
    ISSN: 1432-0681
    Keywords: Key words free-surface flow ; solidification ; strip casting ; steady state ; nonuniqueness ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Summary The paper is concerned with a one-dimensional analysis of plane open-channel flow with continuous solidification. The process is of relevance for recent developments in the casting of steel and other metals. The bottom of the channel consists of a rotating casting roll and a horizontal cooling table, where the solidified material is withdrawn with given velocity. The study is restricted to the region downstream of the top of the casting roll. Surface tension is neglected. In the main part of the analysis inviscid fluid flow is considered since the Reynolds number is very large in the applications. It is found that the steady-state solutions are nonunique in a certain parameter range. In addition to a continuous solution, there are two solutions including hydraulic jumps, with one hydraulic jump being located on the casting roll, the other one on the cooling table. Regarding the stability of the non unique solutions, the evolution of disturbances is investigated numerically as an initial-value problem. It is concluded that the hydraulic jump on the cooling table is unstable, while the other discontinuous solution as well as the continuous solution are stable for sufficiently small disturbances. Which stable solution is attained in the steady state, depends on the history of the process. Friction at the liquid/solid interface is taken into account in the last part of the analysis. A constant friction coefficient is assumed. It is found that the history of the process determines the steady-state solution if, and only if, the friction coefficient is sufficiently small. For larger values of the friction coefficient, the steady-state solution is unique and independent of the history of the transient process. Furthermore, for sufficiently large friction coefficients, stable hydraulic jumps are found, in contrast to the inviscid case, also on the cooling table.
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    Journal of statistical physics 101 (2000), S. 731-746 
    ISSN: 1572-9613
    Keywords: attractive Bose–Einstein condensates ; nonlinear Schrödinger equation ; stability ; ground state ; variational arguments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We propose the critical nonlinear Schrödinger equation with a harmonic potential as a model of attractive Bose–Einstein condensates. By an elaborate mathematical analysis we show that a sharp stability threshold exists with respect to the number of condensate particles. The value of the threshold agrees with the existing experimental data. Moreover with this threshold we prove that a ground state of the condensate exists and is orbital stable. We also evaluate the minimum of the condensate energy.
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    Aquatic geochemistry 6 (2000), S. 1-17 
    ISSN: 1573-1421
    Keywords: lakes ; density ; compressibility ; expansibility ; conductivity ; stability ; pvt properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Geosciences
    Notes: Abstract In recent years, a number of workers have studied the stability of deep lakes such as Lake Tanganyika, Lake Baikal and Lake Malawi. In this paper, the methods that can be used to determine the effect that the components of lakes have on the equation of state are examined. The PVT properties of Lakes have been determined by using apparent molal volume data for the major ionic components of the lake. The estimated PVT properties (densities, expansibility and compressibilities) of the lakes are found to be in good agreement with the PVT properties (P) of seawater diluted to the same salinity. This is similar to earlier work that showed that the PVT properties of rivers and estuarine waters could also be estimated from the properties of seawater. The measured densities of Lake Tanganyika were found to be in good agreement (± 2 × 10-6 g cm-3) with the values estimated from partial molal properties and the values of seawater at the same total salinity (ST = 0.568‰). The increase in the densities of Lake Tanganyika waters increased due to changes in the composition of the waters. The measured increase in the measured density (45 × 10-6 g cm-3) is in good agreement (46 × 10-6 g cm-3) with the values calculated for the increase in Na+, HCO3 -, Mg2+, Ca2+ and Si(OH)4. Methods are described that can be used to determine the conductivity salinity of lakes using the equations developed for seawater. By combining these relationships with apparent molal volume data, one can relate the PVT properties of the lake to those of seawater.
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    Journal of intelligent and robotic systems 27 (2000), S. 195-209 
    ISSN: 1573-0409
    Keywords: wall-climbing robot ; electromagnetic grippers ; stability ; additional support element ; sliding and turning over conditions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Legged-climbing robot is considered. Each foot of the robot has an electromagnet system for robot"s holding on a metal surface. This surface can be both vertical and inclined, including negative slope. Analytical calculation of robot stability under turn over or sliding conditions has been made. Critical slopes have been determined. One of these slopes corresponds to minimal reserve of robot stability towards sliding and another to minimal reserve of robot stability towards turning-over. As total reserve of stability of a robot is always equal to the minimal one of these reserves. Additional support elements of elastic material with high coefficient of friction, along with electromagnet, allows to increase minimal reserve of robot stability towards sliding. The use of such support elements leads to redistributing force of normal support reaction between electromagnet (which surface has low coefficient of friction) and additional support element (which surface has high coefficient of friction). It is just what leads to increasing the total friction force and as a consequence to increasing of minimal reserve of robot stability towards sliding.
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    Catalysis letters 68 (2000), S. 55-58 
    ISSN: 1572-879X
    Keywords: promoting effect ; B2O3 ; Cu/ZnO/Al2O3 catalyst ; methanol synthesis ; stability
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The addition of B2O3 to a Cu/ZnO/Al2O3 catalyst increased the activity of the catalyst for methanol synthesis after an induction period during the reaction. The stability of the B2O3-containing Cu/ZnO/Al2O3 catalyst was greatly improved by the addition of a small amount of colloidal silica to the catalyst.
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    ISSN: 1572-879X
    Keywords: potassium desorption ; stability ; excitation ; iron catalyst ; Rydberg atoms
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    Topics: Chemistry and Pharmacology
    Notes: Abstract Well‐characterized catalyst model compounds of KAlO2 and KFeO2 are investigated by thermal desorption of potassium from the material. The desorbing fluxes of ions, atoms and highly excited states (field ionizable Rydberg states) were studied with surface and field ionization detectors in a vacuum apparatus. From the Arrhenius plots the activation energies for desorption of K and K+ were determined. The chemical state of potassium at the surfaces is concluded to be: ionic on KAlO2 (with the K desorption barrier of 1.76 eV) and covalent on KFeO2 (barrier of 2.73 eV). These results agree with the data obtained earlier for industrial catalysts for ammonia and styrene production. They are interpreted in terms of the Schottky cycle, which is completed for KAlO2 and fails for KFeO2. This failure indicates a non‐equilibrium desorption process. K Rydberg states are only found to desorb from KFeO2, in agreement with the suggestion that such states in some way are responsible for the catalytic activity.
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    Acta biotheoretica 48 (2000), S. 207-218 
    ISSN: 1572-8358
    Keywords: Dynamical population ; fishing efforts ; metapopulation ; time scales ; aggregation method ; equilibrium ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract This work presents a specific stock-effort dynamical model. The stocks correspond to two populations of fish moving and growing between two fishery zones. They are harvested by two different fleets. The effort represents the number of fishing boats of the two fleets that operate in the two fishing zones. The bioeconomical model is a set of four ODE's governing the fishing efforts and the stocks in the two fishing areas. Furthermore, the migration of the fish between the two patches is assumed to be faster than the growth of the harvested stock. The displacement of the fleets is also faster than the variation in the number of fishing boats resulting from the investment of the fishing income. So, there are two time scales: a fast one corresponding to the migration between the two patches, and a slow time scale corresponding to growth. We use aggregation methods that allow us to reduce the dimension of the model and to obtain an aggregated model for the total fishing effort and fish stock of the two fishing zones. The mathematical analysis of the model is shown. Under some conditions, we obtain a stable equilibrium, which is a desired situation, as it leads to a sustainable harvesting equilibrium, keeping the stock at exploitable densities.
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    Journal of computational analysis and applications 2 (2000), S. 293-308 
    ISSN: 1572-9206
    Keywords: parabolic equations ; ADI scheme ; stability
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    Topics: Mathematics
    Notes: Abstract An ADI scheme for solving three-dimensional parabolic equations withfirst-order derivatives and variable coefficients has been developed basedon our previous papers and the idea of the modified upwind differencescheme. This ADI scheme is second-order accurate and unconditionallystable. Further, a small parameter can be chosen which makes it suitablefor simulating fast-transient phenomena or for computations on fine spatialmeshes. The method is illustrated with numerical examples.
