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  • 1
    Electronic Resource
    Electronic Resource
    Glomus claroideum forms an arbuscular mycorrhiza-like symbiosis with the hornwort Anthoceros punctatus (2000)
    Springer
    Mycorrhiza 10 (2000), S. 15-21 
    Details
    ISSN: 1432-1890
    Keywords: Anthoceros punctatus ; Arbuscular mycorrhiza ; Bryophytes ; Glomus ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Glomus claroideum (Schenck & Smith emend. Walker & Vestberg) were investigated for ability to form arbuscular mycorrhiza-like symbioses with the hornwort Anthoceros punctatus (L.). Spores were transferred to a cellulose acetate filter on water agar and a small portion of an Anthoceros thallus was placed directly upon the spores. Light-microscope observations 20 days after inoculation revealed branched hyphae growing within the thallus. After 45 days, arbuscules and vesicles were studied by light- and electron-microscopy. After 60 days in water agar culture, the colonised Anthoceros thalli were transferred to a low-nutrient medium agar. Hyphae spread in the agar and newly formed spores were observed 5 weeks after the transfer. After 4 months, about 1000 spores were formed in each Petri dish. This is the first report of an experimentally established arbuscular mycorrhiza-like symbiosis between an identified fungus belonging to the Glomales and a bryophyte.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005720050282
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration (2000)
    Springer
    Bulletin of experimental biology and medicine 129 (2000), S. 359-361 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02439270
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  • 3
    Electronic Resource
    Electronic Resource
    The need for speed. II. Myelin in calanoid copepods (2000)
    Springer
    Journal of comparative physiology 186 (2000), S. 347-357 
    Details
    ISSN: 1432-1351
    Keywords: Key words Crustacean ; Sensorimotor ; Ultrastructure ; Multilamellar sheath ; Myelinated axons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Speed of nerve impulse conduction is greatly increased by myelin, a multi-layered membranous sheath surrounding axons. Myelinated axons are ubiquitous among the vertebrates, but relatively rare among invertebrates. Electron microscopy of calanoid copepods using rapid cryofixation techniques revealed the widespread presence of myelinated axons. Myelin sheaths of up to 60 layers were found around both sensory and motor axons of the first antenna and interneurons of the ventral nerve cord. Except at nodes, individual lamellae appeared to be continuous and circular, without seams, as opposed to the spiral structure of vertebrate and annelid myelin. The highly organized myelin was characterized by the complete exclusion of cytoplasm from the intracellular spaces of the cell generating it. In regions of compaction, extracytoplasmic space was also eliminated. Focal or fenestration nodes, rather than circumferential ones, were locally common. Myelin lamellae terminated in stepwise fashion at these nodes, appearing to fuse with the axolemma or adjacent myelin lamellae. As with vertebrate myelin, copepod sheaths are designed to minimize both resistive and capacitive current flow through the internodal membrane, greatly speeding nerve impulse conduction. Copepod myelin differs from that of any other group described, while sharing features of every group.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003590050435
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  • 4
    Electronic Resource
    Electronic Resource
    Absorption and Disposition of a Selective Aldosterone Receptor Antagonist, Eplerenone, in the Dog (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1426-1431 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007597713530
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  • 5
    Electronic Resource
    Electronic Resource
    Allometric Pharmacokinetic Scaling: Towards the Prediction of Human Oral Pharmacokinetics (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 410-418 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007520818956
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  • 6
    Electronic Resource
    Electronic Resource
    Physiological Modeling of Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01 (7-Hydroxystaurosporine), Caused by Slow Dissociation of UCN-01 from Human α1-Acid Glycoprotein (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 553-564 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007512832006
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  • 7
    Electronic Resource
    Electronic Resource
    Evaluation of Using Dog as an Animal Model to Study the Fraction of Oral Dose Absorbed of 43 Drugs in Humans (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 135-140 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007552927404
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  • 8
    Electronic Resource
    Electronic Resource
    An Isolated In-Situ Rat Head Perfusion Model for Pharmacokinetic Studies (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 127-134 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007500910566
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Antitumor Effect of Doxorubicin Carried by Stealth and Remote Loading Proliposome (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 782-787 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007543805947
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  • 10
    Electronic Resource
    Electronic Resource
    Potential Role of P-Glycoprotein in Affecting Hepatic Metabolism of Drugs (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 903-905 
    Details
    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
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007570517183
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  • 11
    Electronic Resource
    Electronic Resource
    Confidence Interval Criteria for Assessment of Dose Proportionality (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1278-1283 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026451721686
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  • 12
    Electronic Resource
    Electronic Resource
    A Human Physiologically-Based Model for Glycyrrhzic Acid, A Compound Subject to Presystemic Metabolism and Enterohepatic Cycling (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1516-1525 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007661209921
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  • 13
    Electronic Resource
    Electronic Resource
    Influence of Stereoselective Pharmacokinetics in the Development and Predictability of an IVIVC for the Enantiomers of Metoprolol Tartrate (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1019-1025 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007595725360
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  • 14
    Electronic Resource
    Electronic Resource
    In Vivo Specific Binding Characteristics and Pharmacokinetics of a 1,4-Dihydropyridine Calcium Channel Antagonist in the Senescent Mouse Brain (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 844-850 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007512426420
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  • 15
    Electronic Resource
    Electronic Resource
    Pharmacokinetic-Pharmacodynamic Modelling of Morphine Transport Across the Blood-Brain Barrier as a Cause of the Antinociceptive Effect Delay in Rats—A Microdialysis Study (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1220-1227 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026414713509
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  • 16
    Electronic Resource
    Electronic Resource
    Biodistribution of Amphotericin B When Delivered Through Cholesterol Hemisuccinate Vesicles in Normal and A. Fumigatus Infected Mice (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1236-1242 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026418814417
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    Safety, Toxicokinetics and Tissue Distribution of Long-Term Intravenous Liposomal Amphotericin B (ambisome®): A 91-day Study in Rats (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1494-1502 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1007605024942
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    New Insights into the Pharmacokinetics and Metabolism of (R,S)-Ifosfamide in Cancer Patients Using a Population Pharmacokinetic-Metabolism Model (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 645-652 
    Details
    ISSN: 1573-904X
    Keywords: (R,S)-Ifosfamide ; R2-, R3-, S2-, S3-DCE-IFF ; iterative-two stage analysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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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    URL: http://dx.doi.org/10.1023/A:1007561727948
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  • 19
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    Electronic Resource
    Structural changes during early embryogenesis in wheat pollen (2000)
    Springer
    Protoplasma 211 (2000), S. 94-102 
    Details
    ISSN: 1615-6102
    Keywords: Androgenesis ; Embryogenesis ; Microspore culture ; Pollen ; Ultrastructure ; Wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary We have made a detailed cytological examination of the development of wheat embryoids, monitoring their initial divisions from two to ten cells by both light and electron microscopy. According to our observations the first embryogenic division is symmetrical. After the androgenesis induction treatment, there is a decrease in ribosome population with cells that have inactive nucleoli made up almost exclusively of a dense fibrillar component. This population is restored after initial embryogenic divisions. During the initial divisions the embryogenic pollen grains do not appear to change in size and the pollen wall remains intact. The exine undergoes no modification but the intine thickens, and we have observed that the thickness of the intine can be used as a cytological marker of androgenesis. The walls separating the cells obtained after embryogenic division contained numerous plasmodesmata. The beginnings of embryo polarization and cell differentiation could be made out in the very early pollen embryoids.
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    URL: http://dx.doi.org/10.1007/BF01279902
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    Effects of glutathione on thiol redox systems, chromosomal aberrations, and the ultrastructure of meristematic root cells ofPicea abies (L.) Karst. (2000)
    Springer
    Protoplasma 212 (2000), S. 227-235 
    Details
    ISSN: 1615-6102
    Keywords: Glutathione ; Root ; Chromosomal aberration ; Ultrastructure ; Picea abies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Young spruce seedlings (Picea abies [L.] Karst.) grown in hydroponic culture were exposed to three different concentrations (50,100, and 500 μM) of reduced glutathione for 24 h. These physiologically relevant concentrations of glutathione had a multiple effect on the investigated tissue. Feeding of glutathione to roots increased the concentrations of thiols (glutathione, cysteine, and γ-glutamyl-cysteine) in roots, decreased the rate of cell divisions, induced mitotic abnormalities, and affected the cell ultrastructure. Electron micrographs showed effects such as advanced vacuolation, dilated rough-endoplasmic-reticulum cisternae, and separations of the plasma membrane from the cell wall.
