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  • 1
    Electronic Resource
    Electronic Resource
    Apoptosis and p53 gene expression in male reproductive tissues of cadmium exposed rats (1999)
    Springer
    BioMetals 12 (1999), S. 131-139 
    Details
    ISSN: 1572-8773
    Keywords: cadmium ; apoptosis ; RT-PCR ; p53 gene expression ; testes ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Reverse transcription (RT) PCR technique was used to investigate the mechanism of apoptosis induced by Cd and the change of its related genes in testes and prostate of rats. Adult male rats were given a single (s.c.) injection of CdC l2 0, 2.5, 5.0, 10 μmol/kg. 48 h and 72 h after administration of Cd, animals were sacrificed. The results indicated that Cd can induce apoptosis in testes via p53-independent pathway. No apoptosis occurred in prostate in any of the Cd-exposed groups. There was a clearly negative relationship in testes between p53 gene expression and Cd exposure and this dose-response relationship was observed both at 48 h and 72 h. There was a very small increase of this gene expression in the dorsolateral lobe of the prostate in Cd exposed groups. The other apoptosis related gene, bcl-x, was not detectable in either control or Cd-exposed group in testes and dorsal prostate. Although the MT-I gene was expressed in testes or dorsal prostate both in control and exposed groups, no overexpression of MT-I gene was found after administration of Cd . The expression of MT-I in the ventral prostate was not detected in the control group, but a weak expression was found after Cd exposure. Since p53 is a tumo r suppressor gene which can inhibit tumorigenesis, the consequence of a Cd-induced decrease of p53 in testes may have a relation to the known risk of Cd tumorigenesis in this tissue.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009273711068
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  • 2
    Electronic Resource
    Electronic Resource
    The role of calcium in apoptosis (1998)
    Springer
    BioMetals 11 (1998), S. 375-382 
    Details
    ISSN: 1572-8773
    Keywords: apoptosis ; programmed cell death (PCD) ; calcium ; DAP-Kinase ; calcineurin ; ALG-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract In this chapter various aspects of apoptosis or programmed cell death (PCD) influenced by calcium as a mediator of signal transduction have been reviewed. Attention has been focused on recently described calcium-binding proteins such as ALG-2 or on a new calcium/calmodulin-dependent kinase, the death asso-ciated protein kinase or DAP-kinase. Both play a central role in apoptotic processes. Calcineurin, which normally is involved in the regulation of T-cell proliferation, is reported to interact with the apoptosis protec-tion protein bcl-2. Its possible involvement in the decision process whether T-cell activation leads to prolif-eration or apoptosis is discussed.© Kluwer Academic Publishers
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009226316146
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  • 3
    Electronic Resource
    Electronic Resource
    Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models (1998)
    Springer
    European journal of clinical pharmacology 53 (1998), S. 337-341 
    Details
    ISSN: 1432-1041
    Keywords: Key words Amikacin ; Neonate ; Pharmacokinetics ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The population pharmacokinetics of amikacin, in neonates, was investigated using the nonlinear mixed effects model (NONMEM). Methods: One hundred and six steady-state amikacin serum levels were obtained from 53 black neonates with a mean gestational age of 35.1 weeks and mean age at the start of treatment of 3.1 days. A one-compartment model was used to fit the data. Results: The final models for clearance (CL) and volume of distribution (V) were: where WT = birth weight (kg) and P = 1.28 for girls and 1.0 for boys. Inclusion of other fixed effect parameters in the model did not significantly improve the fit of the data. The inter-individual variability for CL and V were 18% and 13%, respectively. Intra-individual variability was 29%. Mean (95% CI) values of CL, V and half-life were 0.048 (0.045, 0.051) l· h−1· kg−1, 0.434 (0.414, 0.453) l· kg−1 and 6.4 (6.2, 6.6) h respectively. Conclusion: Birth weight was an important determinant of both CL and V and, in this data set, gender was also found to influence CL. Mean population pharmacokinetic values were within the range of those previously derived for other neonatal populations using traditional methods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050389
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  • 4
    Electronic Resource
    Electronic Resource
    Sibutramine pharmacokinetics in young and elderly healthy subjects (1999)
    Springer
    European journal of clinical pharmacology 54 (1999), S. 847-849 
    Details
    ISSN: 1432-1041
    Keywords: Key words Sibutramine ; Pharmacokinetics ; Age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. Methods: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. Results: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in kel. Conclusions: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050565
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and bioequivalence evaluation of two generic formulations of oral artesunate (1998)
    Springer
    European journal of clinical pharmacology 53 (1998), S. 375-376 
    Details
    ISSN: 1432-1041
    Keywords: Key words Artesunate ; Dihydroartemisinin ; Pharmacokinetics ; Bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050397
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  • 6
    Electronic Resource
    Electronic Resource
    Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 593-598 
    Details
    ISSN: 1432-1041
    Keywords: Key words Irbesartan ; Warfarin ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. Methods: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5–10 mg on days 2–21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15–21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (Cmax), time to reach Cmax (tmax), the area under the concentration–time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the Cmin of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). Results: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma Cmin concentrations of S-warfarin and irbesartan were also not affected. Conclusions: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050678
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  • 7
    Electronic Resource
    Electronic Resource
    Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 667-669 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporin ; Orlistat ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We detected markedly decreased cyclosporin blood levels in a heart-transplanted patient after the gastrointestinal lipase inhibitor orlistat was accidentally added to the treatment program to control for his obesity. Therefore, we determined cyclosporin plasma concentration time kinetics with and without orlistat reexposition in this patient. Methods: Plasma concentration time kinetics of whole blood cyclosporin levels in an obese heart-transplant patient were measured using a standard monoclonal fluorescence polarisation immunoassay. Results were obtained in hourly intervals up to 12 h without and with co-therapy of 3 × 120 mg orlistat (Xenical, Roche Ltd., Switzerland). The orlistat re-exposition was started the day before taking blood samples. Results: Cyclosporin trough levels (98 ng/ml vs 52 ng/ml), maximum concentrations (532 ng/ml vs 74 ng/ml) and the area under the blood drug concentration-time curve (2832 ng h ml−1 vs 700 ng h ml−1) were greatly reduced with orlistat. Conclusions: Orlistat markedly decreased blood cyclosporin concentrations, possibly due to an interference with its absorption in the small intestine. To avoid potential dangerous under-immunosuppression, orlistat should not be used in patients taking cyclosporin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050690
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function (1999)
    Springer
    European journal of clinical pharmacology 54 (1999), S. 953-958 
    Details
    ISSN: 1432-1041
    Keywords: Key words AT1 receptor antagonist ; Blood pressure ; Candesartan cilexetil ; Candesartan ; Pharmacokinetics ; Renin angiotensin system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A 〉60 nl · min−1 · 1.73 m−2, group B 30–60 ml · min−1 · 1.73 m−2 and group C 15–30 ml · min−1 · 1.73 m−2). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUCinf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050581
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a novel 5-lipoxygenase inhibitor (ABT-761) in pediatric patients with asthma (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 715-719 
    Details
    ISSN: 1432-1041
    Keywords: Key words ABT-761 ; Pharmacokinetics ; Asthma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of an N-hydroxyurea analog, ABT-761 in asthmatic pediatric patients with asthma were investigated. Methods: A total of 24 patients were enrolled into this 8-day single- and multiple-dose study. Patients received daily doses of ABT-761 according to their body weight: patients of 20–38 kg received 50 mg; patients 〉38 kg but ≤55 kg received 100 mg, and patients ≥55 kg received 150 mg. Results: The mean values for the terminal phase t1/2 were 16–17 h after multiple-dose administration. When normalized for body weight, the mean day 8 Clf values for 50-, 100-mg, and 150-mg doses were 0.57 (n = 13), 0.51 (n = 10), and 0.43 (n = 1) ml · min−1 · kg−1, respectively, while the mean Vz/f values ranged from 0.75 to 0.77 l · kg−1. The mean accumulation ratio observed (day 8 to day 1 AUC0–24 ratio) of ABT-761 was approximately 1.7, which is consistent with the t1/2 of this drug. Body weight, age, and body surface area were virtually identical in explaining the variability in dose-normalized Cmax and AUC values (R 2 = 0.61–0.68). The percents of variance explained by these three variables were within a range of 3% for each pharmacokinetic parameter. Conclusions: The pharmacokinetics of ABT-761 in children were similar to those previously reported in adults. Body weight, age, or body surface area can be used to provide dosing adjustment for ABT-761 in pediatric patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050540
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  • 10
    Electronic Resource
    Electronic Resource
    Can oral contraceptive steroids influence the elimination of nifedipine and its primary pryidine metabolite in humans? (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 729-734 
    Details
    ISSN: 1432-1041
    Keywords: Key words Oral contraceptives ; Nifedipine ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To investigate the influence of oral contraceptives on cytochrome P450 3A4 (P450NF) activity. Methods: In 23 healthy women, the pharmacokinetics of nifedipine and its main metabolite dehydronifedipine in plasma were assessed after a single oral dose, prior to and after intake of one of two oral contraceptive formulations, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). Results: While the intake of two oral contraceptives for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine, mean AUC0–23.5 h and the mean Cmax values of dehydronifedipine were significantly lower in both groups tested/(24% in group A and 25% in group B). This observation may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. The activation of the same or other metabolic degradation mechanism(s) could explain this result. Conclusion: The investigation presented demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing ability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050543
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  • 11
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and safety of propiverine in patients with fatty liver disease (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 767-771 
    Details
    ISSN: 1432-1041
    Keywords: Key words Propiverine ; Fatty liver disease ; Pharmacokinetics ; Adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The present study was designed to assess the pharmacokinetics of propiverine after single and multiple dosing in patients with and without fatty liver disease. Methods: The serum concentration-time curves of propiverine and its main metabolite propiverine-N-oxide were investigated in 12 patients with mild to moderate impairment of liver function (mean antipyrine clearance 26.0 ml · min−1) and in 12 controls (antipyrine clearance 42.8 ml · min−1). Subjects were treated orally with propiverine hydrochloride (Mictonorm) for 5 days (15 mg t. i. d.) to reach steady state. Results: No significant differences were observed for propiverine and its main metabolite with regard to peak serum concentration (Cmax), area under the serum concentration-time curve (AUC) and elimination half-life (t1/2). Adverse events were reported by 12 patients. Five patients with fatty liver disease and seven patients with normal liver function complained of dry mouth and/or blurred vision. All adverse events reported were transient and mild. Conclusion: No pharmacokinetic differences relevant for safety were observed, comparing patients with and without fatty liver disease following repeated oral administration of propiverine. Thus there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050549
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  • 12
    Electronic Resource
    Electronic Resource
    Limited-sampling strategy models for estimating the area under the plasma concentration–time curve for amlodipine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 651-657 