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    Journal of dynamics and differential equations 12 (2000), S. 117-167 
    ISSN: 1572-9222
    Keywords: singular perturbation ; standing pulses ; stability ; Hopf bifurcation ; reaction-diffusion system
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    Topics: Mathematics
    Notes: Abstract Bifurcation phenomena from standing pulse solutions of the problem $$\varepsilon \tau u_t = \varepsilon ^2 u_{xx} + f(u,v),{\text{ }}v_t = v_{xx} + g(u,v)$$ is considered. ε(〉0) is a sufficiently small parameter and τ is a positive one. It is shown that there exist two types of destabilization of standing pulse solutions when τ decreases. One is the appearance of travelling pulse solutions via the static bifurcation and the other is that of in-phase breathers via the Hopf bifurcation. Furthermore which type of destabilization occurs first with decreasing τ is discussed for the piecewise linear nonlinearities f and g.
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    Celestial mechanics and dynamical astronomy 78 (2000), S. 227-241 
    ISSN: 1572-9478
    Keywords: stability ; normal form ; spin-orbit resonance
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    Topics: Physics
    Notes: Abstract We consider a model of spin-orbit interaction, describing the motion of an oblate satellite rotating about an internal spin-axis and orbiting about a central planet. The resulting second order differential equation depends upon the parameters provided by the equatorial oblateness of the satellite and its orbital eccentricity. Normal form transformations around the main spin-orbit resonances are carried out explicitly. As an outcome, one can compute some invariants; the fact that these quantities are not identically zero is a necessary condition to prove the existence of nearby periodic orbits (Birkhoff fixed point theorem). Moreover, the nonvanishing of the invariants provides also the stability of the spin-orbit resonances, since it guarantees the existence of invariant curves surrounding the periodic orbit.
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    Fish physiology and biochemistry 23 (2000), S. 225-232 
    ISSN: 1573-5168
    Keywords: methylisoborneol ; catfish ; cytochrome P450 ; biotransformation ; pharmacokinetics
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    Topics: Biology
    Notes: Abstract 2-Methylisoborneol (MIB) and structurally related terpenoid compounds are responsible for millions of dollars of lost revenue to catfish farmers. In an attempt to determine enzymatic pathways of biotransformation and elimination of MIB, the in vitro metabolism of MIB was examined in the Ulvade strain of channel catfish (Ictalurus punctatus). Although cytochrome P450 (CYP) activities were observed and correlated with expression of specific isoforms (i.e. steroid hydroxylation and CYP3A expression), no metabolites of MIB were observed. To determine whether extrahepatic biotransformation may be occurring the in vivo metabolism and disposition of 14C-MIB was examined in Uvalde, USDA-103 channel catfish, and a channel catfish X blue catfish (Ictalurus furcatus) hybrid species. Confirming in vitro hepatic studies, no metabolites were observed in plasma from animals treated with an intra-arterial dose of 14C-MIB. 14C-MIB elimination was predicted using a two compartment model in each strain of fish. There was no significant difference in terminal half-lives between strains but possible differences in total body clearance and apparent volumes of distribution which may be related to higher lipid content in the hybrids. Results of these studies indicate biotransformation has no involvement in MIB elimination and that other physiological processes may play a more significant role in MIB disposition within Ictalurid fish species.
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    ISSN: 1573-5168
    Keywords: amberjack ; myosin heavy chain ; cDNA ; α-helix ; coiled coils ; stability
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    Topics: Biology
    Notes: Abstract The structural stability of fish myosin depends upon species and temperatures of water in which fish live. Primary, secondary, and quaternary structures of myosin heavy chain (MyHC) from three species of fish living at different temperature ranges have been compared with those of rabbit MyHC in order to investigate the differences in stability. Primary structure of MyHC, although being accessible for warm-water and cold-water fish (carp and walleye pollack), was not available in previous for tropical-water fish literature; so in this study primary structure of MyHC of the tropical-water fish amberjack has been determined by cloning and sequencing its cDNA. The MyHC has 1938 amino acid residues (AA), which are almost as much as as those of carp and walleye pollack. The amberjack MyHC is 91–95% homologous with other fish and rabbit MyHCs. There is a discernible difference between animal species with stable myosin rod (amberjack, carp, and rabbit) and walleye pollack with unstable rod. Stable rod species have a high probability of forming coiled-coil around the COOH-terminal end of the rod, while the pollack has a low coiled-coil formation probability. In addition, the average scores of the coiled-coil for myosin rod were rabbit (1.738) 〉 amberjack (1.691) 〉 carp (1.680) 〉 walleye pollack (1.674) which correlated exactly with the observed stability. The results suggest that coiled-coil forming ability, particularly around the COOH-terminal end, directs structural stability of fish myosin rod.
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    Applications of mathematics 45 (2000), S. 161-176 
    ISSN: 1572-9109
    Keywords: reaction-diffusion system ; unilateral conditions ; quasivariational inequality ; Leray-Schauder degree ; eigenvalue ; stability
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    Topics: Mathematics
    Notes: Abstract We consider a reaction-diffusion system of the activator-inhibitor type with unilateral boundary conditions leading to a quasivariational inequality. We show that there exists a positive eigenvalue of the problem and we obtain an instability of the trivial solution also in some area of parameters where the trivial solution of the same system with Dirichlet and Neumann boundary conditions is stable. Theorems are proved using the method of a jump in the Leray-Schauder degree.
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    Circuits, systems and signal processing 19 (2000), S. 423-435 
    ISSN: 1531-5878
    Keywords: Time-varying autoregressive models ; stability ; smoothness priors ; Tihkonov regularization ; constrained optimization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract The stability of time-varying autoregressive (AR) models is an important issue in such applications as time-varying spectrum estimation and electroencephalography simulation and estimation. In some cases, such as time-varying spectrum estimation, the models that exhibit roots near unit moduli are difficult to use. Thus a tighter stability condition such as stability with a positive margin is needed. A time-varying AR model is stable with a positive margin if the moduli of the roots of the time-varying characteristic polynomial are somewhat less than unity for every time instant. Recently, a new method for the estimation of the time-varying AR models was introduced. This method is based on the interpretation of the underdetermined time-varying prediction equations as an ill-posed inverse problem that is solved by Tikhonov regularization. The method is referred to as the deterministic regression smoothness priors (DRSP) scheme. In this paper, a stabilization method in which the DRSP scheme is augmented with nonlinear stability constrainst is proposed. The problem is formulated so that stability with a positive margin can also be achieved. The problem is solved iteratively with an exterior point algorithm. The performance of the algorithm is studied with a simulation. It is shown that the proposed approach is well suited to stable modeling of signals containing narrowband transitions.
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  • 37
    ISSN: 1573-5060
    Keywords: chile ; double haploid ; pepper ; pungency ; stability ; within-genotype variance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The response, in terms of capsaicinoid content, of chile (Capsicum annuum L.) genotypes to different environments was studied. Double haploidlines, an F1 hybrid, and an open-pollinated cultivar estimated the genotype, environment, and genotype-by-environment interaction effect on the total capsaicinoids and on individual capsaicinoids. Significant differences were observed among the genotypes and among genotype-by-environment interactions over the environments. Among the genotypes in an environment, the within-genotype variances were also significantly different. The double haploid line, HDA 207, had low within-genotype variance for individual and total capsaicinoids, with the exception of the isomer of dihydrocapsaicin. Also for HDA 270, the genotype-by-environment interaction was negligible for individual and total capsaicinoids, Indicating stability across environments.
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  • 38
    ISSN: 1573-5060
    Keywords: Avena ; genetic correlation ; genotype-environmentinteraction ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract In order to test if selection can improve a population's adaptation to diverse environments simultaneously, three cycles of recurrent selection based on grain yield in Iowa, Idaho, and Norway were practiced in an oat (Avena sativaL.) population developed from North American, Scandinavian, and wild species (A. sterilis L.) germplasm sources. Specific objectives were to determine if selection: increased mean yields across environments and within all environments; changed the genetic correlation of yields in different environments; and changed genetic variation for yield within the population. We evaluated 100 to 210 randomly-chosen families from each cycle of selection at three Iowa locations, in Idaho, and in Norway for two years. Grain yield within each location and mean yields across locations increased significantly over cycles of selection. Mean yields across locations expressed as a percent of the original population mean increased at a rate of 2.6% per year. Several families from the third cycle population exhibited both high mean yields across locations and consistently high yields within all locations. Average genetic correlations of yield in different environments were higher in the second cycle than in the original population. A trend of reduced genetic variation and heritability was observed in Iowa only. These results suggest that we successfully improved mean population yield both within and across locations, and yield stability across environments, and in developing families with outstanding adaptation to diverse environments.