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    URL: http://dx.doi.org/10.1007/BF01282923
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    2-Methylisoborneol disposition in three strains of catfish: absence of biotransformation (2000)
    Springer
    Fish physiology and biochemistry 23 (2000), S. 225-232 
    Details
    ISSN: 1573-5168
    Keywords: methylisoborneol ; catfish ; cytochrome P450 ; biotransformation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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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    URL: http://dx.doi.org/10.1023/A:1007834720306
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    Pharmacology of Fluorinated Pyrimidines: Eniluracil (2000)
    Springer
    Investigational new drugs 18 (2000), S. 373-381 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1006453500629
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    Mechanism-Based Modeling of Functional Adaptation Upon Chronic Treatment with Midazolam (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 321-327 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1007505223519
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    Population Pharmacokinetic/ Pharmacodynamic Modeling of Cetrorelix, a Novel LH-RH Antagonist, and Testosterone in Rats and Dogs (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 328-335 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1007557207590
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    Bioequivalence of Methylphenidate Immediate-Release Tablets Using a Replicated Study Design to Characterize Intrasubject Variability (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 381-384 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1007560500301
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    Pharmacokinetics of a Hematoregulatory Peptide (SK&F 107647) in Healthy Male Volunteers and in Patients with Colorectal or Pancreatic Adenocarcinoma Not Amenable to Standard Therapy (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 385-390 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1007512617139
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    In Vivo Absorption Properties of Orally Administered Recombinant Human Interleukin-11 (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 482-485 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; recombinant human interleukin-11 ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007545524408
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    Ultrastructure and anatomy of nematode-induced syncytia in roots of susceptible and resistant sugar beet (2000)
    Springer
    Protoplasma 211 (2000), S. 39-50 
    Details
    ISSN: 1615-6102
    Keywords: Beta vulgaris ; Cyst nematodes ; Histology ; Resistance mechanism ; Syncytium ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Using susceptible and resistant sugar beet lines, comparative analyses of root histology and ultrastructure were made during invasion by nematodes and the induction and formation of specific feeding structures (syncytia).The resistant line carried the resistance geneHs1pro−1.Nematodes were able to invade and induce functional syncytia in roots of resistant and susceptible lines. However, syncytia in resistant roots were smaller and less hypertrophied. The vacuolar system of syncytia in susceptible plants contained many small vacuoles. In resistant plants vacuoles were larger but less numerous. Smooth endoplasmic reticulum prevailed in syncytial protoplasts of susceptible plants, whereas almost only rough endoplasmic reticulum occurred in syncytia in resistant plants. The most conspicuous and hitherto undescribed trait of syncytia in resistant roots was the initial appearance of loose, and later compact, aggregations of the endomembrane system which composed most of the endoplasmicreticulum system of syncytia at later stages. Syncytia in resistant plants usually degraded before the nematodes reached their adult stage. The appearance of membrane aggregations and the other resistance-specific features are discussed in relation to their possible effects on syncytium function and role in nematode resistance.
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    URL: http://dx.doi.org/10.1007/BF01279898
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    Effect of osmotic stress on tolerance of air-drying and cryopreservation ofArabidopsis thaliana suspension cells (2000)
    Springer
    Protoplasma 214 (2000), S. 227-243 
    Details
    ISSN: 1615-6102
    Keywords: Arabidopsis thaliana ; Cryopreservation ; Dehydration ; Thermal analysis ; Sucrose ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Arabidopsis thaliana suspension cells were preserved in liquid nitrogen for over three years, using embedding of cells in calcium-alginate prior to subculture in sucrose-enriched medium, air-drying, and direct quenching in liquid nitrogen. Survival of cells reached 34%, yielding regrowth at the surface of all cryopreserved beads in less than 7 days. Following pretreatment and dehydration, the water content dropped from 2300% to 34% with respect to dry weight. Differential scanning calorimetry showed that glass transition occurred on cooling, followed by a slight crystallization event on rewarming. The survival of cells was independent of the cooling rate. The tolerance of the acute dehydration step increased progressively with sucrose pretreatment duration, indicating the requirement for adaptative cellular alterations. Ultrastructural studies revealed several changes in cells after sucrose pretreatment prolonged from 1 to 7 days: reversal of the initially plasmolyzed state, microvacuolation, numerous autophagic structures, scarcity of ribosomes, increase in number and size of starch grains. No cell division seemed to occur during this period. After air-drying and after a freeze-thaw cycle, followed by 24 h rehydration, regenerating cells had recovered a high level of ultrastructural organization and contained numerous polysomes suggesting an intense metabolic activity. Trehalose, a cryoprotective disaccharide not considered to be a metabolic substrate, yielded only 70% regrowth after freezing. Biochemical analysis showed that soluble sugars accumulated during the pretreatment, essentially sucrose or trehalose; the monosaccharide content also increased. In the light of these results, the action of sucrose in inducing freezing tolerance is discussed.
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    Larva-adult relationships in an ancestral dipteran: A re-examination of sensillar pathways across the antenna and leg anlagen of Chaoborus crystallinus (DeGeer, 1776; Chaoboridae) (1999)
    Springer
    Development genes and evolution 209 (1999), S. 103-112 
    Details
    ISSN: 1432-041X
    Keywords: Key words Imaginal disc ; Axonal trajectories ; Ultrastructure ; Chaoborus (Insecta ; Diptera)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  In one of his classical studies on insect metamorphosis, Weismann compared the imaginal anlagen of the ancestral phantom midge, Chaoborus, with those of advanced brachycerans. We have expanded his findings on the relationships between larval and imaginal organs using electron microscopy and cobalt backfilling of the antenna and leg anlagen and the axonal trajectories of corresponding larval sensilla. We show that both primordia are confluent with the larval antennae and ”leg” sensilla (an ancestral Keilin organ), respectively. These fully developed larval organs represent the distal tips of the imaginal anlagen rather than separate cell clusters. The axons of the larval antenna and leg sensilla project across the corresponding anlagen to their target neuromeres within the central nervous system (CNS). Within the discs, nerves composed of these larval axons, developing afferent fibres and efferences ascending from the CNS are found. Both the structure of the primordia and the axonal trajectories thus relate the situation found in advanced brachycerans with that seen in more ancestral insects. In addition, the larval antennae, legs, wings and even the eyes possess very similar afferent pioneer trajectories supporting the idea that the described pattern is generally used in the ontogeny of sensory systems.
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    URL: http://dx.doi.org/10.1007/s004270050232
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    Isolation and characterization of a Clostridium sp. with cinnamoyl esterase activity and unusual cell envelope ultrastructure (1999)
    Springer
    Archives of microbiology 172 (1999), S. 139-149 
    Details
    ISSN: 1432-072X
    Keywords: Key wordsClostridium xylanolyticum ; Cinnamic acid ; Esterase ; Lignocellulose ; Sporogenesis ; Ultrastructure ; Cell envelope
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Microorganisms that hydrolyse the ester linkages between phenolic acids and polysaccharides in plant cell walls are potential sources of enzymes for the degradation of lignocellulosic waste. An anaerobic, mesophilic, spore-forming, xylanolytic bacterium with high hydroxy cinnamic acid esterase activity was isolated from the gut of the grass-eating termite Tumilitermes pastinator. The bacterium was motile and rod-shaped, stained gram-positive, had an eight-layered cell envelope, and formed endospores. Phylogenetic analysis based on 16S rRNA indicated that the bacterium is closely related to Clostridium xylanolyticum and is grouped with polysaccharolytic strains of clostridia. A wide range of carbohydrates were fermented, and growth was stimulated by either xylan or cellobiose as substrates. The bacterium hydrolysed and then hydrogenated the hydroxy cinnamic acids (ferulic and p-coumaric acids), which are esterified to arabinoxylan in plant cell walls. Three cytoplasmic enzymes with hydroxy cinnamic acid esterase activity were identified using non-denaturing gel electrophoresis. This bacterium possesses an unusual multilayered cell envelope in which both leaflets of the cytoplasmic membrane, the peptidoglycan layer and the S layer are clearly discernible. The fate of all these components was easily followed throughout the endospore formation process. The peptidoglycan component persisted during the entire morphogenesis. It was seen to enter the septum and to pass with the engulfing membranes to surround the prespore. It eventually expanded to form the cortex, verification for the peptidoglycan origin of the cortex. Sporogenic vesicles, which are derived from the cell wall peptidoglycan, were associated with the engulfment process. Spore coat fragments appeared early, in stage II, though spore coat formation was not complete until after cortex formation.