    Details
    ISSN: 1432-1041
    Keywords: Key words Amlodipine ; Limited-sampling models ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. Methods: Sixteen healthy volunteers received single 5-mg oral doses of amlodipine, as reference or test formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma concentrations of amlodipine (n = 288), measured by mass spectrometry, were used to develop LSS models. Results: Linear regression analysis of the AUC0–72 and a “jack-knife” validation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R2 = 0.99; bias〈0.01%; precision = 0.03%) the AUC0–72 of amlodipine for each formulation. Validation tests indicate that the 2-point LSS model developed for the reference formulation predicts accurately (R2〉0.90): (a) the individual AUC0–72 for the test formulation in the same group of volunteers; (b) the individual AUC0–72 for the same reference formulation in another bioequivalence study in Brazilian volunteers; (c) the average AUC0–72 reported in seven additional international studies performed under protocols similar to the present investigation; (d) the individual AUC0–72 corresponding to concentration data points provided by a first-order compartmental pharmacokinetic model, when the relative values of either the absorption rate (K abs) or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original values. Conclusions: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this calcium antagonist, at reduced costs of sample acquisition and analysis, and avoiding sampling at “unsociable” hours.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050688
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  • 13
    Electronic Resource
    Electronic Resource
    Bioavailability of intranasal formulations of dihydroergotamine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 677-680 
    Details
    ISSN: 1432-1041
    Keywords: Key words Dihydroergotamine ; Absorption ; Intranasal ; Randomly methylated β-cyclodextrin (RAMEB) ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma concentration–time curve (AUC0–8 h), Frel(t=8 h) and Cmax/ AUC(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050692
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  • 14
    Electronic Resource
    Electronic Resource
    Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 469-474 
    Details
    ISSN: 1432-1041
    Keywords: Key words CYP2D6 ; Genetic polymorphism ; Metoprolol ; Pharmacokinetics ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Aim: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. Methods: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. Results: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCτ), minium steady-state concentration (Cmin ss) and average steady-state concentration (Cav ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for Css max , t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050495
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  • 15
    Electronic Resource
    Electronic Resource
    Distribution and metabolism of N G-nitro-l-arginine methyl ester in patients with septic shock (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 627-631 
    Details
    ISSN: 1432-1041
    Keywords: Key wordsl-NAME ; Pharmacokinetics ; Septic shock
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of N G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. Methods: Blood was sampled at intervals before, during and after 12-h infusion of l-NAME 1 mg · kg−1 · h−1 in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined. Results: Incubation of l-NAME with plasma and blood in vitro revealed hydrolysis to N G-nitro-l-arginine (l-NOARG), the active inhibitor of NO synthesis. l-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg · kg−1 · h−1 of l-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of l-NOARG (Cmax 6.2 μg · ml−1 at 12 h) whereas l-NAME concentrations reached a plateau within 1.5 h (Cmax 1.0 μg · ml−1). After the infusion was stopped l-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas l-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for l-NAME was 0.45 l · kg−1 body weight and 1.96 l · kg−1 for l-NOARG. The renal clearance for l-NOARG was 3.5% of total body clearance for l-NOARG, whereas l-NAME could not be detected in urine. Conclusion: We conclude that vasoconstriction with l-NAME in septic patients may result from hydrolysis to l-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for l-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite l-NOARG follows other pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050525
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  • 16
    Electronic Resource
    Electronic Resource
    Estimation of the area under the concentration-versus-time curve of carboplatin following irinotecan using a limited sampling model (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 725-727 
    Details
    ISSN: 1432-1041
    Keywords: Key words Carboplatin ; Irinotecan ; Limited sampling model ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: The aim of this study was to develop limited sampling models for estimating the area under the concentration-versus-time curve (AUC) of carboplatin. Methods: Based on pharmacokinetic analyses of 14 patients who received 300 mg · m2 of carboplatin over a 90-min infusion following irinotecan, we developed limited sampling models with stepwise multiple linear regression analysis. We validated these models to be unbiased and precise using pharmacokinetic data of a second group of 14 patients. We also compared the observed and the predicted AUC in the patients using Calvert's formula with the patients' renal function. Results: We developed the following models: AUC (mg · ml−1 · min) = 0.784 × C4 + 1.30 (r 2 = 0.930) and AUC = 0.100 × C0.25 + 0.597 × C4 + 0.140 (r 2 = 0.992), where C0.25 and C4 denote unbound plasma concentrations (μg · ml−1) of carboplatin at 0.25 h and 4 h after the end of infusion, respectively. These models were validated to be unbiased and precise: a mean prediction error (MPE) with standard deviation (SD) = 2.41 (9.45)% and a root mean squared error (RMSE) = 9.42% for the one-sample model, and MPE with (SD) = 1.22 (5.56)% and RMSE = 5.49% for the two-sample model. We also calculated predicted AUC in the patients using Calvert's formula: MPE with (SD) =−5.87 (21.5)% and RMSE = 21.5%. Conclusions: These estimations were, as expected, more accurate than the prediction using Calvert's formula based on patients' renal function. The result of this study confirmed the idea that the pharmacokinetic parameters derived from limited sampling models would be more suitable for pharmacokinetic analysis of carboplatin than those obtained using Calvert's formula.
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    URL: http://dx.doi.org/10.1007/s002280050542
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    Pharmacokinetics of oxypolygelatine in healthy volunteers (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 49-51 
    Details
    ISSN: 1432-1041
    Keywords: Key words Oxypolygelatine ; Pharmacokinetics ; Healthy volunteers ; Tolerability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg−1 body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml−1, the area under the plasma concentration/time curve (AUC0∞) was calculated to 70.135 (15.861) μg · h · ml−1. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cltot) of 24.6 (6.8) ml · min−1. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites.
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    URL: http://dx.doi.org/10.1007/s002280050591
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    Absence of interaction between erythromycin and a single dose of clozapine (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 221-226 
    Details
    ISSN: 1432-1041
    Keywords: Key words Clozapine ; Erythromycin ; CYP3A4 ; Pharmacokinetics ; Drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0–12 h. Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1−1 in the control phase and 1180 (659) nmol h · 1−1 in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1−1 and 77 (40) nmol · 1−1, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l · h−1 and 46 (37) l · h−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h−1 and 7.8 (9.4) l · h−1, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h−1 and 1.8 (1.7) l · h−1, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h−1 and 1.0 (0.7) l · h−1, respectively) between the two phases. Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.
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    URL: http://dx.doi.org/10.1007/s002280050621
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    Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 125-130 
    Details
    ISSN: 1432-1041
    Keywords: Key words Pregnanolone ; Pharmacokinetics ; Premenstrual syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Pregnanolone is a 3α-hydroxylated-5β-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. Methods: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. Results: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml · min−1 · kg−1 and 64.0 ml · min−1 · kg−1, depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. Conclusion: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects.
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    URL: http://dx.doi.org/10.1007/s002280050606
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    Development of a general method of limited sampling for the determination of AUC for a drug that displays two-compartment pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 213-219 
    Details
    ISSN: 1432-1041
    Keywords: Key words Limited sampling ; Area under the curve ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objectives: To develop a method of limited sampling that would enable accurate estimation of the area under the concentration time curve (AUC) when using the log trapezoidal method. Methods: A series of datasets were simulated. Each dataset comprised 1000 subjects. Each subject was “administered” an intravenous bolus dose of a drug that displays two compartment pharmacokinetics. In the first series of simulations, a variety of combinations of the number of sampling times (K) and number of replicate measurements (R) at each of these times were tested, where K × R = 12 (i.e. N = 12). The times that each of the K samples were taken were chosen to be those that divided the AUC into K − 1 trapezoids of equal area. The concentration-time curves were estimated based on a priori estimates of the population parameters. The best combination of K and R was tested under various conditions of parameter variability and assay variability. The combinations were compared with a conventional sampling strategy, where N = 12, K = 12 (R = 1). Results: The combination K = 4 and R = 3 proved to be the “best”. It had similar accuracy to the conventional method. The best limited sampling combination was superior to the conventional method when assay variability was high (CV = 30%), was similar when assay variability was 15%, but the conventional method became statistically superior when assay variability was 7.5% or less. The accuracy of the best limited sampling combination was inversely related to the parameter variability. If K was set to 4 and R allowed to increase to 6 (i.e. N≠ 12), there was no further gain in accuracy. Conclusion: The proposed method of limited sampling is at least as accurate as the conventional intensive sampling technique, but more efficient in terms of sampling.
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    URL: http://dx.doi.org/10.1007/s002280050620
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    Renal handling of drugs in the healthy elderly Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 205-211 
    Details
    ISSN: 1432-1041
    Keywords: Key words Elderly ; Pharmacokinetics ; Renal function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions. Methods: We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (Cin) and para-aminohippurate [PAH (CPAH)] clearance (infusion clearance technique), endogenous (CCr) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of β-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days. Results: Cin was significantly (P 〈 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml · min−2 · 1.73 m−2 in the young], but remained within the normal range (〉90 ml · min−2 · 1.73 m−2). In contrast, CCr was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml · min−1 in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml · min−1]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) μg · h−1 · ml−1 in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) μg · ml−1], but the proportion of the drug excreted in urine was marginally (P 〈 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly. Conclusions: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly.
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    URL: http://dx.doi.org/10.1007/s002280050619
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    The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 337-340 
    Details
    ISSN: 1432-1041
    Keywords: Keywords Verapamil ; Grapefruit juice ; Pharmacokinetics ; Hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. Methods: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUCv) and its metabolite D-617 (AUCM) were calculated before and after GJ ingestion. The peak serum concentration (Cmax) and the time until its appearance (tmax) were also determined. Results: GJ did not affect Cmax, tmax, AUCv or AUVm. The AUCv/AUCm ratio (AUCR) was slightly, but significantly, increased after GJ (1.67 vs 1.92). Conclusions: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil.