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  • 39
    ISSN: 1573-4943
    Keywords: Methanol dehydrogenase ; Ca2+ ; binding ; activity ; stability
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    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of exogenously added Ca2+ on the enzymatic activity and structural stability of methanol dehydrogenase were studied for various Ca2+ concentrations. Methanol dehydrogenase activity increased significantly with increasing concentration of Ca2+, approaching saturation at 200 mM Ca2+. The effect of Ca2+ on the activation of MDH was time dependent and Ca2+ specific and was due to binding of the metal ions to the enzyme. Addition of increasing concentration of Ca2+ caused a decrease of the intrinsic tryptophan fluorescence intensity in a concentration-dependent manner to a minimum at 200 mM, but with no change in the fluorescence emission maximum wavelength or the CD spectra. The results revealed that the activation of methanol dehydrogenase by Ca2+ occurred concurrently with the conformational change. In addition, exogenously bound Ca2+ destabilized MDH. The potential biological significance of these results is discussed.
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    International journal of fracture 105 (2000), S. 57-79 
    ISSN: 1573-2673
    Keywords: Interface toughness ; interface debonding ; stability ; adhesive interface ; bimaterial.
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    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract In this paper, we studied the interface debonding when a crack perpendicularly approaches an interface between two dissimilar elastic materials. An interface toughness law was first defined according to an adhesive model governing the interface fracture. By analysing the interaction between the normally approaching crack and the interface crack and by tacking account of the adhesive forces at ends of the interfacial crack, a model for studying the interface debonding and the debonding stability was established. It is observed that the interface debonding toughness depends strongly on the mixed mode locally produced over the plastic adhesive zone of the interface. Moreover, the interface debonding may be unstable, i.e. the interface debonding length may jump from an initial value to a certain final value under critical remote loading. This jump may be surprisedly important in certain cases. These results agree with the experimental works gathered so far and can be used to explain the mechanism of 'crack arrestor' formed by an interface.
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    Multidimensional systems and signal processing 11 (2000), S. 109-124 
    ISSN: 1573-0824
    Keywords: 2-D linear systems ; optimal control ; stability ; unit memory linear repetitive processes ; numerical methods
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    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract Because many optimal control problems require solution using iterative procedures they fall naturally in the realm of 2-D systems where the two dimensions are response time horizon and iteration index, respectively. The paper uses this observation to employ 2-D systems theory, in the form of unit memory repetitive process techniques, to analyse local stability and convergence behaviour of a continuous optimal control algorithm based on dynamic system optimisation and parameter estimation. Existing work is extended to incorporate unmatched terminal constraints. Necessary and sufficient conditions for stability are obtained whose evaluation require the solution of a difficult eigenvalue problem. The paper shows how solutions can be achieved using numerical and graphical facilities of MATLAB.
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    Multidimensional systems and signal processing 11 (2000), S. 339-358 
    ISSN: 1573-0824
    Keywords: 2-D systems ; descriptor systems ; singular systems ; stability
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    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract In this paper, we discussthe jump behavior and stability problems for 2-D linear shift-invariantsingular systems under the standard boundary conditions. It isshown that once a boundary condition or the input is inadmissiblein the classical sense, a group of non-causal or backward jumpsof the system states will be incited. This interpretation releasesthe conventional admissibility constraints on the boundary conditionsand inputs. Based on this observation, a systematic stabilitytheory is developed for 2-D singular systems. The well-knownbasic stability theorem for the 1-D singular systems or 2-D regularsystems is thus extended to the 2-D singular case.
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    Journal of elasticity 61 (2000), S. 49-81 
    ISSN: 1573-2681
    Keywords: collagen structure ; stability ; rupture criterion ; growth mechanics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract Intracranial saccular aneurysms remain an enigma; it is not known why they form, why they enlarge, or why only some of them rupture. Nonetheless, there is general agreement that mechanics plays an essential role in each aspect of the natural history of these potentially deadly lesions. In this paper, we review recent findings that discount limit point instabilities under quasi-static increases in pressure and resonance under dynamic loading as possible mechanisms of enlargement of saccular aneurysms. Indeed, recent histopathological data suggest that aneurysms enlarge due to a stress-mediated process of growth and remodeling of collagen, the primary load-bearing constituent within the wall. We submit that advanced theoretical, experimental, and numerical studies of this process are essential to further progress in treating this class of pathologies. The purpose of this review is to provide background and direction that encourages elasticians to contribute to this important area of research.
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    Letters in mathematical physics 53 (2000), S. 313-320 
    ISSN: 1573-0530
    Keywords: partial differential equations ; nonlinearities ; symmetries ; stability ; minimization
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    Topics: Mathematics , Physics
    Notes: Abstract We suggest a simple but general method of establishing symmetry properties of stable solutions of nonlinear elliptic equations. The method relies on characterization of symmetry breaking with a help of zero modes and on a generalization of the Perron–Frobenius theory.
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    Journal of optimization theory and applications 106 (2000), S. 431-439 
    ISSN: 1573-2878
    Keywords: multidimensional polynomial theory ; robustness ; Kharitonov theorem ; stability ; Schur polynomials ; inverse Kharitonov problem ; Rouché theorem
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract In this note, the problem of the robust stability for a two-dimensional (two-variable) Schur polynomial which is the characteristic polynomial of a discrete-time linear time-invariant system is investigated. A new approach based on the Rouché theorem is adopted. The extension to the robust stability for multidimensional (multivariable) polynomials is also provided. Interesting sufficient conditions for such robust stability are derived. A two-dimensional example is included to support the theoretical result.
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    Journal of optimization theory and applications 106 (2000), S. 527-550 
    ISSN: 1573-2878
    Keywords: vector optimization ; set-valued mappings ; constraint sets ; stability
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    Topics: Mathematics
    Notes: Abstract In vector optimization, several authors have studied the upper and lower semicontinuity for mappings involving constraints in topological vector spaces partially ordered through a cone with nonempty interior. In this paper, we give conditions about the upper and lower semicontinuity in the case that the ordering cone in the parameter space has possibly empty interior, as it happens in many function spaces and seqence spaces.
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    Journal of optimization theory and applications 105 (2000), S. 417-440 
    ISSN: 1573-2878
    Keywords: mixed solutions ; weak Stackelberg problems ; existence ; stability ; weak convergence of probability measures
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    Topics: Mathematics
    Notes: Abstract We are concerned with ∈-mixed solutions for weak Stackelberg problems corresponding to two-player nonzero-sum noncooperative games. Two cases are considered: (i) mixed strategies for only the second player; (ii) mixed strategies for both players. After giving basic results relating convergence of functions and weak convergence of probability measures, we establish existence and stability results for ∈-mixed solutions under general assumptions of minimal character without any convexity assumption. Our results improve previous work of Mallozzi and Morgan (Refs. 1–2).
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    Journal of optimization theory and applications 104 (2000), S. 165-174 
    ISSN: 1573-2878
    Keywords: Systems theory ; stability ; robust stability ; linear systems ; discrete-time systems ; robustness ; polynomial theory ; Kharitonov theorem ; inverse Kharitonov problem ; Rouche theorem
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    Topics: Mathematics
    Notes: Abstract The paper investigates the problem of the robust stability of Schur polynomials. Recently, a new approach based on the Rouche theorem of classical complex analysis has been adopted for the solution of this problem. In this paper, an improvement of the previous solution is presented. This is the optimum solution of the robust stability problem for Schur polynomials, which is obtained by solving a minimization problem and is better than other methods in robust stability literature. Three numerical examples are given to illustrate the proposed method.
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    Journal of optimization theory and applications 106 (2000), S. 165-182 
    ISSN: 1573-2878
    Keywords: Vector optimization ; asymptotically minimizing sequences ; extended well-posedness ; stability ; vector variational principle
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    Topics: Mathematics
    Notes: Abstract In this paper, the concept of extended well-posedness of scalar optimization problems introduced by Zolezzi is generalized to vector optimization problems in three ways: weakly extended well-posedness, extended well-posedness, and strongly extended well-posedness. Criteria and characterizations of the three types of extended well-posedness are established, generalizing most of the results obtained by Zolezzi for scalar optimization problems. Finally, a stronger vector variational principle and Palais-Smale type conditions are used to derive sufficient conditions for the three types of extended well-posedness.