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    URL: http://dx.doi.org/10.1007/s002030050753
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    Assuming Peripheral Elimination: Its Impact on the Estimation of Pharmacokinetic Parameters of Muscle Relaxants (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 491-512 
    Details
    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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    Distribution of a 20-Mer Phosphorothioate Oligonucleotide, CGP69846A (ISIS 5132), into Airway Leukocytes and Epithelial Cells Following Intratracheal Delivery to Brown-Norway Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1542-1549 
    Details
    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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    Pharmacokinetic Features and Metabolism of Calphostin C, A Naturally Occurring Perylenequinone with Antileukemic Activity (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1003-1009 
    Details
    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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    Characterization of Ocular Pharmacokinetics of Beta-Blockers Using a Diffusion Model After Instillation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1596-1601 
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    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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    URL: http://dx.doi.org/10.1023/A:1018964823193
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    A Pharmacokinetic Model for Tenidap in Normal Volunteers and Rheumatoid Arthritis Patients (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1608-1615 
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    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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    URL: http://dx.doi.org/10.1023/A:1018969024101
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    Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 176-185 
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    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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    URL: http://dx.doi.org/10.1023/A:1011907920641
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    Pharmacokinetics of Aminolevulinic Acid After Intravesical Administration to Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 288-295 
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    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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    Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1093-1097 
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    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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    URL: http://dx.doi.org/10.1023/A:1018900219616
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    Pharmacokinetics of Methotrexate in the Extracellular Fluid of Brain C6-Glioma After Intravenous Infusion in Rats (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1219-1225 
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    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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    URL: http://dx.doi.org/10.1023/A:1018945529611
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    Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1226-1232 
    Details
    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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    URL: http://dx.doi.org/10.1023/A:1014814313681
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    Influence of Crystal Habit on Trimethoprim Suspension Formulation (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 261-265 
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    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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    Venous Irritation, Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 930-938 
    Details
    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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    Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 944-948 
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    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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    Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 117-122 
    Details
    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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    Relationship Between Etomidate Plasma Concentration and EEG Effect in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 924-929 
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    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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    URL: http://dx.doi.org/10.1023/A:1018894523734
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    Pharmacokinetics and Tissue Disposition in Monkeys of an Antisense Oligonucleotide Inhibitor of Ha-Ras Encapsulated in Stealth Liposomes (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1309-1315 
    Details
    ISSN: 1573-904X
    Keywords: antisense phosphorothioate oligonucleotide ; stealth liposome ; pharmacokinetics ; monkey ; capillary gel electrophoresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study examined the pharmacokinetics and tissue distribution of an antisense oligonucleotide ISIS 2503, formulated in stealth (pegylated) liposomes (encapsulated) or in phosphate-buffered saline (unencapsulated). Methods. Encapsulated or unencapsulated ISIS 2503 was administered to rhesus monkeys by intravenous infusion. The concentrations of ISIS 2503 and metabolites in blood, plasma, and tissue samples were determined by capillary gel electrophoresis. Results. Plasma concentrations of encapsulated ISIS 2503 decreased mono-exponentially after infusion with a mean half-life of 57.8 hours. In contrast, the concentration of unencapsulated ISIS 2503 in plasma decreased rapidly with a mean half-life of 1.07 hours. Both encapsulated and unencapsulated ISIS 2503 distributed widely into tissues. Encapsulated ISIS 2503 distributed primarily to the reticulo-endothelial system and there were few metabolites observed. In contrast, unencapsulated ISIS 2503 distributed rapidly to tissue with highest concentration seen in kidney and liver. Nuclease-mediated metabolism was extensive for unencapsulated oligonucleotide in plasma and tissues. Conclusions. The data suggest that stealth liposomes protect ISIS 2503 from nucleases in blood and tissues, slow tissue uptake, and slow the rate of clearance from the systemic circulation. These attributes may make these formulations attractive for delivering oligonucleotides to sites with increased vasculature permeability such as tumors or sites of inflammation.
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    URL: http://dx.doi.org/10.1023/A:1014822219133
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    Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1694-1701 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; liposomes ; pharmacokinetics ; tissue distribution ; toxicity ; toxicokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.
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    URL: http://dx.doi.org/10.1023/A:1018997730462
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    Distribution and Binding Kinetics of Ciprofloxacin and Ofloxacin in the Hindlimb of the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 587-591 
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    ISSN: 1573-904X
    Keywords: quinolones ; pharmacokinetics ; permeability ; tissue binding ; hindlimb
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011939616948
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    Analyzing Rich Data Using Different Methods Provided by NONMEM: Pharmacokinetics of Telmisartan Following Intravenous Infusion to Healthy Volunteers (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 772-776 
    Details
    ISSN: 1573-904X
    Keywords: nonlinear mixed effects modeling (NONMEM) ; pharmacokinetics ; telmisartan ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011997229669
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    Effects of Hyperlipidemia on the Pharmacokinetics of Nifedipine in the Rat (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 309-313 
    Details
    ISSN: 1573-904X
    Keywords: hyperlipidemia ; hypercholesterolemia ; nifedipine ; pharmacokinetics ; protein binding ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used. Methods. Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg−1 given iv, ip and po). Total plasma cholesterol levels increased from 0.82−2.02 to 5.27−11.05 mmol L−1 48 h post P407 administration (Ig kg−1, ip). Protein binding studies were conducted by an ultrafiltration method. Results. Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and ip doses, respectively, thereby increasing AUC0−∞, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0−∞ was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%. Conclusions. The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.
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    Megasporogenesis in Arabidopsis thaliana L.: an ultrastructural study (1999)
    Springer
    Sexual plant reproduction 12 (1999), S. 99-109 
    Details
    ISSN: 1432-2145
    Keywords: Key words Arabidopsis thaliana ; Megasporogenesis ; Meiosis ; Ultrastructure ; Cellular polarity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  In this study, megasporogenesis of the plant model Arabidopsis thaliana was investigated by electron microscopy for the first time. The data described here could constitute a reference for future investigations of Arabidopsis mutants. During the beginning of meiosis the megaspore mother cell shows a polarity created by unequal distribution of organelles in the cytoplasm. Plastids accumulate in the chalazal region and long parallel saccules of endoplasmic reticulum, small vacuoles and some dictyosomes are found in the micropylar region. Plasmodesmata are abundant in the chalazal cell wall. The nucleus is almost centrally localized and contains a prominent excentric nucleolus and numerous typical synaptonemal complexes. After the second division of meiosis the four megaspores are separated by thin cell walls crossed by numerous plasmodesmata and do not show significant cellular organization. The young functional megaspore is characterized by a large nucleus and a large granular nucleolus. The cytoplasm is very electron dense due to the abundance of free ribosomes and contains the following randomly distributed organelles: mitochondria, a few short saccules of endoplasmic reticulum, dictyosomes and undifferentiated plastids. However, there is no apparent polarity, except for the distribution of some small vacuoles which are more abundant in the micropylar region of the cell. The degenerating megaspores are extremely electron dense and do not show any substructure.
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    Cytochrome P450 Enzymes and Drug Metabolism—Basic Concepts and Methods of Assessment (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 309-323 
    Details
    ISSN: 1573-6830
    Keywords: cytochrome P450 ; enzyme inhibition ; enzyme induction ; pharmacokinetics ; drug interaction ; in vitro assessment ; clinical assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. The cytochrome P450 enzyme family is one of the major drug metabolizing systems in man. 2. Factors such as age, gender, race, environment, and drug treatment may have considerable influence on the activity of these enzymes. 3. There are now well-established in vitro techniques for assessing the role of specific cytochrome P450 enzymes in the metabolism of drugs, as well as the inhibitory or inducing effects of drugs on enzyme activity. In vitro data have been utilized to predict clinical outcomes (i.e., pharmacokinetic interactions), with close correlations between in vitro and in vivo data. 4. This information can be of considerable practical assistance to clinicians, to help with rational prescribing or to prevent or minimize the potential for drug interactions.