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    URL: http://dx.doi.org/10.1007/s002280050470
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    Comparative pharmacokinetic study of oral and rectal formulations of artesunic acid in healthy volunteers (1998)
    Springer
    European journal of clinical pharmacology 54 (1998), S. 411-414 
    Details
    ISSN: 1432-1041
    Keywords: Key words Artesunic acid ; Pharmacokinetics ; Malaria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: A single cross-over, comparative pharmacokinetic study of oral and rectal formulations of 200 mg artesunic acid in 12 healthy Malaysian volunteers is reported. Methods: Plasma concentrations of artesunic acid and dihydroartemisinin were determined simultaneously by HPLC with electrochemical detection. The test drug was well tolerated and no undesirable adverse effects were observed. Results: Comparison of pharmacokinetic parameters of artesunic acid after oral and rectal administration showed statistically significant differences in t max and AUC, with no changes for C max and t 1/2. As for dihydroartemisinin, differences were observed for t max and C max but not for AUC. Conclusion: There appear to be pharmacokinetic differences between oral and rectal modes of administration. The significance of these findings should be explored in malaria patients before appropriate therapeutic regimens are devised.
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    URL: http://dx.doi.org/10.1007/s002280050484
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    Population pharmacokinetic analysis of pirmenol in healthy volunteers and patients with arrhythmia (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 77-78 
    Details
    ISSN: 1432-1041
    Keywords: Key words Pirmenol ; Arrhythmia ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050596
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    Grapefruit juice has no effect on quinine pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 393-398 
    Details
    ISSN: 1432-1041
    Keywords: Key words Grapefruit juice ; Quinine ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated. Methods: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control), full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance liquid chromatography method. Results: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma drug concentration (Cmax), the time to reach Cmax (tmax), the terminal elimination half-life (t1/2), the area under the concentration–time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine metabolite were slightly changed when volunteers received grapefruit juice. The mean Cmax of the metabolite (0.25 ± 0.09 mg l−1, mean ± SD) while subjects received full-strength grapefruit juice was significantly less than during the control period (0.31 ± 0.06 mg l−1, P 〈 0.05) and during the intake of half-strength grapefruit juice (0.31 ± 0.07 mg l−1, P 〈 0.05). Conclusion: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut.
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    Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 461-467 
    Details
    ISSN: 1432-1041
    Keywords: Key words Entacapone ; Levodopa ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared with each other. Results: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.
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    URL: http://dx.doi.org/10.1007/s002280050657
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    The effect of short-term dipyrone administration on cyclosporin pharmacokinetics (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 475-478 
    Details
    ISSN: 1432-1041
    Keywords: Key words Cyclosporin ; Dipyrone ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. Objective: To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. Methods: Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. Results: CSA concentrations over time were reduced after dipyrone (ANOVA, P 〈 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P 〈 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 ± 2.6 h vs 2.1 ± 0.6 h, P 〈 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration–time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. Conclusions: Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.
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    Biological effects of a relatively low concentration of 1-b-D-arabinofuranosylcytosine in K562 cells: Alterations of the cell cycle, erythroid-differentiation, and apoptosis (1998)
    Springer
    Molecular and cellular biochemistry 187 (1998), S. 211-220 
    Details
    ISSN: 1573-4919
    Keywords: 1-β-D-arabinofuranosylcytosine ; cell cycle ; apoptosis ; differentiation ; K562 cells ; c-myc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Therapeutic strategies for leukemia are directed to induction of differentiation and apoptosis as well as growth inhibition. One of the key antileukemic agents, 1-β-D-arabinofuranosylcytosine (ara C), is clinically applied according to these therapeutic aims. However, the molecular effects of 0.1 μg/ml of ara C, a concentration that corresponds to the serum level in leukemic patients on a conventional dose of ara C, have not been well disclosed. Here, we addressed these issues using K562 cells which derived from a blastic crisis of chronic myeloid leukemia. DNA synthesis of treated cells was suppressed from 1-6 h. But, it recovered at 12 h and no further inhibition was observed. The number of cells was not decreased but DNA fragmentation was observed at 72 h. The number of erythroid-differentiated cells also increased to 30% at 72 h. Along with treatment, no marked alteration of mRNAs for cell cycle-regulating genes was found and the retinoblastoma gene product remained hyperphosphorylated throughout treatment. The expression of mRNAs for apoptosis-regulating genes also remained unchanged, except for slight down-regulation of Bax. c-myc protein was not found later than 48 h, and Max mRNA was downregulated. c-jun was immediately induced, followed by the fluctuated expression level along with treatment. These findings suggest that the 0.1 μg/ml ara C changed the proliferation, differentiation and death of K562 cells in a biphasic manner. In the early phase, DNA synthesis was inhibited without altering the expression of cell cycle regulating-genes. In the latter phase, cell death and erythroid- differentiation occurred in accordance with the down-regulation of c-myc.
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    URL: http://dx.doi.org/10.1023/A:1006874931249
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    Apparent cleavage of poly(ADP-ribose) polymerase in non-apoptotic mouse LTA cells: An artifact of cross-reactive secondary antibody (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 245-249 
    Details
    ISSN: 1573-4919
    Keywords: poly(ADP-ribose) polymerase ; apoptosis ; word ; antibody cross-reactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Proteolytic cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to fragments of 89 kD and 24 kD is widely observed during apoptotic cell death. In the present study, labelling of a Mr ∼89000 polypeptide was demonstrated in untreated mouse LTA cells during probing of immunoblots with C-2-10 monoclonal anti-PARP antibody. The source of the labeling was traced to the secondary antibody preparation, which labeled a Mr ~89000 polypeptide in murine LTA cells but not in human cells. These observations indicate that assessment of PARP cleavage must be (1) performed with appropriate controls when new cell lines are investigated and (2) carefully interpreted in light of additional biochemical or morphological data demonstrating apoptotic changes.
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    URL: http://dx.doi.org/10.1023/A:1006808001462
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    Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant (1998)
    Springer
    Molecular and cellular biochemistry 186 (1998), S. 159-168 
    Details
    ISSN: 1573-4919
    Keywords: ischemia ; dedifferentiation ; apoptosis ; chronic hibernating myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes. Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.
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    URL: http://dx.doi.org/10.1023/A:1006887803970
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    Dissociation of vitamin D3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells (1998)
    Springer
    Molecular and cellular biochemistry 188 (1998), S. 13-20 
    Details
    ISSN: 1573-4919
    Keywords: vitamin D ; anti-estrogens ; apoptosis ; MCF-7 cells ; cell cycle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Our studies have identified 1,25(OH)2D3 as a coordinate regulator of proliferation and apoptosis in breast cancer cells. In MCF-7 cells, 1,25(OH)2D3 down regulates the estrogen receptor (ER), suggesting that the effects of 1,25(OH)2D3 may be linked to disruption of estrogen regulated survival signals. Although studies have demonstrated that 1,25(OH)2D3 inhibits growth of ER negative breast cancer cells, previous data were generated by comparison of cell lines derived from heterogeneous human tumors and harboring diverse genetic alterations. To provide more conclusive evidence for independent growth regulatory pathways mediated by antiestrogens and 1,25(OH)2D3, we examined vitamin D3 sensitivity in MCF-7 cells selected for resistance to ICI 182, 780 (Zeneca, Macclesfield, UK). The clones we selected for resistance to ICI 182,780 retain functional VDR and undergo 1,25(OH)2D3 mediated growth arrest and apoptosis, in vitro and in vivo, despite loss of estrogen dependence. Cell cycle data indicate that treatment of parental or anti-estrogen resistant MCF-7 clones with 1,25(OH)2D3, in the presence or absence of ICI 182,780, increases the percentage of cells in G0G1 while reducing the number of cells in S phase. In addition, 1,25(OH)2D3 induces characteristic features of apoptosis, including DNA fragmentation, in both parental and anti-estrogen resistant MCF-7 cells. Furthermore, we report that cells selected for vitamin D3 resistance retain sensitivity to ICI 182,780 mediated growth arrest and apoptosis. This work emphasizes that vitamin D3 compounds and anti-estrogens trigger growth arrest and apoptosis in breast cancer cells by distinct mechanisms, and that breast cancer cell sensitivity to 1,25(OH)2D3 is not diminished during the progression to estrogen independence.
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    URL: http://dx.doi.org/10.1023/A:1006879213501
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    Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase (1999)
    Springer
    Molecular and cellular biochemistry 196 (1999), S. 13-21 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; DNA fragmentation ; GSHPx-1 knockout mice ; GSHPx-1 transgenic mice ; ischemia/repurfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Apoptosis, a genetically controlled programmed cell death, has been found to play a role in ischemic reperfusion injury in several animal species including rats and rabbits. To examine whether this is also true for other animals, an isolated perfused mouse heart was subjected to 30 min of ischemia followed by 2 h of reperfusion. Experiments were terminated before ischemia (baseline), after ischemia, and at 30, 60, 90 and 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis and DNA laddering. The in situ end labeling (ISEL) technique was used to detect apoptotic cardiomyocyte nuclei while DNA laddering was evaluated by subjecting the DNA obtained from the cardiomyocytes to 1.8% agarose gel electrophoresis followed by photographing under UV illumination. The results of our study revealed that apoptotic cells appear only after 60 min of reperfusion as demonstrated by the intense fluorescence of the immunostained genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results were corroborated with the findings of DNA fragmentation showing increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the internucleosomal DNA length (about 180 bp). Since our previous studies showed a role of glutathione peroxidase (GSHPx) in apoptotic cell death, we performed identical experiments using isolated hearts from GSHPx-l knockout mice and transgenic mice overexpressing GSHPx-l. GSHPx-l knockout mice showed evidence of apoptotic cell death even after 30 min of reperfusion. Significant number of apoptotic cells were found in the cardiomyocytes as compared to non-transgenic control animals. To the contrary, very few apoptotic cells were found in the hearts of the transgenic mice overexpressing GSHPx-l. Hearts of GSHPx-l knockout mice were more susceptible to ischemia/reperfusion injury while transgenic mice overexpressing GSHPx- 1 were less susceptible to ischemia reperfusion injury compared to non-transgenic control animals. The results of this study clearly demonstrate a role of GSHPx in ischemia/reperfusion-induced apoptosis in mouse heart.
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    URL: http://dx.doi.org/10.1023/A:1006905910140
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    Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 199 (1999), S. 169-178 
    Details
    ISSN: 1573-4919
    Keywords: MKP-1 ; Fas ligand ; Fas ; apoptosis ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (Δγm), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.