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    Annals of operations research 99 (2000), S. 251-265 
    ISSN: 1572-9338
    Keywords: stochastic programming ; bond portfolio management ; interest ratescenarios ; stability ; sensitivity
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    Topics: Mathematics , Economics
    Notes: Abstract The bond portfolio management problem is formulated as a multiperiod two-stage or multistage stochastic program based on interest rate scenarios. These scenarios depend on the available market data, on the applied estimation and sampling techniques, etc., and are used to evaluate coefficients of the resulting large scale mathematical program. The aim of the contribution is to analyze stability and sensitivity of this program on small changes of the coefficients – the (scenario dependent) values of future interest rates and prices. We shall prove that under sensible assumptions, the scenario subproblems are stable linear programs and that also the optimal first-stage decisions and the optimal value of the considered stochastic program possess acceptable continuity properties.
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    Queueing systems 36 (2000), S. 327-349 
    ISSN: 1572-9443
    Keywords: multiclass networks ; networks with feedback ; Skorokhod Problem ; Skorokhod Mapping ; Lipschitz continuity ; stability ; load conditions
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    Topics: Computer Science
    Notes: Abstract We consider a four-class two-station network with feedback, with fluid inputs and a head-of-the-line generalized processor sharing discipline at each station. We derive the Skorokhod Problem associated with the network and obtain algebraic sufficient conditions for Lipschitz continuity of the associated Skorokhod Map. This provides the first example of a multiclass network with feedback for which the associated Skorokhod Problem has been proved to be regular. As an elementary application, we show that under the conditions which guarantee Lipschitz continuity the network is stable if and only if the usual load conditions apply.
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    Queueing systems 34 (2000), S. 1-35 
    ISSN: 1572-9443
    Keywords: multiple access ; CDMA ; rates of convergence ; stability ; functional limit theorems ; transient analysis ; Markov-modulated capture channel
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    Topics: Computer Science
    Notes: Abstract We consider the slotted ALOHA protocol on a channel with a capture effect. There are M 〈 ∞ users each with an infinite buffer. If in a slot, i packets are transmitted, then the probability of a successful reception of a packet is q i. This model contains the CDMA protocols as special cases. We obtain sufficient rate conditions, which are close to necessary for stability of the system, when the arrival streams are stationary ergodic. Under the same rate conditions, for general regenerative arrival streams, we obtain the rates of convergence to stationarity, finiteness of stationary moments and various functional limit theorems. Our arrival streams contain all the traffic models suggested in the recent literature, including the ones which display long range dependence. We also obtain bounds on the stationary moments of waiting times which can be tight under realistic conditions. Finally, we obtain several results on the transient performance of the system, e.g., first time to overflow and the limits of the overflow process. We also extend the above results to the case of a capture channel exhibiting Markov modulated fading. Most of our results and proofs will be shown to hold also for the slotted ALOHA protocol without capture.
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    BIT 40 (2000), S. 62-73 
    ISSN: 1572-9125
    Keywords: Gaussian elimination ; stability ; pivoting
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    Topics: Mathematics
    Notes: Abstract It has been recently shown that large growth factors might occur in Gaussian Elimination with Partial Pivoting (GEPP) also when solving some plausibly natural systems. In this note we argue that this potential problem could be easily solved, with much smaller risk of failure, by very small (and low cost) modifications of the basic algorithm, thus confirming its inherent robustness. To this end, we first propose an informal model with the goal of providing further support to the comprehension of the stability properties of GEPP. We then report the results of numerical experiments that confirm the viewpoint embedded in the model. Basing on the previous observations, we finally propose a simple scheme that could be turned into (even more) accurate software for the solution of linear systems.
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    BIT 40 (2000), S. 226-240 
    ISSN: 1572-9125
    Keywords: Stochastic differential equations ; regularisation ; stability
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    Topics: Mathematics
    Notes: Abstract This paper is devoted to the numerical analysis of ill-posed problems of evolution equations in Banach spaces using certain classes of stochastic one-step methods. The linear stability properties of these methods are studied. Regularisation is given by the choice of the regularisation parameter as α = $$\sqrt {\tau _n }$$ , where τ n is the stepsize and provides the convergence on smooth initial data. The case of the approximation of well-posed problems is also considered.
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    BIT 40 (2000), S. 611-639 
    ISSN: 1572-9125
    Keywords: Runge-Kutta methods ; stability ; convergence ; stiff problems
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    Topics: Mathematics
    Notes: Abstract This paper studies the stability and convergence properties of general Runge-Kutta methods when they are applied to stiff semilinear systems y′(t) = J(t)y(t) + g(t, y(t)) with the stiffness contained in the variable coefficient linear part. We consider two assumptions on the relative variation of the matrix J(t) and show that for each of them there is a family of implicit Runge-Kutta methods that is suitable for the numerical integration of the corresponding stiff semilinear systems, i.e. the methods of the family are stable, convergent and the stage equations possess a unique solution. The conditions on the coefficients of a method to belong to these families turn out to be essentially weaker than the usual algebraic stability condition which appears in connection with the B-stability and convergence for stiff nonlinear systems. Thus there are important RK methods which are not algebraically stable but, according to our theory, they are suitable for the numerical integration of semilinear problems. This paper also extends previous results of Burrage, Hundsdorfer and Verwer on the optimal convergence of implicit Runge-Kutta methods for stiff semilinear systems with a constant coefficients linear part.
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    Set-valued analysis 8 (2000), S. 253-266 
    ISSN: 1572-932X
    Keywords: Hausdorff metric ; linear inequality systems ; stability
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    Topics: Mathematics
    Notes: Abstract In this paper, we propose a Hausdorff metric to measure the “distance” between two linear inequality systems on a real normed space X. For this topology, which comes through a pseudo-metric in the set Σ of linear inequality systems, the closedness of the feasible set mapping is studied, and at the same time a characterization of the stability of the subset Σ c of consistent sytems is given.
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    Advances in computational mathematics 12 (2000), S. 229-250 
    ISSN: 1572-9044
    Keywords: numerical analysis ; shallow water problems ; DIRK methods ; stability ; 65L06 ; 65L20 ; 65M12 ; 65M20
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    Topics: Mathematics
    Notes: Abstract We construct A‐stable and L‐stable diagonally implicit Runge–Kutta methods of which the diagonal vector in the Butcher matrix has a minimal maximum norm. If the implicit Runge–Kutta relations are iteratively solved by means of the approximately factorized Newton process, then such iterated Runge–Kutta methods are suitable methods for integrating shallow water problems in the sense that the stability boundary is relatively large and that the usually quite fine vertical resolution of the discretized spatial domain is not involved in the stability condition.
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    Acta applicandae mathematicae 62 (2000), S. 23-130 
    ISSN: 1572-9036
    Keywords: stability ; functional equations ; Cauchy difference ; semigroup ; inequalities ; approximate
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    Topics: Mathematics
    Notes: Abstract In this paper, we study the stability of functional equations that has its origins with S. M. Ulam, who posed the fundamental problem 60 years ago and with D. H. Hyers, who gave the first significant partial solution in 1941. In particular, during the last two decades, the notion of stability of functional equations has evolved into an area of continuing research from both pure and applied viewpoints. Both classical results and current research are presented in a unified and self-contained fashion. In addition, related problems are investigated. Some of the applications deal with nonlinear equations in Banach spaces and complementarity theory.
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    Circuits, systems and signal processing 19 (2000), S. 13-25 
    ISSN: 1531-5878
    Keywords: Singular systems ; delay ; consistency condition ; stability ; instability
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    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract In this paper, the general class of singular systems with delay and linear constant coefficient singular systems with delay are discussed. First, several definitions of stability are presented for singular systems with delay, and general sufficient stability conditions and instability conditions are obtained. Second, stability and instability are analyzed for linear constant coefficient singular systems with delay.