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    Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know? (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 355-372 
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    ISSN: 1573-6830
    Keywords: enantiomers ; racemic ; chiral ; stereoselective ; pharmacokinetics ; cytochrome P450 ; geometric isomers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties. 2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics. 3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.
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    Metabolism of Tricyclic Antidepressants (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 373-409 
    Details
    ISSN: 1573-6830
    Keywords: antidepressants ; tricyclic ; metabolism ; hydroxy metabolites ; pharmacokinetics ; pharmacogenetics ; drug–drug interactions ; toxicity ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.
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    Metabolism and Pharmacokinetics of Selective Serotonin Reuptake Inhibitors (1999)
    Springer
    Cellular and molecular neurobiology 19 (1999), S. 443-466 
    Details
    ISSN: 1573-6830
    Keywords: selective serotonin reuptake inhibitors ; metabolism ; pharmacokinetics ; fluoxetine ; fluvoxamine ; paroxetine ; sertraline ; citalopram ; cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. 2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring. 3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.
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    Human Interindividual Variability in Parameters Related to Health Risks (1999)
    Springer
    Risk analysis 19 (1999), S. 711-726 
    Details
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
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    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
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    A Sensitive Docetaxel Assay in Plasma by Solid-Phase Extraction and High Performance Liquid Chromatography – UV Detection: Validation and Suitability in Phase I Clinical Trial Pharmacokinetics (1999)
    Springer
    Investigational new drugs 17 (1999), S. 325-333 
    Details
    ISSN: 1573-0646
    Keywords: docetaxel ; plasma assay ; clinical trials ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have developed a specific and sensitive method aiming atdocetaxel (Taxotere®) determination in plasma of treatedpatients. This involved solid-phase extraction of 1 ml of plasmaonto carboxylic acid (CBA) grafted silica cartridges followed byreversed-phase liquid chromatography with UV detection. The bestselectivity was obtained through the use of C18 Uptisphere® asstationary phase. The low limit of quantitation obtained (LOQ:5 ng/ml) allowed measurements of docetaxel up to 24 hours afterone-hour infusions with low dosages of drug (60 mg/m2). Themethod was applied successfully to monitor docetaxel plasma levelswithin two protocols associating fixed dosages of either methotrexate or gemcitabine with escalating doses of Taxotere®.
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    Effects of reserpine on ECL-cell ultrastructure and histamine compartmentalization in the rat stomach (1999)
    Springer
    Cell & tissue research 295 (1999), S. 131-140 
    Details
    ISSN: 1432-0878
    Keywords: Key words ECL cells ; Gastrin ; Reserpine ; Organelles ; Ultrastructure ; Rat (Sprague-Dawley)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The histamine-storing ECL cells in the stomach play a key role in the control of acid secretion. They contain granules, secretory vesicles and microvesicles, and sustained gastrin stimulation results in the additional formation of vacuoles and lipofuscin bodies. The cells are rich in the vesicle monoamine transporter type-2 (VMAT-2), which can be inhibited by reserpine. The present study examines the effect of reserpine on ECL-cell ultrastructure and histamine compartmentalization. Rats received reserpine and/or gastrin. Reserpine was given twice by the intraperitoneal route (25 mg/kg once daily). Gastrin-17 was given by subcutaneous infusion (5 nmol/kg/h), starting at the time of the first reserpine injection and continuing for 4 days when the rats were killed. At this stage, histamine in the oxyntic mucosa was unaffected by reserpine but elevated by gastrin. Immunocytochemical analysis (confocal microscopy) showed ECL-cell histamine in control and gastrin-treated rats to be localized in cytoplasmic organelles (e.g., secretory vesicles). After treatment with reserpine alone or reserpine+gastrin, ECL-cell histamine occurred mainly in the cytosol. Planimetric analysis (electron microscopy) of ECL cells showed reserpine to increase the number, size and volume density of the granules and to reduce the size and volume density of the secretory vesicles. Gastrin reduced the number and volume density of granules and secretory vesicles, increased the number and volume density of microvesicles and caused vacuoles and lipofuscin bodies to appear. Reserpine+gastrin increased the number, volume density and size of the granules. Reserpine prevented the effects of gastrin on secretory vesicles, vacuoles and microvesicles, but did not prevent the development of lipofuscin. Our findings are in line with the views: (1) that preformed cytosolic histamine is taken up by granules/secretory vesicles via VMAT-2, that histamine is instrumental in the transformation of granules into secretory vesicles and in their consequent enlargement and (2) that vacuoles are formed by the fusion of large secretory vesicles.
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    Peripheral synapses at identifiable mechanosensory neurons in the spider Cupiennius salei : synapsin-like immunoreactivity (1999)
    Springer
    Cell & tissue research 295 (1999), S. 13-19 
    Details
    ISSN: 1432-0878
    Keywords: Key words Mechanoreceptors ; Synaptic proteins ; Histochemistry ; Ultrastructure ; Slit sensilla ; Hair sensilla ; Cupiennius salei (Chelicerata)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Indirect immunocytochemical tests were used at the light- and electron-microscopic levels to investigate peripheral chemical synapses in identified sensory neurons of two types of cuticular mechanosensors in the spider Cupiennius salei Keys.: (1) in the lyriform slit-sense organ VS-3 (comprising 7–8 cuticular slits, each innervated by 2 bipolar sensory neurons) and (2) in tactile hair sensilla (each supplied with 3 bipolar sensory cells). All these neurons are mechanosensitive. Application of a monoclonal antibody against Drosophila synapsin revealed clear punctate immunofluorescence in whole-mount preparations of both mechanoreceptor types. The size and overall distribution of immunoreactive puncta suggested that these were labeled presynaptic sites. Immunofluorescent puncta were 0.5–6.8 μm long and located 0.5–6.6 μm apart from each other. They were concentrated at the initial axon segments of the sensory neurons, while the somata and the dendritic regions showed fewer puncta. Western blot analysis with the same synapsin antibody against samples of spider sensory hypodermis and against samples from the central nervous system revealed a characteristic doublet band at 72 kDa and 75 kDa, corresponding to the apparent molecular mass of synapsin in Drosophila and in mammals. Conventional transmissionelectron-microscopic staining demonstrated that numerous chemical synapses (with at least 2 vesicle types) were present at these mechanosensory neurons and their surrounding glial sheath. The distribution of these synapses corresponded to our immunofluorescence results.Ultrastructural examination of anti-synapsin-stained neurons confirmed that reaction product was associated with synaptic vesicles. We assume that the peripheral synaptic contacts originate from efferents that could exert a complex modulatory influence on mechanosensory activity.
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    Survival of rat MCH (melanin-concentrating hormone) neurons in hypothalamus slice culture: histological, pharmacological and molecular studies (1999)
    Springer
    Cell & tissue research 297 (1999), S. 23-33 
    Details
    ISSN: 1432-0878
    Keywords: Key words Melanin-concentrating hormone neurons ; Lateral hypothalamic slice culture ; Immunocytochemistry ; Ultrastructure ; In situ hybridization ; Competitive RT-PCR ; Leptin assay ; Rat (Sprague Dawley)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Hypothalamic slices containing the lateral hypothalamic area (LHA) were prepared from 6- to 8-day-old rats and maintained in stationary culture for up to 35 days in order to analyse how well the melanin-concentrating hormone (MCH) neurons survived. As previously reported for other brain areas, this method yielded a long-term well-preserved organotypic organization. Light- and electron-microscopic investigations showed that differentiation continued and that synaptic contacts developed in vitro. After a period of elimination of damaged cells and fibres, most of the remaining neurons and glial cells retained a normal morphology throughout the culture period. MCH neurons, in particular, survived well as attested by the strong immunocytochemical and in situ hybridization signals still observed after several weeks. In a comparison with the day of explantation, competitive reverse transcription/polymerase chain reaction demonstrated the remarkable stability of the level of MCH mRNA at least until the 20th day in culture; after 30 days, the clear decrease in this level seemed to be correlated with a loss of MCH neurons, rather than with a decrease in MCH expression. After 10 days of culture, the incubation of slices in the presence of the hormone leptin (50 ng/ml) resulted in a strong decrease of MCH gene expression, suggesting that MCH neurons retained their physiological properties. Thus, the LHA slice stationary culture, especially between one and three weeks (i.e. after tissue stabilization and before extensive cell loss), appears to be a suitable method for physiological and pharmacological studies of these neurons.