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    URL: http://dx.doi.org/10.1023/A:1006980326855
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    Poly(ADP-ribosylation) and apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 199 (1999), S. 125-137 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; ADP-ribosylation ; caspases ; PARP ; PARG
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Poly(ADP-ribosylation) is a post-translational modification playing a relevant role in DNA damage recovery, DNA replication and viral integration. Several reports also suggest a modulation of this process during cell death by apoptosis. The aim of this review is to discuss the possible involvement of poly(ADP-ribosylation) during apoptosis, by dealing with general considerations on apoptosis, and further examining the correlation between NAD consumption and cell death, the regulation of poly(ADP-ribose) metabolism in apoptotic cells, the effect of poly(ADP-ribose) polymerase inhibition on cell death occurrence and the use of enzyme cleavage as a marker of apoptosis. Finally, the future prospects of the research in this area will be addressed.
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    URL: http://dx.doi.org/10.1023/A:1006962716377
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    Targets of oxidative stress in cardiovascular system (1998)
    Springer
    Molecular and cellular biochemistry 187 (1998), S. 1-10 
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    ISSN: 1573-4919
    Keywords: oxidant ; cardiovascular system ; signal transduction ; calcium ; mitogen activated protein kinases ; nuclear transcription factors ; tyrosine kinase ; protein kinase C ; superoxide ; hydrogen peroxide ; ischemia-reperfusion ; atherosclerosis ; phospholipases ; apoptosis ; antioxidant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Although oxidants such as superoxide (O2.-) and hydrogen peroxide (H2O2) play a role in host-mediated destruction of foreign pathogens yet excessive generation of oxidants may lead to a variety of pathological complications in the cardiovascular system. An important mechanism by which oxidants cause dysfunction of the cardiovascular system appears to be due to the increase in intracellular free Ca2+ concentration. Oxidants cause cellular Ca2+ mobilization by modulating activities of a variety of regulators such as Na+/H+ and Na+/Ca2+ exchangers, Na+/K+ ATPase and Ca2+ ATPase and Ca2+ channels that are associated with Ca2+ transport in the plasma membrane and the sarco(endo)plasmic reticular membrane of myocardial cells. Recent research have suggested that the increase in Ca2+ level by oxidants plays a pivotal role in indicing several protein kinases such as protein kinase C, tyrosine kinase and mitogen activated protein kinases. Oxindant-mediated alteration of different signal transduction systems and their interations eventually regulate a variety of pathological conditoins such as atherosclerosis, apoptosis and necrosis in the myocardium
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    URL: http://dx.doi.org/10.1023/A:1006802903504
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    Chemical hypoxia triggers apoptosis of cultured neonatal rat cardiac myocytes: Modulation by calcium-regulated proteases and protein kinases (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 141-149 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; cardiomyocyte ; azide ; hypoxia ; word ; calpain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Myocardial infarctions and stroke arise primarily as a result of hypoxia/ischemia-induced cell injury. However, the molecular mechanism of cardiac cell death due to hypoxia has not been elucidated. We showed here that chemical hypoxia induced by 1 mM azide triggered apoptosis of isolated neonatal rat ventricular cardiac myocytes but had no effect on cardiac fibroblasts. The azide-induced cardiomyocyte apoptosis could be characterized by a reversible initiation phase (0-6 h after azide exposure) during which cytosolic ATP levels remained little affected. This was followed by an irreversible execution phase (12-18 h) exhibiting prominent internucleosomal DNA fragmentation, cell membrane leakage, mitochondrial dysfunction, and increased calpain messenger RNA. Blocking extracellular calcium influx or intracellular calcium release was each effective in suppressing myocyte apoptosis. Cell death was also found to be mediated by calcium sensitive signal transduction events based on the use of specific antagonists. Consistent with the induction of calpain expression during apoptosis, blocking de novo protein synthesis and calpain activity inhibited cell death. These regulatory features coupled with the ease of the cell system suggest that the myocyte apoptosis model described here should be useful in the study of events leading to the demise of the myocardium.
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    Biochemical and molecular mechanisms regulating apoptosis (1998)
    Springer
    Molecular and cellular biochemistry 178 (1998), S. 9-25 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; programmed cell death ; signal transduction ; CD95 (Fas) ; p53 ; c-myc ; bcl-2 ; caspases ; DNA fragmentation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract In eukaryotes, the regulation of tissue cell numbers is a critical homeostatic objective that is achieved through tight control of apoptosis, mitosis and differentiation. While much is known about the genetic regulation of cell growth and differentiation, the molecular basis of apoptosis is less well understood. Genes involved in both cell proliferation and apoptosis reflect the role of some stimuli in both of these processes, the cell response depending on the overall cellular milieu. Recent research has given fascinating insights into the complex genetic and molecular mechanisms regulating apoptosis. A picture is emerging of the initiation in certain cells, after an apoptotic trigger, of sequential gene expression and specific signal transduction cascades that guide cells along the cell death pathway. Changes in gene expression precede the better known biochemical and morphological changes of apoptosis. It seems possible that, as a result of increased understanding of the cellular events preceding cell death, apoptosis may become more amenable to manipulation by appropriate drug- and gene-based therapies.
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    URL: http://dx.doi.org/10.1023/A:1006891430596
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    Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide (1998)
    Springer
    Molecular and cellular biochemistry 185 (1998), S. 7-15 
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    ISSN: 1573-4919
    Keywords: human retinoblastoma cells ; apoptosis ; ceramide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological changes without a concomitant production of oligonucleosomal fragments responsible for the DNA ladder and without changes in p53 protein level. Apoptosis was accompanied by accumulation of a modified Bcl-2 protein with a slower-mobility form, and by proteolytic cleavage of PARP. The effect seemed to be specific for C2-ceramide, as C2-dihydroceramide, or other amphiphilic lipid analogues, or products of ceramide hydrolysis were ineffective. The effect also depended on mRNA and protein synthesis as it was markedly inhibited by actinomycin D and cycloheximide. Sphingomyelinase and interleukin-lβ, which are known to activate the sphingomyelin turnover leading to ceramide generation, also induced apoptosis mimicking the effects of ceramide. These findings propose ceramide as an activator of the suicidal program in Y79 cells.
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    URL: http://dx.doi.org/10.1023/A:1006836428202
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    A dual approach in the study of poly (ADP-ribose) polymerase: In vitro random mutagenesis and generation of deficient mice (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 53-60 
    Details
    ISSN: 1573-4919
    Keywords: DNA binding protein ; NAD metabolism ; cellular response to DNA damage ; γ-rays ; alkylating agents ; genomic instability ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract A dual approach to the study of poly (ADP-ribose)polymerase (PARP) in terms of its structure and function has been developed in our laboratory. Random mutagenesis of the DNA binding domain and catalytic domain of the human PARP, has allowed us to identify residues that are crucial for its enzymatic activity. In parallel PARP knock-out mice were generated by inactivation of both alleles by gene targeting. We showed that: (i) they are exquisitely sensitive to γ-irradiation, (ii) they died rapidly from acute radiation toxicity to the small intestine, (iii) they displayed a high genomic instability to γ-irradiation and MNU injection and, (iv) bone marrow cells rapidly underwent apoptosis following MNU treatment, demonstrating that PARP is a survival factor playing an essential and positive role during DNA damage recovery and survival.
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    Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 137-148 
    Details
    ISSN: 1573-4919
    Keywords: PARP ; poly(ADP-ribosyl)ation ; apoptosis ; DNA replication
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have focused on the roles of PARP and poly(ADP-ribosyl)ation early in apoptosis, as well as during the early stages of differentiation-linked DNA replication. In both nuclear processes, a transient burst of PAR synthesis and PARP expression occurs early, prior to internucleosomal DNA cleavage before commitment to apoptosis as well as at the round of DNA replication prior to the onset of terminal differentiation. In intact human osteosarcoma cells undergoing spontaneous apoptosis, both PARP and PAR decreased after this early peak, concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset of substantial DNA and nuclear fragmentation. Whereas 3T3-L1, osteosarcoma cells, and immortalized PARP +/+ fibroblasts exhibited this early burst of PAR synthesis during Fas-mediated apoptosis, neither PARP-depleted 3T3-L1 PARP-antisense cells nor PARP -/- fibroblasts showed this response. Consequently, whereas control cells progressed into apoptosis, as indicated by induction of caspase-3-like PARP-cleavage activity, PARP-antisense cells and PARP -/- fibroblasts did not, indicating a requirement for PARP and poly(ADP-ribosyl)ation of nuclear proteins at an early reversible stage of apoptosis. In parallel experiments, a transient increase in PARP expression and activity were also noted in 3T3-L1 preadipocytes 24 h after induction of differentiation, a stage at which ~95% of the cells were in S-phase, but not in PARP-depleted antisense cells, which were consequently unable to complete the round of DNA replication required for differentiation. PARP, a component of the multiprotein DNA replication complex (MRC) that catalyzes viral DNA replication in vitro, poly(ADP-ribosyl)ates 15 of ~40 MRC proteins, including DNA pol α, DNA topo I, and PCNA. Depletion of endogenous PARP by antisense RNA expression in 3T3-L1 cells results in MRCs devoid of any DNA pol α and DNA pol δ activities. Surprisingly, there was no new expression of PCNA and DNA pol α, as well as the transcription factor E2F-1 in PARP-antisense cells during entry into S-phase, suggesting that PARP may play a role in the expression of these proteins, perhaps by interacting with a site in the promoters for these genes.
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    URL: http://dx.doi.org/10.1023/A:1006988832729
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    Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: Inhibition of cell growth and induction of apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 202 (1999), S. 53-61 
    Details
    ISSN: 1573-4919
    Keywords: breast cancer cells ; anti-apoptotic genes ; apoptosis ; progesterone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53, bcl-2 and survivin genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90% inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 μM progesterone for 72 h. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to 10 μM progesterone. The earliest sign of apoptosis is translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane and can be monitored by the calcium-dependent binding of annexin V in conjunction with flow cytometry. After 24 h of exposure to 10 μM progesterone, cytofluorometric analysis of T47-D breast cancer cells indicated 43% were annexin V-positive and had undergone apoptosis and no cells showed signs of cellular necrosis (propidium iodide negative). After 72 h of exposure to 10 μM progesterone, 48% of the cells had undergone apoptosis and 40% were annexin V positive/propidium iodide positive indicating signs of necrosis. Control untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 h of exposure of T47-D cells to either 1 or 10 μM progesterone, we observed a marked down-regulation of protooncogene bcl-2 protein and mRNA levels. mRNA levels of survivin and the metastatic variant CD44 v7-v10 were also downregulated. Progesterone increased p53 mRNA levels. These results demonstrate that progesterone at relative high physiological concentrations, but comparable to those seen in plasma during the third trimester of human pregnancy, exhibited a strong antiproliferative effect on breast cancer cells and induced apoptosis.