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    Nonlinear dynamics 22 (2000), S. 361-374 
    ISSN: 1573-269X
    Keywords: 4WS vehicle ; time delay ; stability ; Hopf bifurcation
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    Topics: Mathematics
    Notes: Abstract A mathematical model is presented for four-wheel-steeringvehicles, with the time delay in driver's response and the nonlinearityin lateral tyre forces taken into account. It is proved that thevehicle-driver system has a trivial steady state motion, as well aseight non-trivial steady state motions due to the nonlinearity of tyreforces. The asymptotic stability and Hopf bifurcation of the trivialsteady state are analyzed for two control strategies ofrear-wheel-steering. It is shown through the numerical simulations thatthe four-wheel-steering technique based on the bilinear control strategyworks better when the driver's response involves time delay.
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    Cybernetics and systems analysis 36 (2000), S. 916-924 
    ISSN: 1573-8337
    Keywords: stochastic model ; "dangling spider problem" ; stability ; Lyapunov-Krasovskii functional
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    Topics: Computer Science
    Notes: Abstract To study the stability of the stochastic "dangling spider" model, the second Lyapunov method is substantiated for stochastic differential functional equations with the entire previous history.
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    Chemistry of heterocyclic compounds 36 (2000), S. 115-133 
    ISSN: 1573-8353
    Keywords: thiophthalylium salts ; methods of preparation ; structure ; stability ; reactivity ; electrophilic properties
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Methods of preparation, chemical reactions, the structures and reactivity of thiophthalylium ions are reviewed.
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    Journal of scientific computing 15 (2000), S. 441-456 
    ISSN: 1573-7691
    Keywords: modified conjugate gradient method ; conjugate gradient method ; Krylov space ; convergence rate ; stability
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    Topics: Computer Science
    Notes: Abstract We consider the modified conjugate gradient procedure for solving A $$\underline x $$ = $$\underline b $$ in which the approximation space is based upon the Krylov space associated with A 1/p and $$\underline b $$ , for any integer p. For the square-root MCG (p=2) we establish a sharpened bound for the error at each iteration via Chebyshev polynomials in $$\sqrt A$$ . We discuss the implications of the quickly accumulating effect of an error in $$\sqrt A$$ $$\underline b $$ in the initial stage, and find an error bound even in the presence of such accumulating errors. Although this accumulation of errors may limit the usefulness of this method when $$\sqrt A$$ $$\underline b $$ is unknown, it may still be successfully applied to a variety of small, “almost-SPD” problems, and can be used to jump-start the conjugate gradient method. Finally, we verify these theoretical results with numerical tests.
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    Neural processing letters 12 (2000), S. 129-144 
    ISSN: 1573-773X
    Keywords: associative memory ; dynamical systems ; Glauber dynamics ; Hopfield model ; infinite dimensional state space ; stability
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    Topics: Computer Science
    Notes: Abstract A generalization of the Little–Hopfield neural network model for associative memories is presented that considers the case of a continuum of processing units. The state space corresponds to an infinite dimensional euclidean space. A dynamics is proposed that minimizes an energy functional that is a natural extension of the discrete case. The case in which the synaptic weight operator is defined through the autocorrelation rule (Hebb rule) with orthogonal memories is analyzed. We also consider the case of memories that are not orthogonal. Finally, we discuss the generalization of the non deterministic, finite temperature dynamics.
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    Investigational new drugs 18 (2000), S. 373-381 
    ISSN: 1573-0646
    Keywords: clinical pharmacology ; dihydropyrimdine dehydrogenase ; eniluracil ; oral 5-FU ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD)represents one strategy to improve 5-FU therapy, which historically hasbeen associated with unpredictable pharmacological behavior andtoxicity. This is principally due to high interpatientdifferences in the activity of DPD, the enzyme that mediates theinitial and rate-limiting step in 5-FU catabolism. Byinactivating DPD and suppressing the catabolism of 5-FU,eniluracil has dramatically altered the pharmacological profileof 5-FU. The maximum tolerated dose of oral 5-FU given with oraleniluracil (1.0 to 25 mg/m2) is substantially lower thanconventional 5-FU doses. In the presence of eniluracil,bioavailability of 5-FU has increased to approximately 100%, thehalf-life is prolonged to 4 to 6 hours, and systemic clearanceis reduced 〉 20-fold to values comparable the glomerularfiltration rate (46 to 58 mL/min/m2). Renal excretion(∼ 45% to 75%), instead of DPD-related catabolism, is theprincipal route of elimination of oral 5-FU given witheniluracil. Chronic daily administration of oral 5-FU 1.0mg/m2 twice daily with eniluracil 20 mg twice dailyproduces 5-FU steady-state concentrations (8–38 ng/mL) similarto those achieved with protracted intravenous administration onclinically relevant dose-schedules. On a daily × 5regimen, higher 5-FU AUC values are related to neutropenia,whereas elevated 5-FU AUC and steady-state concentrations arerelated to diarrhea when oral 5-FU is given daily with eniluracilon a chronic schedule. The pharmacokinetic behavior of oraleniluracil is similar to that for oral 5-FU. Administration ofeniluracil 10 to 20 mg twice daily completely inactivates DPDactivity both in peripheral blood mononuclear cells and incolorectal tumor tissue, and prolonged inhibition of DPD afterdiscontinuation of eniluracil treatment has been noted. In thepresence of eniluracil, oral administration of 5-FU is feasibleand variation in 5-FU exposure is reduced, with the anticipationof further reduction in variation as dosing guidelines based onrenal function are formulated.
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    Applied mathematics and mechanics 21 (2000), S. 1390-1400 
    ISSN: 1573-2754
    Keywords: suspended solid particles ; continuum phase-coupled model ; stability ; moving jet ; numerical computation ; O359
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract The spatial stability equation of moving jet containing dense suspended solid particles was derived out by means of the continuum phase-coupled model. The stability curves of moving jet for different downstream distances, Reynolds number of flow-field, particle properties and velocities of jetting device are got by the finite difference method based on the asymptotic method and the Eulerian conservative difference scheme. Founded on the analysis of the obtained stability curves it is found that the positive velocity of jetting device widens the unstable frequency range of flow-field but the effect of the negative one is contrary. In addition, particles existing in the flow-field curb the instability of flow-field and the effect enhances with the decrease of Reynolds number of flow-field. These conclusions benefit learning the development of moving two-phase jet.
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    Applied mathematics and mechanics 21 (2000), S. 209-216 
    ISSN: 1573-2754
    Keywords: composite material ; rotational shell ; stability ; nonlinear ; O347.3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract By adopting the energy method, a new method to calculate the stability of the composite shell of revolution is presented. This method takes the influence of nonlinear prebuckling deformations and stresses on the buckling of the shell into account. The relationships between the prebuckling deformations and strains are calculated by nonlinear Kármán equations. The numerical method is used to calculate the energy of the total system. The nonlinear equations are solved by combining gradient method and amendatory Newton iterative method. The computer program is also developed. An example is given to demonstrate the accuracy of the method presented.
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    Applied mathematics and mechanics 21 (2000), S. 237-242 
    ISSN: 1573-2754
    Keywords: system identification ; damped least square ; recursive algorithm ; convergence ; stability ; O231 ; O241
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract The recursive least square is widely used in parameter identification. But it is easy to bring about the phenomena of parameters burst-off. A convergence analysis of a more stable identification algorithm-recursive damped least square is proposed. This is done by normalizing the measurement vector entering into the identification algorithm. It is shown that the parametric distance converges to a zero mean random variable. It is also shown that under persistent excitation condition, the condition number of the adaptation gain matrix is bounded, and the variance of the parametric distance is bounded.
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    Reaction kinetics and catalysis letters 71 (2000), S. 33-40 
    ISSN: 1588-2837
    Keywords: Pt-USY ; de-NOx ; HC-SCR ; propene ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Selective catalytic reduction of NOx by propene has been investigated on Pt-USY and compared to other Pt-catalysts. The catalyst was characterized by XRD, Ar adsorption at 87 K, TEM, and CO chemisorption, and tested in a gas mixture system in excess oxygen. Pt-USY shows an excellent activity in the reaction, with a molar NOx conversion of 90% at 475 K. Stability during time-on-stream and resistance to SO2 and H2O in the feed stream has also been investigated. Pt-USY performs better under lean-burn conditions than other Pt-catalysts on ZSM-5, Al2O3, or SiO2. The selectivity to N2 was similar for all the catalysts (∼30%), the other major product being N2O.