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    Ultrastructure and distribution dynamics of chloride cells in tilapia larvae in fresh water and sea water (1999)
    Springer
    Cell & tissue research 297 (1999), S. 119-130 
    Details
    ISSN: 1432-0878
    Keywords: Key words Chloride cells (mitochondria-rich cells) ; Teleost larvae ; Osmoregulation ; Immunohistochemistry ; Quantification ; Ultrastructure ; Oreochromis mossambicus (Teleostei)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Integumental and branchial chloride cells of tilapia larvae (Oreochromis mossambicus) were studied at the light-microscopical and ultrastructural level. Total numbers and distribution of chloride cells were quantified after immunostaining of cross sections of the entire larvae with an antibody against the α-subunit of Na+/K+-ATPase. The majority (66%) of Na+/K+-ATPase-immunoreactive (ir) cells, i.e. chloride cells, of freshwater tilapia larvae were located extrabranchially up to 48 h after hatching. Five days after hatching, the majority (80%) of chloride cells were found in the buccal cavity. Transfer of 24-h-old larvae to 20% sea water speeded up this process; 24 h after transfer (i.e. 48 h after hatching), the majority (59%) of chloride cells were located in the buccal cavity. The branchial chloride cell population of 24-h- and 120-h-old larvae consisted of immature, mature, apoptotic and necrotic chloride cells. However, relatively more immature chloride cells were observed in freshwater larvae (42–63%) than in (previously studied) freshwater adults (21%), illustrating the developmental state of the gills. After transfer to sea water, the incidence of degenerative chloride cells did not change. Furthermore, the incidence of immature cells had decreased and a new subtype of chloride cells, the ”mitochondria-poor” cells, appeared more frequently. These mitochondria-poor chloride cells were characterised by an abundant tubular system and relatively few mitochondria, which were aligned at the border or concentrated in one part of the cytoplasm. Most of these cells did not contact the water. The function of their enhanced appearance after seawater transfer is unknown.
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    A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug (1999)
    Springer
    Investigational new drugs 17 (1999), S. 49-56 
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    ISSN: 1573-0646
    Keywords: pharmacokinetics ; capecitabine ; 5-fluorouracil ; phase I trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.
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    URL: http://dx.doi.org/10.1023/A:1006263400888
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    Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 559-575 
    Details
    ISSN: 1573-8744
    Keywords: T-helper cells ; trafficking ; rebound ; corticosteroids ; circadian rhythm ; methylprednisolone ; drug interactions ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.
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    URL: http://dx.doi.org/10.1023/A:1020974408657
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    Drug–Drug Pharmacodynamic Interaction Detection by a Nonparametric Population Approach. Influence of Design and of Interindividual Variability (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 531-554 
    Details
    ISSN: 1573-8744
    Keywords: drug–drug interactions ; NPML ; experimental design ; pharmacodynamic variability ; pharmacokinetics ; entropy ; covariate ; second stage model ; controlled trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.
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    URL: http://dx.doi.org/10.1023/A:1023290530853
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    Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 301-323 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; effect compartment model ; indirect response ; sigmoid E max ; tiagabine ; GABA uptake inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg −1 $$(\bar x \pm SE,{\text{ }}n = 23)$$ $$96 \pm 9$$ ml min -1 kg−1, 1.5ŷ0.1 L kg−1 and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min −1 and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates $$(\bar x \pm SE)$$ were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min −1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.
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    URL: http://dx.doi.org/10.1023/A:1020999114109
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    Rapid Attainment of Steady-State Plasma Drug Concentrations Within Precise Limits in Multicompartment Mammillary Systems (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 325-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously described a method of rapidly obtaining a specified steady-state plasma concentration of an intravenous drug within precise limits. However the method is limited to drugs whose disposition may be characterized by an open two-compartment system. In this paper, we illustrate how the method can be extended to drugs whose disposition may be characterized by a mammillary model with any number of compartments. Refinements of our previous technique are also described.
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    A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 329-338 
    Details
    ISSN: 1573-8744
    Keywords: propofol ; anaesthesia ; pharmacokinetics ; compartment models ; effect compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.
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    URL: http://dx.doi.org/10.1023/A:1020903315017
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    Population Pharmacokinetics and Pharmacodynamics of the Anti-CD11a Antibody hu1124 in Human Subjects with Psoriasis (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 397-420 
    Details
    ISSN: 1573-8744
    Keywords: psoriasis ; hu1124 ; CD11a ; CD3-positive lymphocytes ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1–3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration–time profile suggested that the clearance of hu1124 was saturable above 10 μg/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (〉0.025 μg/ml) in the plasma. When hu1124 levels fell below 3 μg/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7–10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 μg/ml and saturation required more than 10 μg/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 μg/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
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    Constructing a Prediction Interval for Time to Reach a Threshold Concentration Based on a Population Pharmacokinetic Analysis: An Application to Basiliximab in Renal Transplantation (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 213-230 
    Details
    ISSN: 1573-8744
    Keywords: prediction interval ; pharmacokinetics ; population analysis ; NONMEM ; inverse regression ; immunosuppressives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.
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    Indirect-Response Modeling of Desmopressin at Different Levels of Hydration (1999)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 27 (1999), S. 513-529 
    Details
    ISSN: 1573-8744
    Keywords: desmopressin ; indirect-response modeling ; overhydration ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20ml·kg −1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 μg of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 β) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc ) and at steady state (Vss ) were estimated to be 1.34 (SD 0.35) ml·min −1 ·kg −1 , 151 (SD28) ml·kg −1 , and 386 (SD 63) ml·kg −1 , respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0 ). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p〈0.0001). The mean values for IC50 and the sigmoidicity factor (γ) were 3.7 (SD 1.2) pg·ml −1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.
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    URL: http://dx.doi.org/10.1023/A:1023238514015
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    A Physiological Pharmacokinetic Model for Solute Disposition in Tissues Below a Topical Application Site (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1392-1398 
    Details
    ISSN: 1573-904X
    Keywords: topical application ; dermal absorption ; cutaneous perfusion ; pharmacokinetics ; binding ; half life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
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    Structure and function of the human oocyte-cumulus-corona cell complex before and after ovulation (1999)
    Springer
    Protoplasma 206 (1999), S. 270-277 
    Details
    ISSN: 1615-6102
    Keywords: Cumulus oophorus ; Ovarian follicle ; Fertilization ; Ultrastructure ; Immunocytochemistry ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The fine structure of the human cumulus oophorus has been reviewed on the basis of scanning and transmission electron microscopic observations as well as of immunofluorescence data. Tissues sampled from preovulatory ovarian follicles and cumulus-enclosed oocytes and fertilized eggs (collected from the oviduct or obtained during in vitro fertilization procedures) have been evaluated from a microtopographic and morphodynamic point of view in order to better clarify the possible role of this population of cells. In particular, the following aspects have been studied and discussed: the presence of multiple close contacts (modulated by the interposition of the zona pellucida) between the oocyte surface and the long microvillous evaginations projecting from the inner aspect of corona cells surface (through these structures the intraovarian cumulus oophorus may control oocyte growth and metabolism up until the time of ovulation); the occurrence of different subpopulations of cells (steroid-synthetic cells, cells producing adhesive proteins, leukocytes, macrophages) in the postovulatory, extraovarian cumulus oophorus surrounding oocytes, zygotes and early developing embryos. All these elements found in the cumulus mass may positively act, through their paracrine activities, on the chemical composition of the microenvironment in which fertilization occurs.