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    Role of nitric oxide in the induction of apoptosis by smokeless tobacco extract (1999)
    Springer
    Molecular and cellular biochemistry 200 (1999), S. 51-57 
    Details
    ISSN: 1573-4919
    Keywords: smokeless tobacco ; apoptosis ; nitric oxide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Smokeless tobacco usage is, a growing public health concern in the United States. Lesions of the oral cavity have been clearly linked to smokeless tobacco use. The objective of this study was to determine the biochemical effects of smokeless tobacco extract (STE) exposure upon hamster cheek pouch cell (HCPC-1) cultures. HCPC-1 cells were exposed to a 5 -fold dose-range of STE (0.5, 1.0 and 2.5%) over a time-course of 24-96 h. Following each exposure we measured various biochemical parameters of cell proliferation and cell death. Cell viability, cell cycle progression and S-phase DNA synthesis were measured as markers of cell proliferation. We measured lactate dehydrogenase leakage as a marker of cell membrane damage and cell death due to necrosis. No significant alterations were observed in cell cycle progression and cell proliferation as a result of exposure to STE. LDH measured colorimetrically indicated no significant effect with the lower doses (0.5, 1.0 and 2.5% STE). Apoptosis measured as the A0 peak and by the TUNEL procedure revealed that STE caused significant rates of apoptosis. Maximal apoptosis was noted between 48-96 h. In order to probe the mechanism further we measured the levels of nitrites as an indicator of nitric oxide (NO) in the media. NO levels were significantly elevated at the doses that caused an induction of apoptosis. The results from this study indicate that STE causes a dose-dependent induction of apoptosis and that this is mediated by nitric oxide.
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    Yeasts Reduce the Stimulatory Effect of Acetate Esters from Apple on the Germination of Botrytis cinerea Conidia (1999)
    Springer
    Journal of chemical ecology 25 (1999), S. 1555-1565 
    Details
    ISSN: 1573-1561
    Keywords: Yeasts ; Botrytis cinerea ; apple ; volatiles ; gray mold ; biological control ; fungal interaction ; acetate esters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The fungus, Botrytis cinerea, causes decay in apples in postharvest storage. Conidia of B. cinerea on polycarbonate membranes were incubated on filter paper disks saturated with water or suspensions of yeasts (2 × 106 CFU/filter) and then exposed for 24 hr at 22°C to 0–16 μl of ethyl, butyl, or hexyl acetates injected into the headspaces of 500-cc glass jars. Germination of conidia was increased by exposure to 4–16 μl of ethyl acetate compared to the no-ester controls. Conidia were stimulated to germinate by 4 μl of butyl acetate and 8 μl of hexyl acetate, but greater volumes were toxic to germination. The yeasts Cryptococcus laurentii and Sporobolomyces roseus were more effective at reducing the stimulatory effect than Saccharomyces cerevisiae. Acetate esters also stimulated germination of conidia on polycarbonate membranes on apples inside jars. Cryptococcus laurentii or S. roseus suppressed this effect more than S. cerevisiae. Germination of conidia on a membrane on water inside a 3.9-liter jar containing an apple was 2.5-fold greater than the no-apple control. Butyl acetate increased Botrytis infection of apple wounds. Butyl and hexyl acetate were detected by GLC in the headspace of Golden Delicious apples. Results indicated that some acetate esters produced by apple stimulated germination of B. cinerea conidia, and this effect was suppressed by yeasts.
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    Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion (1998)
    Springer
    Molecular and cellular biochemistry 186 (1998), S. 139-145 
    Details
    ISSN: 1573-4919
    Keywords: apoptosis ; DNA fragmentation ; ischemia/reperfusion ; ischemic preconditioning ; myocardial adaptation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Apoptosis or programmed cell death is a genetically controlled response for cells to commit suicide and is associated with DNA fragmentation or laddering. The common inducers of apoptosis include oxygen free radicals/oxidative stress and Ca2+ which are also implicated in the pathogenesis of myocardial ischemic reperfusion injury. To examine whether ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15, 30 or 60 min of ischemia as well as 15 min of ischemia followed by 30, 60, 90 or 120 min of reperfusion. At the end of each experiment, the heart was processed for the evaluation of apoptosis and DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG® in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from the hearts to 1.8% agarose gel electrophoresis and photographed under UV illumination. The results of our study revealed apoptotic cells only in the 90 and 120 min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscopy. None of the ischemic hearts showed any evidence of apoptosis. These results were corroborated with the findings of DNA fragmentation which showed increased ladders of DNA bands in the same reperfused hearts representing integer multiples of the internucleosomal DNA length (about 180 bp). The presence of apoptotic cells and DNA fragmentation in the myocardium were completely abolished by subjecting the myocardium to repeated short-term ischemia and reperfusion which also reduced the ischemic reperfusion injury as evidenced by better recovery of left ventricular performance in the preconditioned myocardium. The results of this study indicate that reperfusion of ischemic heart, but not ischemia, induces apoptotic cell death and DNA fragmentation which can be inhibited by myocardial adaptation to ischemia.
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    Clostridial toxins: Molecular probes of Rho-dependent signaling and apoptosis (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 37-42 
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    ISSN: 1573-4919
    Keywords: Rho ; GTPase ; toxins ; Clostridium ; signal transduction ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The Rho family small GTPases are members of the Ras superfamily of small GTPases. Rho proteins were first determined to act as key regulators of many types of actin cytoskeletal-dependent cellular functions. Recent work by several investigators indicates that Rho GTPases are also critical modulators of several important intracellular and nuclear signal transduction pathways. Certain clostridial toxins and exoenzymes covalently modify, and thereby inactivate, specific types of Rho family GTPases. As such, these microbial enzymes have proven invaluable in helping to identify structural and functional attributes of Rho GTPases.
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    Functional analysis of poly(ADP-ribose) polymerase in Drosophila melanogaster (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 103-108 
    Details
    ISSN: 1573-4919
    Keywords: Poly(ADP-ribose) polymerase ; Drosophila melanogaster ; alternative splicing ; apoptosis ; DNA repair ; development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Poly(ADP-ribose) polymerase (PARP) is conserved in eukaryotes. To analyze the function of PARP, we isolated and characterized the gene for PARP in Drosophila melanogaster. The PARP gene consisted of six translatable exons and spanned more than 50 kb. The DNA binding domain is encoded by exons 1-4. Although the consensus cleavage site of CED-3 like protease during apoptosis is conserved from human to Xenopus laevis PARPs, it is neither conserved in the corresponding region of Drosophila nor Sarcophaga peregrina. There are two cDNAs species in Drosophila. One cDNA could encode the full length PARP protein (PARP I), while the other is a truncated cDNA which could encode a partial-length PARP protein (PARP II), which lacks the automodification domain and is possibly produced by alternative splicing. The expression of these two forms of PARP in E. coli demonstrated that while PARP II has the catalytic NAD-binding domain and DNA-binding domain it is enzymatically inactive. On the other hand PARP I is active. A deletion mutant of PARP gene could grow to the end of embryogenesis but did not grow to the adult fly. These results suggest that the PARP gene plays an important function during the development of Drosophila.
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    URL: http://dx.doi.org/10.1023/A:1006920429095
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    Newly discovered anti-inflammatory properties of the benzamides and nicotinamides (1999)
    Springer
    Molecular and cellular biochemistry 193 (1999), S. 119-125 
    Details
    ISSN: 1573-4919
    Keywords: benzamides ; nicotinamides ; apoptosis ; inflammation ; NF-kB ; DNA repair
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports [14-16] have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 ï 50 mg/kg doses of 3-CPA or MCA, and 100-200 μM doses of MCA could also inhibit NF-kB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kB, which in turn inhibits TNFalpha and induces apoptosis.
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    Growth arrest and induction of apoptosis in breast cancer cells by antisense depletion of protein kinase A-RIα subunit: p53-independent mechanism of action (1999)
    Springer
    Molecular and cellular biochemistry 195 (1999), S. 25-36 
    Details
    ISSN: 1573-4919
    Keywords: antisense oligonucleotide ; apoptosis ; cAMP-dependent protein kinase ; cancer cells ; growth inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type 1 (PKA-I) has been correlated with cancer cell growth. We have investigated the effects of sequence-specific inhibition of RIα gene expression on the growth of MCF-7 human breast cancer cells. We report that RIα antisense treatment results in a reduction in RIα expression at both mRNA and protein levels and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology, cleavage of poly(ADP-ribose) polymerase (PARP) and appearance of apoptotic nuclei. In addition, bcl-2 protein level was reduced and p53 expression increased in growth arrested cells. Interestingly, RIα antisense inhibited cell viability and induced apoptosis in the absence of p53, suggesting that these actions of RIα antisense are exerted independent of p53. In contrast, two- and four-base mismatched control oligonucleotides had no effect on either cell growth or morphology. These results demonstrate that the RIα antisense, which efficiently depletes the growth stimulatory molecule RIα, induces cell differentiation and apoptosis, providing a new approach to combat breast cancer cell growth.
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    TNF-α induced altered signaling mechanism in human neutrophil (1999)
    Springer
    Molecular and cellular biochemistry 197 (1999), S. 97-108 
    Details
    ISSN: 1573-4919
    Keywords: neutrophil ; PKC ; TNF-α ; apoptosis ; DNA fragmentation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract In the present study we investigated the TNF-α induced signal transduction mechanism in human neutrophil. Exogenously added TNF-α affects both PKC activity and its translocation from cytosol to the membrane. Endogenous protein phosphorylation pattern is inhibited in TNF-α induced neutrophil in Ca-dependent and Ca-independent manner, including a major 47 and 66 kDa cytosolic proteins, which may be implicated in superoxide anion generation. However TNF-α dose dependently enhances the expression of ζ-PKC isotype but not the β-PKC. Morphology and cell cytotoxicity are studied in TNF-α treated neutrophil to understand the TNF-α induced cell death or apoptosis and these experiment is further confirmed by DNA fragmentation analysis. These results clearly demonstrate that TNF-α induces cellular death of human neutrophil at least in part by enhanced expression of Ca-independent ζ-PKC. These observations provide an insight towards understanding the function of ζ-PKC in apoptotic pathway.