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    Journal of mathematical chemistry 28 (2000), S. 325-340 
    ISSN: 1572-8897
    Keywords: numerical method ; stability ; Hopf bifurcation ; coupled oscillator
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    Topics: Chemistry and Pharmacology , Mathematics
    Notes: Abstract A second-order accurate numerical method has been proposed for the solution of a coupled non-linear oscillator featuring in chemical kinetics. Although implicit by construction, the method enables the solution of the model initial-value problem (IVP) to be computed explicitly. The second-order method is constructed by taking a linear combination of first-order methods. The stability analysis of the system suggests the existence of a Hopf bifurcation, which is confirmed by the numerical method. Both the critical point of the continuous system and the fixed point of the numerical method will be seen to have the same stability properties. The second-order method is more competitive in terms of numerical stability than some well-known standard methods (such as the Runge–Kutta methods of order two and four).
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    Applied mathematics and mechanics 21 (2000), S. 1177-1186 
    ISSN: 1573-2754
    Keywords: elastic foundation ; pipe conveying fluid ; coupled-mode flutter ; stability ; power series method ; 0353
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract The governing equation of solid-liquid couple vibration of pipe conveying fluid on the elastic foundation was derived. The critical velocity and complex frequency of pipe conveying fluid on Winkler elastic foundation and two-parameter foundation were calculated by power series method. Compared with pipe without considering elastic foundation, the numerical results show that elastic foundation can increase the critical flow velocity of static instability and dynamic instability of pipe. And the increase of foundation parameters may increase the critical flow velocity of static instability and dynamic instability of pipe, thereby delays the occurrence of divergence and flutter instability of pipe. For higher mass ratio β, in the combination of certain foundation parameters, pipe behaves the phenomenon of restabilization and redivergence after the occurrence of static instability, and then coupled-mode flutter takes place.
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    ISSN: 1573-0778
    Keywords: CHO cells ; gel microdrops ; human antibody ; population parameters ; productivity ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract The long-term stability of high-level expression is the mostimportant factor to consider when choosing cell lines for the expression of recombinant proteins. Declining volumetricyields in large-scale fermentation can be caused by changes affecting the cell population as a whole such as loss in viability, depletion of nutrients or accumulation of metabolites affecting cell growth. Alternatively, geneticinstability may lead to the outgrowth of a less productive,metabolically favored sub-population. Currently a variety ofparameters are measured to monitor the condition of cells infermenters including glucose uptake, lactate accumulation andoxygen consumption; in addition, periodic viable cell countsallow the determination of the growth rate and viability of the population. All of these methods measure the condition ofthe cell population as a whole and changes must involve a significantly large proportion of the total culture in orderto be detectable. Here we report on a method that allows theevaluation of the productivity of individual cells. Using the gel microdrop secretion assay, we detected the appearance ofa sub-population of cells with lower productivity. Subsequentanalysis of the culture confirmed the existence of lower productivity cells with a lower vector copy number. Therefore,the single cell secretion assay proved to be a rapid method todetect and isolate a low productivity variant of the producer cell line.
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    Dynamics and control 10 (2000), S. 255-276 
    ISSN: 1573-8450
    Keywords: continuous-time systems ; frequency weighted model reduction ; gradient flow ; optimization ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract Inthis paper, a model reduction technique based on optimizationis presented. The objective function minimized is the impulseenergy of the overall system. An extension of the technique tothe frequency weighted case is also presented, where single-sidedor double-sided weightings can be incorporated in the reductionprocedure. The paper proposes an alternative to find an optimizationsolution by solving ordinary differential equations which aregradient flow associated with the objective function to be minimized.Two examples are presented to illustrate the effectiveness ofthe method.
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    Dynamics and control 10 (2000), S. 47-61 
    ISSN: 1573-8450
    Keywords: stability ; robust control ; Lyapunov approach ; discrete system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology
    Notes: Abstract Control design of nonlinear discrete-time uncertain systems with (possibly fast) uncertain parameters is considered. We study the effect of only partially compensating the uncertainty. The optimal choice of a design parameter, which indicates the amount of compensation, is recommended.
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    ISSN: 1573-904X
    Keywords: benzodiazepines ; pharmacokinetics ; EEG ; operational model of agonism ; receptor binding ; muscimol-induced Cl−uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A mechanism-based model is applied to analyse adaptivechanges in the pharmacodynamics of benzodiazepines upon chronictreatment in rats. Methods. The pharmacodynamics of midazolam was studied in ratswhich received a constant rate infusion of the drug for 14 days, resultingin a steady-state concentration of 102 ± 8 ng·ml−1. Vehicle treated ratswere used as controls. Concentration-EEG effect data were analysed onbasis of the operational model of agonism. The results were comparedto data obtained in vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEGeffect was non-linear. In midazolam pre-treated rats the maximum EEGeffect was reduced by 51 ± 23 μV from the original value of 109 ±15 μV in vehicle treated group. Analysis of this change on basis ofthe operational model of agonism showed that it can be explained bya change in the parameter tissue maximum (Em) rather than efficacy(τ). In the in vitro studies no changes in density, affinity or functionalityof the benzodiazepine receptor were observed. Conclusions. It is concluded that the observed changes in theconcentration-EEG effect relationship of midazolam upon chronic treatmentare unrelated to changes in benzodiazepine receptor function.
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  • 76
    ISSN: 1573-904X
    Keywords: luteinising hormone-releasing hormone (LH-RH) antagonist ; cetrorelix ; pharmacokinetics ; population PK/PD-modeling ; testosterone ; rat ; dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Population models for thepharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasinghormone (LH-RH) antagonist, and the pharmacodynamic response ontestosterone production were investigated in rats and dogs. Methods. The plasma concentrations of CET and testosterone weredetermined after intravenous and subcutaneous injections. Thepopulation PK/PD-models were developed using P-PHARM software. Results. Absolute bioavailability of cetrorelix was 100% in rats and97% in dogs. In rats, the pharmacokinetics was explained by atwo-compartment model with saturable absorption, while athree-compartment model was used in dogs. Testosterone suppression in both specieswas described by a sigmoid Emax model with maximum effect (Emax)considered as total hormonal suppression. The duration of testosteronesuppression in rats was longer at higher doses. The populationelimination half-lifes after iv-dose were 3.0 h in rats and 9.3 h in dogs.Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in ratsand dogs, respectively. Conclusions. A population pharmacokinetic model was developed toexplain the dissolution rate limited absorption from the injection site.The suppression of testosterone could be described by an indirectinhibitory sigmoid Emax model. In both species 1-2 ng/ml CET inplasma was necessary to suppress testosterone production.
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  • 77
    ISSN: 1573-904X
    Keywords: methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
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  • 78
    ISSN: 1573-904X
    Keywords: SK&F 107647 ; peptide ; pharmacokinetics ; hematore gulatory ; adenocarcinoma ; cytokines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe the pharmacokinetics of SK&F 107647, a synthetichematoregulatory peptide, in healthy volunteers and in patientswith adenocarcinoma.Methods. SK&F 107647 pharmacokinetics were evaluated in 2dose-escalation studies. Volunteers received SK&F 107647 as single15-minute iv infusion doses of 1, 10, 100, 500, and 1000 μg/kg. Cancerpatients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1μg/kg once daily for 10 days. Drug concentrations were quantified in plasmaand urine of healthy volunteers and on days 1 and 10 in plasma ofcancer patients receiving the two top dose levels.Results. In volunteers, mean clearance (CL) ranged from 76.7 to 101ml/hour/kg; mean volume of distribution at steady-state (Vss)rangedfrom 175 to 268 ml/kg. Most of the administered dose was renallyexcreted as intact peptide within 24 hours postinfusion. In patients,mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150ml/kg and terminal half-life from 2.1 to 3.4 hours. There was littleaccumulation of drug. In both studies, linear pharmacokinetics wasobserved. Clearance approached normal glomerular filtration rate(GFR) in volunteers and correlated with creatinine clearance incancer patients.Conclusions. SK&F 107647 exhibits linear pharmacokinetics, a smallVss, and clearance, primarily renal, approaching normal GFR.