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    URL: http://dx.doi.org/10.1007/BF01288215
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    Anatomical and ultrastructural changes of the floral nectary ofPisum sativum L. during flower development (1999)
    Springer
    Protoplasma 206 (1999), S. 57-72 
    Details
    ISSN: 1615-6102
    Keywords: Anatomy ; Floral nectary ; Modified stomata ; Phloem ; Pisum sativum ; Stereology ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The floral nectary ofPisum sativum L. is situated on the receptacle at the base of the gynoecium. The gland receives phloem alone which departed the vascular bundles supplying the staminal column. Throughout the nectary, only the companion cells of the phloem exhibited wall ingrowths typical of transfer cells. Modified stomata on the nectary surface served as exits for nectar, but stomatal pores developed well before the commencement of secretion. Furthermore, stomatal pores on the nectary usually closed by occlusion, not by guard-cell movements. Pore occlusion was detected most frequently in post-secretory and secretory glands, and less commonly in pre-secretory nectaries. A quantitative stereological study revealed few changes in nectary fine structure between buds, flowers secreting nectar, and post-secretory flowers. Dissolution of abundant starch grains in plastids of subepidermal secretory cells when secretion commenced suggests that starch is a precursor of nectar carbohydrate production. Throughout nectary development, mitochondria were consistently the most plentiful organelle in both epidermal and subepidermal cells, and in addition to the relative paucity of dictyosomes, endoplasmic reticulum, and their associated vesicles, the evidence suggests that floral nectar secretion inP. sativum is an energy-requiring (eccrine) process, rather that granulocrine.
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    Ultrastructural study of the relationship between generative and vegetative cells inMagnolia ×soulangeana Soul.-Bod. pollen grains (1999)
    Springer
    Protoplasma 206 (1999), S. 87-96 
    Details
    ISSN: 1615-6102
    Keywords: Plasmalemmic cord ; Pollen grain ; Ultrastructure ; Magnolia ×soulangeana
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary InMagnolia ×soulangeana pollen grains the generative cell (GC) does not become totally free within the vegetative cell (VC), at least until the pollen tube emergence. Due to a deviation in its detachment process from the sporoderm, the opposing ends of the VC plasmalemma do not fuse themselves when the GC moves away from the intine. Consequently, the interplasmalemmic space surrounding the GC does not become isolated but rather maintains continuity with the sporoderm through a complex formation that we have called plasmalemmic cord. The real existence of this formation was confirmed through serial sectioning showing the plasmalemmic cord to consist of the VC plasmalemma. In its initial portion it is occupied by a reasonably accentuated wall ingrowth of the inner layer of the intine (intine 3). In the remainder portion, neither of the cytochemical tests used in this work have revealed the presence of a significant amount of wall material. However, ultrathin sections of samples processed either chemically or by cryofixation showed the existence of an intricate system of tubules and vesicles, some of which are evaginations of the VC plasmalemma. The hypothesis that the plasmalemmic cord may have a role in the complex interactions between the two pollen cells is discussed.
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    Distribution and transmission of endosymbiotic microorganisms in the oocytes of the pig louse,Haematopinus suis (L.) (Insecta: Phthiraptera) (1999)
    Springer
    Protoplasma 209 (1999), S. 207-213 
    Details
    ISSN: 1615-6102
    Keywords: Endosymbiont ; Mycetocyte ; Mycetome ; Oocyte ; Transovarial transmission ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary All anoplurans live symbiotically with prokaryotic microorganisms hosted in specialized cells, termed mycetocytes. In nymphs and males mycetocytes are distributed between midgut epithelial cells. In females, besides the midgut, mycetocytes are found in the reproductive organs where they are located at the base of ovarioles in contact with lateral oviducts. The mycetocyte-associated symbionts are transmitted from one generation to the next transovarially. Here, the results of histological and ultrastructural studies on the distribution and transmission of symbiotic microorganisms within the ovaries of the anopluranHaematopinus suis are presented. Interestingly, during advanced oogenesis (i.e., choriogenesis) of this species all symbionts are localized extracellularly and form a tight mass located at the posterior pole of the oocyte just below the hydropyle. In insects studied so far, such localization of transovarially transmitted microorganisms has been reported only in the closely related speciesHaematopinus eurysternus.
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    Effect of high-level oxygen exposure on the peroxidase activity and the neuromelanin-like pigment content of the nerve net in the earthworm, Lumbricus terrestris (1999)
    Springer
    Cell & tissue research 295 (1999), S. 349-354 
    Details
    ISSN: 1432-0878
    Keywords: Key words Neuromelanin ; Neuron ; Peroxidase ; Oxygen metabolism ; High-definition light microscopy ; Electron microscopy ; Ultrastructure ; Cytochemistry ; Substantia nigra ; Lumbricusterrestris (Annelida)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Histochemical examination of 1-μm tissue sections from the dorsal nerve plexus of the earthworm, Lumbricus terrestris, reveals multiple brown intraneuronal granules. These granules contain material morphologically and histochemically consistent with neuromelanin. When viewed with transmission electron microscopy, these were seen as single membrane-enclosed biphasic granules with diameters of 370–730 nm. Exposure of L. terrestris to high-level environmental oxygen resulted in an increase in the number of neuromelanin-like pigment granules within the neurons of the circular muscle layer. As measured by ortho-phenylenediamine hydrochloride, the endogenous peroxidase activity of extracts from worms incubated in high-level environmental oxygen was 51% more than controls. The endogenous peroxidase activity was localized in situ with 3,3-diaminobenzidine (DAB) and was found to increase in and around the neuromelanin-like pigment-containing neurons within the circular muscle layer. These studies suggest that the nerve net of L. terrestris may serve as a model to study the role of neuromelanin production in oxidative stress and its relationship to endogenous peroxidases.
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    The distribution and ultrastructure of class II MHC-positive cells in human dental pulp (1999)
    Springer
    Cell & tissue research 295 (1999), S. 151-158 
    Details
    ISSN: 1432-0878
    Keywords: Key words Class II MHC-positive cells ; Human leukocyte antigen-DR ; Dental pulp ; Dendritic cells ; Macrophages ; Ultrastructure ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The distribution and ultrastructure of class II major histocompatibility complex (MHC)-positive cells were investigated in human dental pulp, employing immunohistochemistry using an anti-human leukocyte antigen (HLA)-DR-monoclonal antibody. HLA-DR-immunopositive cells, appearing spindle-like or dendritic in profile, were densely distributed throughout the dental pulp. Under the electron microscope, these cells exhibited various sizes of vesicles containing clear or opaque contents, multivesicular bodies and characteristic fine tubulovesicular structures in their cytoplasm. Some reactive cells possessed coated pits and vesicles including electron-dense materials, indicating an active endocytosis. At the periphery of the pulp tissue, the HLA-DR-immunopositive cells were predominantly situated in the subodontoblastic layer, with some located in the odontoblast layer and/or predentin and extending their cytoplasmic processes into the dentinal tubules. Cell processes of these cells occasionally made contact with several odontoblast processes in the same way as the nerve fibers in the predentin. These cells never contained the typical phagosomes frequently observed in the HLA-DR-immunoreactive macrophages in the subodontoblastic layer and the pulp core. The results suggest that the HLA-DR-immunopositive cells in the odontoblast layer and/or predentin have some regulatory function on the odontoblasts under physiological conditions, in addition to their involvement in the initial defense reaction after tooth injury.