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    Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone (1999)
    Springer
    Molecular and cellular biochemistry 201 (1999), S. 25-32 
    Details
    ISSN: 1573-4919
    Keywords: rotenone ; apoptosis ; oncogenes ; liver cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Rotenone decreases the incidence of hepatocellular carcinoma and lowers rates of hepatocellular proliferation. In an effort to delineate mechanisms involved, the in vivo effect of rotenone on liver mitochondrial metabolism, apoptotic machinery as well as elements of the hepatic signal transduction pathways were investigated. Mitochondria from livers of male B6C3F1 mice fed a standard diet containing 600 ppm rotenone for 7 days were uncoupled or inhibited when succinate or glutamate plus malate were used as the substrate, respectively. These livers also showed a significant increase in apoptosis compared with control livers. Furthermore, rotenone increased the expression of c-myc mRNA to 5-fold of control values within 3 days, an effect which was still observed (3-fold) after 7 days. Levels of p53 mRNA were also increased 3-fold after 1 day, but declined to control levels by 7 days. Rotenone also caused a transient, yet marked increase in liver particulate glyceraldehyde phosphate dehydrogenase (GAPDH) protein expression, while it did not alter the expression of the cytosolic form of the enzyme. Conversely, mRNA of the proto-oncogene H-ras showed a decline of 35% after 3 days of rotenone treatment, and remained diminished for the duration of the experiment. These data suggest that rotenone may act as an anticancer agent by diminishing mitochondrial bioenergetics which prevents basal hepatocyte proliferation and lowers the threshold for liver cells with DNA damage to undergo apoptosis.
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    Ouabain Induces Apoptosis on PHA-Activated Lymphocytes (1998)
    Springer
    Bioscience reports 18 (1998), S. 1-7 
    Details
    ISSN: 1573-4935
    Keywords: Ouabain ; apoptosis ; lymphocytes ; c-myc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Apoptotic cell death plays a critical role in immune system homeostasis, and c-myc protooncogene deregulated expression is a component of this programmed genomic response. Pharmacological intervention and modulation of peripheral lymphocytes apoptosis would have important implications. The present results indicate that ouabain, a specific inhibitor of Na+K+-ATPase, promotes an increased expression of c-myc mRNA, and induces apoptosis in PHA-stimulated lymphocytes. Furthermore, this ouabain-induced apoptosis cannot be counteracted by the addition of exogenous IL-2.
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    Heat Shock Stress Induces Cleavage and Activation of PAK2 in Apoptotic Cells (1998)
    Springer
    The protein journal 17 (1998), S. 485-494 
    Details
    ISSN: 1573-4943
    Keywords: Heat shock ; apoptosis ; PAK2 ; caspase-3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Heat shock induces a stress response in mammalian cells and can also lead to apoptotic cell death. Here we report that a 36-kDa myelin basic protein (MBP) kinase detected by an in-gel kinase assay can be drastically activated in several cell types by heat shock. Immunoblot analysis revealed that this 36-kDa MBP kinase can be recognized by an antibody against the C-terminal region of a family of p21Cdc42/Rac-activated kinases (PAKs). By using this antibody and a PAK2-specific antibody against the N-terminal region of PAK2 as tools, we further demonstrated that heat shock can induce cleavage of PAK2 to generate a 36-kDa C-terminal catalytic fragment in mouse Balb/c 3T3 and human Hep 3B cells. The kinetic profile of appearance of the 36-kDa C-terminal catalytic fragment of PAK2 matched exactly with the activation of the 36-kDa MBP kinase in these cells induced by heat shock. In addition, the heat shock-induced cleavage and activation of PAK2 was found to be closely associated with both DNA fragmentation and activation of an ICE/CED-3 family cysteine protease termed caspase-3 in heat shock-treated Hep 3B cells. Moreover, blockage of the activation of caspase-3 by pretreating the cells with two specific tetrapeptidic inhibitors of caspases (Ac-DEVD-cho and Ac-YVAD-cmk) could substantially diminish the extent of heat shock-induced cleavage/activation of PAK2. Overall, our results point out that PAK2 is cleaved and activated during the heat shock-induced apoptotic cell death process and suggest that caspase-3 is involved in this process.
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    Preparative High-Resolution Two-Dimensional Electrophoresis Enables the Identification of RNA Polymerase B Transcription Factor 3 as an Apoptosis-Associated Protein in the Human BL60–2 Burkitt Lymphoma Cell Line (1999)
    Springer
    The protein journal 18 (1999), S. 225-231 
    Details
    ISSN: 1573-4943
    Keywords: Two-dimensional electrophoresis ; MALDI-MS ; apoptosis ; RNA polymerase B transcription factor 3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Apoptosis or programmed cell death is essential in the process of controlling lymphocyte growth and selection. We identified RNA polymerase B transcription factor 3 (BTF3), which is associated with anti-IgM antibody-mediated apoptosis, using a subclone of the human Burkitt lymphoma cell line BL60. To identify the transcription factor BTF3, which is expressed only in minor amounts, we used preparative high-resolution two-dimensional gel electrophoresis (2DE) employing carrier ampholytes for isoelectric focusing. Comparison of the 2DE protein patterns from apoptotic and nonapoptotic cells showed BTF3 as a predominantly altered protein spot. The characterization of the differentially expressed transcription factor and 13 marker proteins described in this study were performed by internal Edman microsequencing and/or by peptide mass fingerprinting using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The proteome analysis was significantly improved by performing the newly developed preparative high-resolution two-dimensional gels employing high protein concentrations.
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    Protein Kinase C Targeting in Antineoplastic Treatment Strategies (1999)
    Springer
    Investigational new drugs 17 (1999), S. 227-240 
    Details
    ISSN: 1573-0646
    Keywords: apoptosis ; protein kinase C ; sphingoid bases ; safingol ; diglyceride ; bryostatin 1 ; staurosporine ; 7-hydroxy staurosporine (UCN-01) ; 4′-N-benzoyl staurosporine (CGP-41251) ; calphostin C (UCN-1028c)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Neoplastic cell survival is governed by a balance between pro-apoptotic and anti-apoptotic signals. Noteworthy among several anti-apoptotic signaling elements is the protein kinase C (PKC) isoenzyme family, which mediates a central cytoprotective effect in the regulation of cell survival. Activation of PKC, and subsequent recruitment of numerous downstream elements such as the mitogen-activated protein kinase (MAPK) cascade, opposes initiation of the apoptotic cell death program by diverse cytotoxic stimuli. The understanding that the lethal actions of numerous antineoplastic agents are, in many instances, antagonized by cytoprotective signaling systems has been an important stimulus for the development of novel antineoplastic strategies. In this regard, inhibition of PKC, which has been shown to initiate apoptosis in a variety of malignant cell types, has recently been the focus of intense interest. Furthermore, there is accumulating evidence that selective targeting of PKC may prove useful in improving the therapeutic efficacy of established antineoplastic agents. Such chemosensitizing strategies can involve either (a) direct inhibition of PKC (e.g., following acute treatment with relatively specific inhibitors such as the synthetic sphingoid base analog safingol, or the novel staurosporine derivatives UCN-01 and CGP-41251) or (b) down-regulation (e.g., following chronic treatment with the non-tumor-promoting PKC activator bryostatin 1). In preclinical model systems, suppression of the cytoprotective function(s) of PKC potentiates the activity of cytotoxic agents (e.g., cytarabine) as well as ionizing radiation, and efforts to translate these findings into the clinical arena in humans are currently underway. Although the PKC-driven cytoprotective signaling systems affected by these treatments have not been definitively characterized, interference with PKC activity has been associated with loss of the mitogen-activated protein kinase (MAPK) response. Accordingly, recent pre-clinical studies have demonstrated that pharmacological disruption of the primary MEK-ERK module can mimic the chemopotentiating and radiopotentiating actions of PKC inhibition and/or down-regulation.
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    Activation-Induced Apoptosis of Peripheral Lymphocytes Treated with 7-Hydroxystaurosporine, UCN-01 (1999)
    Springer
    Investigational new drugs 17 (1999), S. 335-341 
    Details
    ISSN: 1573-0646
    Keywords: UCN-01 ; IL-2 receptor ; Fas ; Fas-ligand ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 7-hydroxystaurosporine (UCN-01) is a new anticancer agentwhich exerts an inhibitory effect on cell cycle check points andis currently under phase I clinical trials in US and Japan.Preliminary clinical data indicated that UCN-01 remained inplasma at high concentrations for long periods of time. Thisunavoidable high plasma drug exposure is likely to lead tohematological toxicities in patients. In the present study,cultured human peripheral blood lymphocytes (PBLs) were used toevaluate the possible hematological toxicities of UCN-01treatment. UCN-01 induces apoptosis, and the induction ofapoptosis-related surface markers were also examined toinvestigate the involvement of these molecules in UCN-01-inducedapoptosis in PBLs. in vitroviability of PBLs wasdecreased by high dose of UCN-01 (25 μM, 3-day exposure). Thiseffect of UCN-01 was significantly suppressed by the presence ofhuman serum, suggesting that some specific inhibitory factor(s)in human serum may antagonize the lympholytic effect of UCN-01.The percentage of annexin V-positive PI-negative cells increasedwith exposure to UCN-01 in a time- and dose-dependent manner; byup to 30.3% after exposure to 25 μM UCN-01 for 3 days.At the same time, the expression of both interleukin-2 receptor(IL-2R, CD25) and Fas (CD95), analyzed by flow cytometry, wasinduced. Con A-stimulated PBLs were more sensitive toUCN-01-induced apoptosis than non-stimulated lymphocytes andUCN-01 increased the sFas-L released into culture medium from conA-stimulated PBLs. Therefore, lymphocyte depletion mediated byactivation-induced apoptosis is likely to occur in patientstreated with UCN-01 at high doses.
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    Pilot study in humans on the pharmacokinetics and safety of propofol 6% SAZN (1999)
    Springer
    Pharmacy world & science 21 (1999), S. 239-240 
    Details
    ISSN: 1573-739X
    Keywords: anaesthesia ; Clinical pharmacology ; Emulsion formulation ; Fat emulsion ; Propofol ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In a pilot study on the first application of Propofol 6% SAZN in humans, the pharmacokinetics and safety of the new product seem to be similar to those of Propofol 1% SAZN and Diprivan®‐10 after bolus injection. The results will have to be confirmed in a larger clinical study in order to develop Propofol 6% SAZN as an alternative for Diprivan®‐10.