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  • 79
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; recombinant human interleukin-11 ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 80
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    Acta mechanica Sinica 16 (2000), S. 264-272 
    ISSN: 1614-3116
    Keywords: nonlinear dynamics ; bifurcation ; stability ; fluid-solid interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract This paper studies interactions of pipe and fluid and deals with bifurcations of a cantilevered pipe conveying a steady fluid, clamped at one end and having a nozzle subjected to nonlinear constraints at the free end. Either the nozzle parameter or the flow velocity is taken as a variable parameter. The discrete equations of the system are obtained by the Ritz-Galerkin method. The static stability is studied by the Routh criteria. The method of averaging is employed to examine the analytical results and the chaotic motions. Three critical values are given. The first one makes the system lose the static stability by pitchfork bifurcation. The second one makes the system lose the dynamical stability by Hopf bifurcation. The third one makes the periodic motions of the system lose the stability by doubling-period bifurcation.
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  • 81
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    Applied mathematics and mechanics 21 (2000), S. 987-994 
    ISSN: 1573-2754
    Keywords: stability ; chaos ; averaging method ; Galerkin method ; viscoelastic column ; O322
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract The dynamical stability of a homogeneous, simple supported column, subjected to a periodic axial force, is investigated. The viscoelastic material is assumed to obey the Leaderman nonlinear constitutive relation. The equation of motion was derived as a nonlinear integro-partial-differential equation, and was simplified into a nonlinear integro-differential equation by the Galerkin method. The averaging method was employed to carry out the stability analysis. Numerical results are presented to compare with the analytical ones. Numerical results also indicate that chaotic motion appears.
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  • 82
    ISSN: 1573-5125
    Keywords: discharge effects on lotic invertebrates ; disturbance ; persistence ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Temporal and spatial trends were examined in benthic macroinvertebrate and physical-chemical data collected for at least ten years at ten sites along the plains reach of the Cache la Poudre River, Colorado, USA. A distinct longitudinal environment gradient was found as many of the water chemistry parameter levels changed downstream from the reference site. Seasonal Kendall analyses on individual sites indicated that several chemical parameters, including conductivity, un-ionized NH3-N and NO2-N have increased since the beginning of the study within most sites. Levels of some parameters (e.g., dissolved oxygen, un-ionized NH3-N) violated aquatic life standards a few times during the study. Over 175 taxa of macroinvertebrates (primarily insects) were collected in the study reach from 1981–1996. Results from detrended correspondence analyses (DCA) on macroinvertebrate data indicated that this stretch of the river exhibited little longitudinal change beyond the two farthest upstream sites. There was a decline in macroinvertebrate density and total number of taxa within most individual sites during 1983–1984, corresponding with the highest recorded discharge in 75 years (1983) and a prolonged, heavy spring runoff in 1984. Taxa richness and density recovered to pre-1983 levels within a few months to a year following the high flows at most sites. These findings suggested that the macroinvertebrate assemblages had low resistance to disturbance, but high resilience. However, the results from DCAs and Kendall's Coefficient of Concordance (W) on individual sites for the entire study period suggested a similar macroinvertebrate community structure through time. It would appear that the composition and abundance of the lotic macroinvertebrate assemblages in the Poudre River has remained relatively constant over the long-term. This has occurred even with some potentially negative changes in water chemistry and increased urban development.
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  • 83
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    Neural processing letters 10 (1999), S. 267-271 
    ISSN: 1573-773X
    Keywords: recurrent neural networks ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract In this paper, we point out that the conditions given in [1] are sufficient but unnecessary for the global asymptotically stable equilibrium of a class of delay differential equations. Instead, we prove that under weaker conditions, it is still global asymptotically stable.
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  • 84
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    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    ISSN: 1573-8744
    Keywords: muscle relaxants ; peripheral elimination ; pharmacokinetics ; peripheral concentrations ; volume of distribution ; pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10 ) and peripheral compartments(k20 ). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss ) are also mostly significant when k20 is smaller than k10 . Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20 , the rate of transfer from the central compartment (k12 ) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.
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  • 85
    ISSN: 1432-0770
    Keywords: Key words: Hebbian learning rule ; attractor dynamics ; symmetric connections ; multiplicative normalization ; self-organization ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract. While learning and development are well characterized in feedforward networks, these features are more difficult to analyze in recurrent networks due to the increased complexity of dual dynamics – the rapid dynamics arising from activation states and the slow dynamics arising from learning or developmental plasticity. We present analytical and numerical results that consider dual dynamics in a recurrent network undergoing Hebbian learning with either constant weight decay or weight normalization. Starting from initially random connections, the recurrent network develops symmetric or near-symmetric connections through Hebbian learning. Reciprocity and modularity arise naturally through correlations in the activation states. Additionally, weight normalization may be better than constant weight decay for the development of multiple attractor states that allow a diverse representation of the inputs. These results suggest a natural mechanism by which synaptic plasticity in recurrent networks such as cortical and brainstem premotor circuits could enhance neural computation and the generation of motor programs.
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  • 86
    ISSN: 1573-904X
    Keywords: antisense ; Brown-Norway rat ; oligodeoxynucleotide ; pulmonary delivery ; ISIS 2105 ; pharmacokinetics ; airway inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. Methods. The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naïve and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. Results. CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITCJ-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages 〉 eosinophils = neutrophils 〉 〉 lymphocytes. Conclusions. The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
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  • 87
    ISSN: 1573-904X
    Keywords: calcitonin ; polyethylene glycol ; PEGylation ; peptide ; tryptic digestion ; stability ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To separate and characterize the different positional isomers of mono-PEGylated salmon calcitonins (mono-PEG-sCTs) and to evaluate the effects of the PEGylation site on the stability of different mono-PEG-sCTs in rat kidney homogenate. Methods. Mono-PEG-sCTs were prepared using succinimidyl carbonate monomethoxy polyethylene glycol (5,000 Da) and separated by gel-filtration HPLC followed by reversed-phase HPLC. To characterize PEGylated sCTs, matrix-assisted laser desorption ionization time of flight mass spectrometry (M ALDI-TOF MS) and reversed-phase HPLC of the trypsin digested samples were performed. Mono-PEG-sCTs and sCT in rat kidney homogenates were measured by column-switching reversed-phase HPLC with on-line detection of the radioiodinated samples using a flow-through radioisotope detector. Results. Three different mono-PEGylated sCTs were separated by reversed-phase gradient HPLC. From the MALDI-TOF MS analysis, the average molecular weight of mono-PEG-sCTs was confirmed as around 8650 Da. The presence of PEG moiety in the mono-PEG-sCTs was also manifested by the fact that the distance between two adjacent mass spectum lines was 44 Da which corresponds to PEG monomer unit. Tryptic digestion analysis demonstrated that these mono-PEG-sCTs are 3 positional isomers of N-terminus, Lys18- and Lys11-residue modified mono-PEGylated sCTs. The degradation half-life of these 3 positional isomers in rat kidney homogenates significantly increased in order of the N-terminus (125.5 min), Lys11- (157.3 min), and Lysl8-residue modified mono-PEGylated sCT (281.5 min) over the native sCT (4.8 min). Conclusions. Three positional isomers of mono-PEGylated sCTs were purified and characterized. Of these, the resistance to proteolytic degradation was highest for the Lysl8-residue modified mono-PEG-sCT. These studies demonstrate that the in vivo stability of PEGylated sCTs is highly dependent on the site of PEG molecule attachment.
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  • 88
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; Calphostin C ; HPLC ; perylenequinone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the pharmacokinetic features and metabolism of calphostin C, a naturally occurring perylenequinone with potent antileukemic activity. Methods. HPLC-based quantitative detection methods were used to measure calphostin C levels in lysates of leukemic cells and in plasma of mice treated with calphostin C. The plasma concentration-time data were analyzed using the WinNonlin program. In vitro esterases and a microsome P450 preparation in conjunction with a LC-MS(API-EI) system were used to study the metabolism of calphostin C. Results. An intracellular exposure level (AUC0−6h) of 257 μM·h was achieved after in vitro treatment of NALM-6 cells with calphostin C at a 5 μM final concentration in culture medium. After intraperitoneal (i.p.) injection of a 40 mg/kg nontoxic bolus dose of calphostin C, the estimated Cmax was 2.9 μM, which is higher than the effective in vitro concentration of calphostin C against leukemic cells. Drug absorption after i.p. administration was rapid with an absorption half-life of 24.2 min and the estimated tmax was 63.0 min. Calphostin C was cleared with an elimination half-life of 91.3 min. An inactive and smaller metabolite (calphostin B) was detected in plasma of calphostin C-treated mice with a tmax of 41.3 min. Esterase (but not P450) treatment of calphostin C in vitro yielded an inactive metabolite (calphostin B) of the same size and elution profile. Conclusions. Target plasma calphostin C concentrations of potent antileukemic activity can be reached in mice at nontoxic dose levels. This pilot pharmacokinetic study of calphostin C combined with the availability of the described quantitative HPLC method for its detection in cells and plasma provide the basis for future preclinical evaluation of calphostin C and its potential as an anti-leukemic drug.