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    URL: http://dx.doi.org/10.1007/s004410051221
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    Androgen-induced changes in Leydig cell ultrastructure and steroidogenesis in juvenile African catfish, Clarias gariepinus (1999)
    Springer
    Cell & tissue research 297 (1999), S. 291-299 
    Details
    ISSN: 1432-0878
    Keywords: Key words Teleost fish ; Puberty ; Testes ; Sex steroids ; Ultrastructure ; Steroidogenesis ; Clarias gariepinus (Teleostei)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  The present report focuses on the mechanism(s) involved in the steroid-induced decrease of androgen production in immature African catfish testes that was observed in previous studies. Juvenile animals were implanted with Silastic pellets containing different 11-oxygenated androgens (11-ketotestosterone, KT; 11β- hydroxyandrostenedione, OHA; 11-ketoandrostenedione, KA), testosterone (T) or estradiol-17β (E2). Control groups received steroid-free pellets. Two weeks later, testis tissue fragments were either incubated with increasing concentrations of catfish luteinizing hormone (LH), or incubated with [3H]-pregnenolone ([3H]-P5) or [3H]-androstenedione ([3H]-A). Tissue fragments were also prepared for the quantitative assessment of Leydig cell morphology. Most of the parameters studied were not affected significantly by implantation of E2. Implantation of all androgens inhibited both the basal and the LH-stimulated androgen secretory capacity in vitro. This was associated with a reduced size of the Leydig cells and loss of half of their mitochondria. The studies on the metabolism of tritiated steroid hormones indicated that steroidogenic steps prior to 11β-hydroxylation, probably C17–20 lyase activity, were affected by all androgens. Although the effects of 11-oxygenated androgens and T on Leydig cells were mostly similar, previous work showed that only the 11-oxygenated androgens stimulated spermatogenesis, suggesting that distinct mechanisms of action are used by 11-oxygenated androgens and T. These mechanisms, however, seem to merge on the same target(s) to impair Leydig cell androgen production. Such a negative feedback mechanism may be of relevance in the context of the decline in androgen secretion per milligram testis tissue that accompanies the first wave of spermatogenesis in pubertal African catfish.
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    URL: http://dx.doi.org/10.1007/s004410051357
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    Echinococcus granulosus: praziquantel treatment against the metacestode stage (1999)
    Springer
    Parasitology research 85 (1999), S. 999-1006 
    Details
    ISSN: 1432-1955
    Keywords: Key wordsEchinococcus granulosus ; Praziquantel ; Metacestode ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The efficacy of praziquantel against the metacestode of Echinococcus granulosus was studied by means of in vitro incubations or in vivo experiments. The results of in vitro incubations indicated that the effectiveness of praziquantel was higher when the parasite material comprised cysts from cyst masses than in the case of intact cysts that retained their adventitial layer. Ultrastructural alterations in the germinal layer of collapsed cysts incubated in vitro were detected. The results obtained in mice after 4 months of treatment demonstrated no significant difference between the control and treated groups with regard to the number and wet weight of developed cysts. However, ultrastructural alterations were detected in the cyst tissue that were similar to those described in the in vitro experiment. In contrast, the effect of chemoprophylaxis on the number and the wet weight of developed cysts was extremely significant as compared with the control value, the efficacy being 99.41% and 98.32%, respectively. Moreover, ultrastructural observations of the cyst tissue revealed loss of its integrity, and no intact cyton was observed in the germinal layer of the developed cyst.
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    URL: http://dx.doi.org/10.1007/s004360050672
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    Morphology and ultrastructure of the anterior adhesive areas of the capsalid monogenean parasites Benedenia rohdei from the gills and B. lutjani from the pelvic fins of Lutjanus carponotatus (Pisces: Lutjanidae) (1999)
    Springer
    Parasitology research 85 (1999), S. 399-408 
    Details
    ISSN: 1432-1955
    Keywords: Key words Monogenea ; Capsalidae ; Benedenia rohdei ; B. lutjani ; Ectoparasites ; Lutjanus carponotatus ; Glands ; Ultrastructure ; Adhesion ; Attachment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The anterior adhesive areas of Benedenia rohdei from the gills and B. lutjani from the pelvic fins of Lutjanuscarponotatus at Heron Island, Australia, were studied using scanning and transmission electron microscopy. All specimens were fixed when detached from host tissue. Both monogenean species have two disc-like anteroventral attachment organs, each of which has an anterolateral adhesive area divided into three adjacent zones by tegument from the ventral surface of the attachment organ. A rod-shaped secretion and a smaller, roughly spherical secretion are associated with the anterior adhesive areas in both species; a third type of secretion occurs anteriorly but outside these adhesive areas. The electron-dense spherical secretory bodies released onto the anterior adhesive zones in these Benedenia spp. are of a single type and differ ultrastructurally from those previously reported in monogeneans living on teleost hosts. A correlation, therefore, between secretion morphology and host type is not supported. No relationship was found between parasite microhabitat and secretion morphology.
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    URL: http://dx.doi.org/10.1007/s004360050566
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    Electrophysiological and ultrastructural correlates of cryoinjury in sciatic nerve of the freeze-tolerant wood frog, Rana sylvatica (1999)
    Springer
    Journal of comparative physiology 169 (1999), S. 351-359 
    Details
    ISSN: 1432-136X
    Keywords: Key words Freeze tolerance ; Sciatic nerve ; Cryoinjury ; Dehydration ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We investigated function and ultrastructure of sciatic nerves isolated from wood frogs (Rana sylvatica) endemic to the Northwest Territories, Canada, following freezing at −2.5 °C, −5.0 °C, or −7.5 °C. All frogs frozen at −2.5 °C, and most frogs (71%) frozen at −5.0 °C, recovered within 14 h after thawing began; however, frogs did not survive exposure to −7.5 °C. Sciatic nerves isolated from frogs frozen at −7.5 °C were refractory to electrical stimulation, whereas those obtained from frogs surviving exposure to −2.5 °C or −5.0 °C generally exhibited normal characteristics of compound action potentials. Frogs responded to freezing by mobilizing hepatic glycogen reserves to synthesize the cryoprotectant glucose, which increased 20-fold in the liver and 40-fold in the blood. Ultrastructural analyses of nerves harvested from frogs in each treatment group revealed that freezing at −2.5 °C or −5.0 °C had little or no effect on tissue and cellular organization, but that (lethal) exposure to −7.5 °C resulted in marked shrinkage of the axon, degeneration of mitochondria within the axoplasm, and extensive delamination of myelin sheaths of the surrounding Schwann cells.
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    URL: http://dx.doi.org/10.1007/s003600050231
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    Articular chondrocytes and synoviocytes in a co-culture system: influence on reactive oxygen species-induced cytotoxicity and lipid peroxidation (1999)
    Springer
    Cell & tissue research 296 (1999), S. 555-563 
    Details
    ISSN: 1432-0878
    Keywords: Key words Chondrocyte ; Synoviocyte ; Co-culture ; Proliferation ; Lipid peroxidation ; Cytotoxicity ; Ultrastructure ; Rat (Wistar)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Objective: A new co-culture system of rat articular chondrocytes and synoviocytes (HIG-82; cell line) was incubated with phorbol myristate acetate (PMA), H2O2 or a combination of Fe2+ and ascorbic acid to simulate inflammation-like radical attacks in articular joints. Methods: Chondrocytes were characterized by immunocytochemistry against collagen type II, transmission electron (TEM) and light microscopy. Lipid peroxidation was investigated by measuring thiobarbituric-acid-reactive material in the supernatants, cytotoxicity by determining release of lactate dehydrogenase and proliferation by measuring [3H]thymidine incorporation, culture protein and DNA. Results: PMA or Fe2+ and ascorbic acid induced lipid peroxidation in chondrocytes and synoviocytes that was decreased significantly in co-cultures. PMA and H2O2 dose dependently induced release of lactate dehydrogenase in chondrocytes, which was lowered in co-cultures or in previously co-cultured chondrocytes to a nearly basal level. In contrast, conditioned media of synoviocyte cultures showed no lowering effect on the radical-induced toxicity. Protection against H2O2-induced damage of cellular membranes by co-culturing was also shown by TEM. Synoviocytes released chondrocyte-stimulating growth factors spontaneously without previous interaction. Conclusion: Chondrocytes establish protective mechanisms against reactive oxygen species via an interaction with synoviocytes. Our co-culture model presents a possible way to study mechanisms of inflammation in articular joints under defined conditions.