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    Determination and pharmacokinetics of dextromoramide in methadone maintenance therapy. (1998)
    Springer
    Pharmacy world & science 20 (1998), S. 83-87 
    Details
    ISSN: 1573-739X
    Keywords: Dextromoramide ; HPLC determination ; Liquid‐liquid extraction ; Methadone ; Methadone maintenance therapy ; Palfium® ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To study the pharmacokinetics of dextromoramide in long‐term opiate addicts on methadone maintenance therapy (MMT) a reverse‐phase HPLC technique was developed to monitor dextromoramide and methadone concentrations in plasma simultaneously. After liquid‐liquid extraction from plasma, dextromoramide and methadone were determined using a Supelcosil LC‐ABZ column and a mobile phase of KH2phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) and UV detection at 206 nm. The method was found to be sufficiently sensitive, specific and reproducible to apply in six subjects on MMT for many years, receiving orally administered dextromoramide as adjuvant. Pharmacokinetic data sets for dextromoramide in each subject were conducted and analysed further, indicating short elimination half‐life values (71 min, range 31‐152 min). Contrary to previous studies, in all subjects tested the pharmacokinetics of dextromoramide are best described using an one‐compartment model.
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    Pharmacokinetics of quinine in African patients with acute falciparum malaria. (1998)
    Springer
    Pharmacy world & science 20 (1998), S. 118-122 
    Details
    ISSN: 1573-739X
    Keywords: Quinine ; Acute falciparum malaria ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of quinine were studied in six Nigerian patients during acute uncomplicated falciparum malaria and convalescent periods. An oral dose of 10 mg/kg quinine dihydrochloride administered 8‐hourly for 7 days gave parasite and fever clearance times of 36.0 ± 16.6 h and 18.0 ± 6.4 h, respectively. From the individual quinine plasma profiles the mean plasma concentration of quinine at the time of parasite clearance was estimated as 4.5 ± 1.1 μg/ml. Plasma quinine levels during malaria rose rapidly reaching a peak around the second and third days and declining thereafter as patients improved clinically. In acute malaria plasma quinine levels were more than two-fold higher than in convalescence; the mean AUC(0-12) in malaria was 37.9 ± 14.7 μg.h/ml compared to 17.9 ± 8.5μg.h/ml in convalescence. The apparent oral clearance (CL/F) and volume of distribution (Vd/F) duri ng the acute phase of the malaria (1.9 ± 0.7 ml/min/kg and 1.8 ± 0.9 l/kg, respectively) were significantly lower than in convalescence (4.5 ± 2.1 ml/min/kg and 4.2 ± 3.2 l/kg). The present data suggest that malaria parasites in African patients are still very sensitive to quinine and that the current dosage of quinine is effective for the treatment of acute falciparum malaria in African patients without augmenting therapy with any other drug such as tetracycline or sulphadoxine-pyrimethamine. It also confirms that malaria significantly alters the pharmacokinetics of quinine in humans.
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    Mechanisms of drug transfer across the human placenta. (1998)
    Springer
    Pharmacy world & science 20 (1998), S. 139-148 
    Details
    ISSN: 1573-739X
    Keywords: Human placenta ; Drug transfer ; Drug transport ; Pharmacokinetics ; Placenta perfusion ; Membrane vesicles ; Cotyledon ; Trophoblast ; Cell culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow‐dependent and membrane‐limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.
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    Effect of hepatic insufficiency on pharmacokinetics and drug dosing (1998)
    Springer
    Pharmacy world & science 20 (1998), S. 183-192 
    Details
    ISSN: 1573-739X
    Keywords: Hepatic disease ; Cirrhosis ; Pharmacokinetics ; Pharmacodynamics ; Dosage adjustment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The liver plays a central role in the pharmacokinetics of many drugs. Liver dysfunction may not only reduce the plasma clearance of a number of drugs eliminated by biotransformation and/or biliary excretion, but it can also affect plasma protein binding which in turn could influence the processes of distribution and elimination. In addition, reduced liver blood flow in patients with chronic liver disease will decrease the systemic clearance of flow limited (high extraction) drugs and portal‐systemic shunting may substantially reduce their presystemic elimination (first‐pass effect) following oral administration. When selecting a drug and its dosage regimen for a patient with liver disease additional considerations such as altered pharmacodynamics and impaired renal excretion (hepatorenal syndrome) of drugs and metabolites should also be taken into account. Consequently, dosage reduction is necessary for many drugs administered to patients with chronic liver disease such as liver cirrhosis.
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    Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer (1999)
    Springer
    Pharmacy world & science 21 (1999), S. 184-189 
    Details
    ISSN: 1573-739X
    Keywords: Chemotherapy ; Colorectal cancer ; Fluorouracil ; Folinate ; Leucovorin ; Pharmacokinetics ; Toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment‐induced mucositis significantly increased with (6S)‐folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.
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    Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. (1998)
    Springer
    Pharmacy world & science 20 (1998), S. 149-160 
    Details
    ISSN: 1573-739X
    Keywords: Antibiotics ; Cystic Fibrosis ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight.
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    Tumor Necrosis Factor-Induced Cytotoxicity is Not Related to Rates of Mitochondrial Morphological Abnormalities or Autophagy-Changes that can be Mediated by TNFR-I or TNFR-II (1998)
    Springer
    Bioscience reports 18 (1998), S. 329-340 
    Details
    ISSN: 1573-4935
    Keywords: Tumor necrosis factor ; mitochondria ; autophagy ; apoptosis ; necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Tumor necrosis factor (TNF) may cause apoptosis or necrosis and induces mitochondrial changes that have been proposed to be central to cytotoxicity. We report similar patterns of TNF-induced mitochondrial morphological alterations and autophagy in cell types with differing sensitivity to TNF-induced cytotoxicity. Specific ligation of TNFR-I or TNFR-II induces different rates of apoptosis and mitochondrial morphological change, but similar rates of autophagy. These changes do not invariably lead to cell death, and survival or progression to apoptosis or necrosis following TNF exposure may depend in part on the extent of mitochondrial damage and/or the autophagic capacity of the cell.
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    Verotoxin/Globotriaosyl Ceramide Recognition: Angiopathy, Angiogenesis and Antineoplasia (1999)
    Springer
    Bioscience reports 19 (1999), S. 345-354 
    Details
    ISSN: 1573-4935
    Keywords: Glycolipid ; apoptosis ; intracellular traffic ; multidrug resistance ; ovarian carcinoma ; astrocytoma ; post transplant lymphoproliferative disease ; bone marrow purging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Verotoxin (VT) is involved in the etiology of both hemorrhagic colitis and the hemolytic uremic syndrome which are microvasculopathies of the colon and pediatric renal glomerulus respectively. Thus, VT can be considered a vasotoxin. Cell sensitivity in vitro varies according to the receptor glycolipid (globotriaosyl ceramide-Gb3) expression and also to intracellular trafficking of the receptor/toxin complex, such that in highly sensitive cells, the toxin is targeted to the endoplasmic reticulum and nuclear envelope. Such cells include tumor cells which have become drug resistant. Thus Gb3 is upregulated in certain tumors and when such tumor cells become drug resistant, their sensitivity to verotoxin increases. This may be due to a direct role of the MDR1 drug efflux pump in glycolipid biosynthesis. In addition to the tumor tissue, the toxin receptor may also be expressed in the tumor neovasculature suggesting that activated endothelial cells may be verotoxin sensitive. Thus VT may have both a direct and indirect antineoplastic potential. VT has proved highly effective in a xenograft cancer model and the possible therapeutic use of VT is discussed.
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    Ceramide Glycanase Activities in Human Cancer Cells (1999)
    Springer
    Bioscience reports 19 (1999), S. 449-460 
    Details
    ISSN: 1573-4935
    Keywords: ceramide glycanase ; cancer cells ; glycosphingolipid ; sphingosine ; ceramide ; apoptosis ; PPMP ; PDMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Ceramide glycanase (CGase) activities have been detected in different human tumor cells (colon, carcinoma Colo-205; neuroblastoma, IMR-32; breast cancer lines, SKBr3 and MCF7). However, the level of enzymatic activity is lower in these cells compared to that present in other mammalian tissues reported before (Basu, M., Kelly, P., Girzadas, M. A., Li, Z., and Basu, S. Methods Enzymol. (in press)). The majority of CGase activity was found in the 100,000g soluble supernatant fraction isolated from all these cell lines and tissues. Using the soluble enzyme, the requirement for optimum CGase activity was found to be consistent with previous observations found for rat and rabbit tissues (Basu, M., Dastgheib, S., Girzadas, M. A., O'Donnell, P. H., Westervelt, C. W., Li, Z., Inokuchi, J. I., and Basu, S. (1998) Acta Pol. Biochim. 42:327). The CGase activities from both Colo-205 and IMR-32 cells are optimum at a protein to detergent ratio of one. All the mammalian CGases, including human cancer cells, show an optimum pH between 5.5 and 5.8 in sodium acetate buffer. The CGase activities from cancer cells are found to be cation-independent; however, mercury, zinc, and copper ions seem to inhibit the enzyme activity substantially in both tumor cells lines. The mercury ion inhibition of CGase activities from all different sources indicates a possible structural homology in the CGase proteins. Radiolabeled substrates, labeled at the sphingosine double bond or at the 3-position of sphingosine without modifying double bond of sphingosine were used in this investigation. Both were active substrates with all enzyme preparations isolated from different cancer cells (apparent Km, 500 μM for nLcOse5[3H-DT]Cer and 350 μM for GgOse4[sph-3-3H]Cer with Colo-205 enzyme). Structural analogues of ceramide and sphingosine (L-PPMP, L-PDMP, alkylamines, and Tamoxifen) inhibited cancer cell CGase activities in vitro.