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  • 89
    ISSN: 1573-904X
    Keywords: diffusion model ; drug delivery system ; ocular penetration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
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  • 90
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    Pharmaceutical research 16 (1999), S. 1608-1615 
    ISSN: 1573-904X
    Keywords: tenidap ; pharmacokinetics ; EM algorithm ; nonlinear mixed-effects modelling ; covariates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To develop a pharmacokinetic model for tenidap and to identify important relationships between the pharmacokinetic parameters and available covariates. Methods. Plasma concentration data from several phase I and phase II studies were used to develop a pharmacokinetic model for tenidap, a novel anti-rheumatic drug. An appropriate pharmacokinetic model was selected on the basis of individual nonlinear regression analyses and an EM algorithm was used to perform a nonlinear mixed-effects analysis. Scatter plots of posterior individual pharmacokinetic parameters were used to identify possible covariate effects. Results. Predicted responses were in good agreement with the observed data. A bi-exponential model with zero order absorption was subsequently used to develop the mixed-effects model. Covariate relationships selected on the basis of differences in the objective function, although statistically significant, were not particularly strong. Conclusions. The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.
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  • 91
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    Pharmaceutical research 16 (1999), S. 176-185 
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; pharmacology ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
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  • 92
    ISSN: 1573-904X
    Keywords: aminolevulinic acid ; intravesical ; pharmacokinetics ; photodiagnosis ; bladder ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.
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  • 93
    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
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  • 94
    ISSN: 1573-904X
    Keywords: C6-glioma ; methotrexate ; microdialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Establishment of the pharmacokinetic profile of methotrexate (MTX) in the extracellular fluid (ECF) of a brain C6-glioma in rats. Methods. Serial collection of plasma samples and ECF dialysates after i.v. infusion of MTX (50 or 100 mg/kg) for 4 h. HPLC assay. Results. Histological studies revealed the presence of inflammation, edema, necrosis, and hemorrhage in most animals. In vivo recovery (reverse dialysis) was 10.8 ± 5.3%. MTX concentrations in tumor ECF represented about 1−2% of the plasma concentrations. Rapid equilibration between MTX levels in brain tumor ECF and plasma. ECF concentrations almost reached steady-state by the end of the infusion (4 h), then decayed in parallel with those in plasma. Doubling of the dose did not modify MTX pharmacokinetic parameters (t1/2α, t1/2β, MRT, fb, Vd, and CLT), except for a 1.7-fold increase of AUCPlasma and a 3.8-fold increase in AUCECF which resulted in a 2.3-fold increase in penetration (AUCECF/AUCPlasma). In spite of an important interindividual variability, a relationship between MTX concentrations in plasma and tumor ECF could be established from mean pharmacokinetic parameters. Conclusions. High plasma concentrations promote the penetration of MTX into brain tissue. However, free MTX concentrations in tumor ECF remain difficult to predict consistently.
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  • 95
    ISSN: 1573-904X
    Keywords: HI-240 ; nonnucleoside inhibitor ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values. Results. HI-240 had an elimination half-life of 78.3 ± 2.0 min after i.v. administration and 196.8 ± 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 ± 61 ml/h/kg after i.v. administration and 9339 ± 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 ±1.1 min and a tmax of 95.1 ± 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%. Conclusions. The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
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    Pharmaceutical research 16 (1999), S. 261-265 
    ISSN: 1573-904X
    Keywords: crystal habit ; trimethoprim suspension ; physical stability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The role of crystal habit in influencing the physical stability and pharmacokinetics of trimethoprim suspensions was examined. Methods. Different habits of trimethoprim (TMP) were obtained by recrystallizing the commercial sample (PD) utilizing solvent-change precipitation method. Four distinct habits (microscopic observation) belonging to the same polymorphic state (DSC studies) were selected for studies. Preformulation and formulation studies were carried out on suspension dosage forms containing these crystals. The freshly prepared suspensions were also evaluated for their pharmacokinetic behaviour on healthy human volunteers using a cross over study. Results. Variation of crystallization conditions produces different habits of TMP. Among the different crystal habits exhibiting same polymorphic state, the most anisometric crystal showed best physical stability in terms of sedimentation volume and redispersibility. However, habit did not significantly affect the extent of TMP excreted in urine. Conclusions. Modification of surface morphology without significantly altering the polymorphic state can be utilized for improving physical stability of TMP suspensions. However, the pharmacokinetic profile remains unaltered.
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  • 97
    ISSN: 1573-904X
    Keywords: submicron lipid emulsion ; supersaturation ; tirilazad ; venous irritation ; pharmacokinetics ; tissue distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p 〉 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower Vss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p 〈 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
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  • 98
    ISSN: 1573-904X
    Keywords: bioequivalence ; neural networks ; prediction ; pharmacokinetics ; verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, cmax, tmax) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, cmax, and tmax prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for cmax, and the presence of food, blood pressure, and body-frame for tmax. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.
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  • 99
    ISSN: 1573-904X
    Keywords: WHI-P180 ; pharmacokinetics ; quinazolines ; mast cell inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the present study was to examine the pharma-codynamic and pharmacokinetic features of the novel mast cell inhibitor 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P180) in mice. Methods. A high performance liquid chromatography (HPLC)-based quantitative detection method was used to measure plasma WHI-P180 levels in mice. The plasma concentration-time data was fit to a single compartment pharmacokinetic model by using the WinNonlin program to calculate the pharmacokinetic parameters. A cutaneous anaphylaxis model was used to examine the pharmacodynamic effects of WHI-P180 on anaphylaxis-associated vascular hyperpermeability. Results. The elimination half-life of WHI-P180 in CD-1 mice (BALB/ c mice) following i.v., i.p., or p.o. administration was less than 10 min. Systemic clearance of WHI-P180 was 6742 mL/h/kg in CD-1 mice and 8188 mL/h/kg in BALB/c mice. Notably, WHI-P180, when administered in two consecutive nontoxic i.p. bolus doses of 25 mg/kg, inhibited IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis. Conclusions. WHI-P180 is an active inhibitor of IgE-mediated mast cell responses in vitro and in vivo. Further preclinical characterization of WHI-P180 may improve the efficacy of WHI-P180 in vivo and provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
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  • 100
    ISSN: 1573-904X
    Keywords: etomidate ; pharmacokinetics ; pharmacodynamics ; rat ; electroencephalogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect-plasma concentration relationship of etomidate was studied in the rat using electroencephalographic changes as a pharmacodynamic parameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rats (n = 6) until isoelectric periods of 5 s or longer were observed in the electroencephalogram (EEG). The EEG was continuously recorded during the experiment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signal were quantified using aperiodic analysis in the 2.5−7.5 Hz frequency band. The return of the righting reflex was used as another parameter of anesthesia. Results. A mean dose of 8.58 ± 0.41 mg/kg needed to be infused to reach the end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clearance, volume of distribution at steady-state and elimination half-life averaged 93 ± 6 ml/min/kg, 4.03 ± 0.24 l/kg and 59.4 ± 10.7 min respectively. The EEG effect-plasma concentration relationship was biphasic exhibiting profound hysteresis. Semi-parametric minimization of this hysteresis revealed an equilibration half-life of 2.65 ± 0.15 min, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. The effect-site concentration at the return of the righting reflex was 0.44 ± 0.03 μg/ml. Conclusions. The results of the present study show that the concentration-effect relationship of etomidate can be characterized in individual rats using aperiodic analysis in the 2.5−7.5 Hz frequency band of the EEG. This characterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.
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