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    Phylogenetic affiliation and ultrastructure of uncultured magnetic bacteria with unusually large magnetosomes (1998)
    Springer
    Archives of microbiology 169 (1998), S. 136-147 
    Details
    ISSN: 1432-072X
    Keywords: Key words Magnetic bacteria ; Biomineralization ; Magnetite ; 16S rRNA ; In situ hybridization ; Ultrastructure ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Natural enrichments of magnetic bacteria from the Itaipu lagoon near Rio de Janeiro were dominated by coccoid-to-ovoid morphotypes that produced unusually large magnetosomes. To determine the phylogenetic position of these unusual microorganisms, 16S rRNA genes were retrieved from bacteria magnetically separated from sediment of the Itaipu lagoon by in vitro amplification and cloning of PCR products into a plasmid vector. Partial sequencing of the obtained clones revealed two clusters of closely related sequences affiliated to a distinct lineage consisting exclusively of magnetic bacteria within the α-subclass of Proteobacteria. For a detailed phylogenetic analysis, several almost complete sequences of the 16S rRNA genes were determined. One representative clone of each cluster provided a PCR template for the in vitro transcription of group-specific polynucleotide probes complementary to a variable region of the 16S rRNA molecule. At least three different morphotypes of magnetic bacteria were reliably identified by post-embedding hybridization of ultra-thin sections. Electron microscopic analyses of hybridized cells enabled for the first time a detailed description of the morphological variety and ultrastructure of phylogenetically identified, uncultured magnetic bacteria. Two distinct coccoid bacteria were identified by the transcript probe complementary to the 16S rRNA sequence mabrj12, whereas the probe complementary to the sequence mabrj58 allowed the identification of an ovoid morphotype that displayed magnetosomes with the largest volumes observed to date.
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    URL: http://dx.doi.org/10.1007/s002030050553
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    Pharmacokinetics of antipyrine in rats with different resistance to hypoxia in cold stress (1998)
    Springer
    Bulletin of experimental biology and medicine 126 (1998), S. 1098-1099 
    Details
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; antipyrine ; individual resistance to hypoxia ; cold stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It is shown that the parameters of antipyrine pharmacokinetics during cold exposure depend on individual resistance to hypoxia. High-resistant rats are characterized by less intense metabolism and more rapid normalization of pharmacokinetic parameters than lowresistant rats characterized by shortened elimination half-time corresponding to a more rapid metabolism of xenobiotics under conditions of cold stress.
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    URL: http://dx.doi.org/10.1007/BF02447243
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    Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: propofol ; pharmacokinetics ; pharmacodynamics ; rats ; EEG ; fat emulsion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%®-like fat emulsion (Diprivan-10®, D) or as a 1%- or 6% emulsion in Lipofundin® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, λ2) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, λ2 (p 〈 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,1/2, keo) was observed compared to the other propofol formulations (p〈0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
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    URL: http://dx.doi.org/10.1023/A:1011980432646
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    Guar Gum-Based Sustained Release Diltiazem (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1196-1201 
    Details
    ISSN: 1573-904X
    Keywords: guar gum ; sustained release ; extended release ; diltiazem ; dissolution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions. Methods. Guar gum tablet formulations were prepared and evaluated under a variety of in vitro dissolution conditions. The formulations, along with Dilacor XR®, were administered to a group of eight fasted, healthy volunteers in a four period crossover study. Results. Varying the lot of guar gum as well as using guar from different suppliers had little effect on diltiazem dissolution. Also, dissolution of diltiazem from guar gum tablets was essentially independent of stir speed under normal conditions (USP Apparatus II). The stability of guar-based formulations under stressed conditions (40°C/75% relative humidity for 3 months) was also established. All four formulations gave similar plasma concentrations over time in the healthy volunteers pharmacokinetic study. Conclusions. Guar gum-based matrix tablets represent a simple and economical alternative to existing diltiazem sustained release dosage forms.
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    URL: http://dx.doi.org/10.1023/A:1011931622536
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    Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 883-888 
    Details
    ISSN: 1573-904X
    Keywords: transdermal access ; skin erosion ; transdermal ; dermal interstitial fluid ; sampling ; glucose ; monitoring ; diabetes mellitus ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7−21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3−17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.
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    URL: http://dx.doi.org/10.1023/A:1011924631680
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    Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1474-1479 
    Details
    ISSN: 1573-904X
    Keywords: plasma clearance ; unbound plasma clearance ; inter-species scale-up in plasma clearance ; allometric analysis ; pharmacokinetics ; rat vs. human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the distribution of allometric exponents for relationship of total plasma clearance of 54 extensively metabolized drugs, with wide-ranging linear clearance values, between humans and rats, to provide a rationale for the observed data, and to discuss potential significance of the findings. Methods. Human and rat plasma clearance values of 54 drugs with markedly different physicochemical properties were obtained from the literature. Standard allometric analysis was performed for each drug using both rat and human data. Unbound vs. total plasma clearances were obtained for 15 out of 54 drugs and their correlations between humans and rats were compared. Results. The mean ± SD of the allometric exponent for the 54 drugs studied is 0.660 ± 0.190. The median clearance ratio based on unit body weight is 7.41 and the median exponent is 0.645. Excluding two outliers the correlation coefficient of plasma clearance between humans and rats was 0.745 (p 〈 0.0001). For the 15 drugs, use of unbound plasma clearance approach seems to significantly improve the correlation coefficient compared to total plasma clearance (0.940 vs. 0.841). Conclusions. The present study indicates that on average, humans and rats may eliminate extensively metabolized drugs at a rate similar to that expected from the allometric or body surface area relationship of basal metabolic rate between the two species. A simple statistical distribution hypothesis is used to rationalize the species difference in plasma drug clearance. Rat may serve as an useful animal model to predict (unbound) plasma clearance of drugs in humans.
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    URL: http://dx.doi.org/10.1023/A:1011974226596
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    Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 47-52 
    Details
    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
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    URL: http://dx.doi.org/10.1023/A:1011992518592
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    Effect of Particle Size and Charge on the Disposition of Lipid Carriers After Intratumoral Injection into Tissue-isolated Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 128-132 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; liposome ; emulsion ; intratumoral injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. Methods. Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. Results. In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. Conclusions. The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.
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    URL: http://dx.doi.org/10.1023/A:1011921324952
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    Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1085-1089 
    Details
    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
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    URL: http://dx.doi.org/10.1023/A:1011942530288
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    Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 904-910 
    Details
    ISSN: 1573-904X
    Keywords: GS522 ; oligodeoxynucleotide ; pharmacokinetics ; tritiated ; biodistribution ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400μl, 31.46 μCi/ml) of 3H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t1/2 = 7.6−9.0 min, Cl = 22.0−28.0 ml/min, V = 83.9−132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and 〉0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p 〈 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p 〈 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.
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    URL: http://dx.doi.org/10.1023/A:1011980716659
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    Effect of GF120918, a Potent P-glycoprotein Inhibitor, on Morphine Pharmacokinetics and Pharmacodynamics in the Rat (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 599-605 
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    ISSN: 1573-904X
    Keywords: morphine ; morphine-3-glucuronide ; P-glycoprotein ; pharmacokinetics ; pharmacodynamics ; antinociception ; central nervous system ; analgesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats. Methods. Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC. Results. Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; ke0 was significantly smaller for GF 120918- vs. vehicle-treated and control rats (0.060 ± 0.028 vs. 0.228 ± 0.101 vs. 0.274 ± 0.026 min−1, p=0.0023). EC50 and γ were similar between treatment groups. Conclusions. Pretreatment with GF 120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.
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    URL: http://dx.doi.org/10.1023/A:1011938112599
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  • 96
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    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
    Details
    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
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    URL: http://dx.doi.org/10.1023/A:1011932800729
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  • 97
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    Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1782-1786 
    Details
    ISSN: 1573-904X
    Keywords: bioavailability ; pharmacokinetics ; squalene synthase inhibitor ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38−40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111−120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.
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    URL: http://dx.doi.org/10.1023/A:1011977116543
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  • 98
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    Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1895-1901 
    Details
    ISSN: 1573-904X
    Keywords: IL-10 ; cytokines ; protein ; immunosuppression ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing. Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr. Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration. Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.
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    URL: http://dx.doi.org/10.1023/A:1011918425629
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  • 99
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    Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 228-232 
    Details
    ISSN: 1573-904X
    Keywords: risedronate ; gastrointestinal absorption ; gastrointestinal site ; bisphosphonate ; administration rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
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    URL: http://dx.doi.org/10.1023/A:1011910517200
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  • 100
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    Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 347-351 
    Details
    ISSN: 1573-904X
    Keywords: magnesium ; absolute bioavailability ; stable isotopes ; pharmacokinetics ; ICP-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011947525377
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