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    URL: http://dx.doi.org/10.1023/A:1020220524180
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    Pharmacodynamics and Toxicodynamics of Drug Action: Signaling in Cell Survival and Cell Death (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 790-798 
    Details
    ISSN: 1573-904X
    Keywords: MAPK ; caspases ; chemopreventive agents ; phase II drug metabolizing enzymes ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In therapeutic response to drugs, the plasma concentration range leads to the establishment of a safe and effective dosage regimen. Our hypothesis is that by studying drug concentration-dependent effect on signal transduction mechanisms, a better understanding of the beneficial pharmacodynamic and adverse toxicodynamic responses elicited by the drug may be achieved. Using two classes of chemopreventive compounds (phenolic antioxidants and isothiocyanates), we illustrate the potential utility of two signal transduction pathways elicited by these agents to predict the pharmacodynamic effect (induction of Phase II drug metabolizing enzymes) and the potential toxicodynamic response (stimulation of caspase activity and cytotoxic cell death). At lower concentration, phenolic antioxidants and isothiocyanates activate mitogen-activated protein kinase (MAPK; extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal kinase 1, JNK1) in a concentration-and time-dependent manner. The activation of MAPK by these compounds may lead to the induction of cell survival/protection genes such as c-jun, c-fos, or Phase II drug metabolizing enzymes. However, at higher concentrations, these agents activate another signaling molecule, ICE/Ced3 cysteine protease enzymes (caspases) leading to apoptotic cell death. The activation of these pathways may dictate the fate of the cells/tissues upon exposure to drugs or chemicals. At lower concentrations, these compounds activate MAPK leading to the induction of Phase II genes, which may protect the cells/tissues against toxic insults and therefore may enhance cell survival. On the other hand, at higher concentrations, these agents may activate the caspases, which may lead to apoptotic cell death, and have toxicity. Understanding the activation of these and other signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of gene expression of drug metabolizing enzymes and cytotoxicity. Thus, the study of signaling events in cell survival (hemeostasis) and cell death (cytotoxicity) may have practical application during pharmaceutical drug development.
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    URL: http://dx.doi.org/10.1023/A:1011953431486
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    Mitochondrial Events in the Life and Death of Animal Cells: A Brief Overview (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 291-304 
    Details
    ISSN: 1573-6881
    Keywords: Cell death ; aging ; necrosis ; apoptosis ; mitochondria ; oxidative phosphorylation ; electron transport chain ; ATP synthase ; cytochrome c ; mitochondrial DNA ; reactive oxygen species (ROS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Traditionally, mitochondria have been viewed as the “powerhouse” of the cell, i.e., the site of theoxidative phosphorylation machinery involved in ATP production. Consequently, much of theresearch conducted on mitochondria over the past 4 decades has focused on elucidating both thosemolecular events involved in ATP synthesis by oxidative phosphorylation and those involved inthe biogenesis of the oxidative phosphorylation machinery. While monumental achievements havebeen made, and continue to be made, in the study of these remarkable but extremely complexprocesses essential for the life of most animal cells, it has been only in recent years that a largebody of biological and biomedical scientists have come to recognize that mitochondria participatein other important processes. Two of these are cell death and aging which, not surprisingly, are relatedprocesses both involving, in part, the oxidative phosphorylation machinery. This new awareness hassparked a new and growing area of mitochondrial research, that has become of great interest to awide variety of scientists ranging from those involved in elucidating the role of mitochondria incell death and aging to those interested in either suppressing or facilitating these processes as itrelates to identifying new therapies or drugs for human disease. It is the purpose of this briefintroductory review to provide an overview of those mitochondrial events involved in the life anddeath of animal cells and to indicate how these events might relate to the human aging process.Much more is known, much remains controversial, and even more remains to be learned as indicatedin the excellent set of minireviews that follow.
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    URL: http://dx.doi.org/10.1023/A:1005453700533
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    Mitochondria at the Crossroad of Apoptotic Cell Death (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 321-326 
    Details
    ISSN: 1573-6881
    Keywords: Mitochondria ; apoptosis ; caspases ; cytochrome c ; Fas ; bcl-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract In the past few years, it has become widely appreciated that apoptotic cell death generallyinvolves activation of a family of proteases, the caspases, which undermine the integrity ofthe cell by cleavage of critical intracellular substrates. Caspases, which are synthesized asinactive zymogens, are themselves caspase substrates and this cleavage leads to their activation.Hence, the potential exists for cascades of caspases leading to cell death. However, it has beenrecently recognized that another, perhaps more prominent route to caspase activation, involvesthe mitochondria. Upon receipt of apoptotic stimuli, either externally or internally generated,cells initiate signaling pathways which converge upon the mitochondria to promote release ofcytochrome C to the cytoplasm; cytochrome c, thus released, acts as a potent cofactor incaspase activation. Even cell surface “death receptors” such as Fas, which can trigger directcaspase activation (and potentially a caspase cascade), appear to utilize mitochondria as partof an amplification mechanism; it has been recently demonstrated that activated caspases cancleave key substrates to trigger mitochondrial release of cytochrome c, thereby inducing furthercaspase activation and amplifying the apoptotic signal. Therefore, mitochondria play a centralrole in apoptotic cell death, serving as a repository for cytochrome c.
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    URL: http://dx.doi.org/10.1023/A:1005471701441
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    Mitochondrial Uncoupling: Role of Uncoupling Protein Anion Carriers and Relationship to Thermogenesis and Weight Control “The Benefits of Losing Control” (1999)
    Springer
    Journal of bioenergetics and biomembranes 31 (1999), S. 493-506 
    Details
    ISSN: 1573-6881
    Keywords: Energy expenditure ; reactive oxygen species ; cellular viability ; apoptosis ; necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Uncoupling proteins, a subgroup of the mitochondrial anion transporter superfamily, have beenidentified in prokaryotes, plants, and mammalian cells. Evolutionary conservation of thesemolecules reflects their importance as regulators of two critical mitochondrial functions, i.e.,ATP synthesis and the production of reactive oxygen species (ROS). Although the amino acidsequences of the three mammalian uncoupling proteins, UCP1, UCP2 and UCP3, are verysimilar, each homolog is the product of a unique gene and important differences have beendemonstrated in their tissue-specific expression and regulation. UCP1 and UCP3 appear to bekey regulators of energy expenditure, and hence, nonshivering thermogenesis, either in brownadipose tissue (UCP1) or skeletal muscle (UCP3). UCP2 is expressed more ubiquitously,although generally at low levels, in many tissues. There is conflicting evidence about itsimportance as a regulator of resting metabolic rate. However, evidence suggests that thishomolog might modulate the mitochondrial generation of ROS in some cell types, includingmacrophages and hepatocytes. While the induction of various uncoupling protein homologsprovides adaptive advantages, both to the organism (e.g., thermogenesis) and to individual cells(e.g., reduced ROS), increased uncoupling protein activity also increases cellular vulnerability tonecrosis by compromising the mitochondrial membrane potential. This narrow “risk—benefit”margin necessitates tight control of uncoupling protein activity in order to preserve cellularviability and much remains to be learned about the regulatory mechanisms involved.
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    URL: http://dx.doi.org/10.1023/A:1005452624640
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    Olfactory Responses of Parasitoid Apoanagyrus lopezi to Odor of Plants, Mealybugs, and Plant–Mealybug Complexes (1998)
    Springer
    Journal of chemical ecology 24 (1998), S. 37-48 
    Details
    ISSN: 1573-1561
    Keywords: Apoanagyrus lopezi ; Phenacoccus manihoti ; cassava ; biological control ; resistance ; olfactometer ; herbivore-induced synomones ; volatile chemicals
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Apoanagyrus (Epidinocarsis) lopezi De Santis is an endoparasitoid used in the biological control of the cassava mealybug Phenacoccus manihoti Matile-Ferrero in Africa. The response of naive and mated females of A. lopezi to odors from cassava plant (var. Zanaga), parasitized or unparasitized mealybugs, and plant–mealybug host complexes with or without feeding hosts was investigated in a Y-tube olfactometer. Dual-choice tests revealed that mealybug-infested plants and mealybug-damaged plants were the major sources of volatiles that attract female parasitoids to the microhabitat of its hosts. The emission of volatile chemicals appears not to be limited to the infested plant part but to occur systemically throughout the plant. On their own, unparasitized mealybugs were more attractive than uninfested plants or parasitized mealybugs alone. Parasitization of P. manihoti by A. lopezi decreased the response of parasitoids to mealybugs or mealybug–plant complexes. Plants infested with unparasitized hosts attracted more female parasitoids than plants infested with parasitized mealybugs. These results indicate that, in the long-range host-searching process, females of A. lopezi respond mainly to mealybug-induced synomones, and specific host-derived cues play a minor role.
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    URL: http://dx.doi.org/10.1023/A:1022332711331
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    Suppressive Impact of Glucosinolates in Brassica Vegetative Tissues on Root Lesion Nematode Pratylenchus neglectus (1998)
    Springer
    Journal of chemical ecology 24 (1998), S. 67-80 
    Details
    ISSN: 1573-1561
    Keywords: Brassica ; Pratylenchus neglectus ; nematode ; biological control ; suppression ; glucosinolate ; isothiocyanate ; aliphatic ; 2-phenylethyl ; nematicide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The potential of tissue amendments from a variety of wild and cultivated Brassica spp. to kill the root lesion nematode (Pratylenchus neglectus) in soil was assessed in laboratory experiments. Soil amended with leaf tissues was highly nematicidal, killing 56.2–95.2% of exposed nematodes. Amendment with root tissues was less effective, causing 0–48.3% mortality. Little of the suppressive impact by leaf tissues could be related to either total contents or any individual glucosinolate as determined by HPLC analysis. While the levels of total glucosinolates within root amendments had a nonsignificant relationship to nematode mortality, levels of 2-phenylethyl glucosinolate within root amendments significantly correlated with nematode suppression (P 〈 0.001). Amendment of soils with equimolar levels of purified 2-phenylethyl isothiocyanate resulted in comparable levels of nematode mortality, suggesting that 2-phenylethyl glucosinolate has a role in the suppressive impact of Brassica spp. root tissues.
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    URL: http://dx.doi.org/10.1023/A:1022336812240
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    Inhibition of Water Fern Salvinia minima by Cattail (Typha domingensis) Extracts and by 2-Chlorophenol and Salicylaldehyde (1998)
    Springer
    Journal of chemical ecology 24 (1998), S. 1483-1490 
    Details
    ISSN: 1573-1561
    Keywords: Aquatic plant ; bioassay ; biological control ; phenolic compounds ; phytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The allelopathic potential of a cattail species (Typha domingensis) towards the common water fern (Salvinia minima) was studied in a short-term bioassay. Aqueous extracts of cattail plants (roots, stems, and leaves) as well as two of its phenolic compounds (2-chlorophenol and salicylaldehyde) were found to inhibit the growth of Salvinia when incorporated in the growth medium. After a period of seven days, chlorophyll concentration, fresh weight, dry weight, and number of fronds of Salvinia were compared and correlations were found among the different parameters. The results suggest an inhibitory effect by components of Typha, especially of the root fractions. Results from pure chemicals are in qualitative and quantitative agreement with those obtained from the cattail extracts.
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    URL: http://dx.doi.org/10.1023/A:1020955615868
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    Allelopathic Suppression of Pseudomonas solanacearum Infection of Tomato (Lycopersicon esculentum) in a Tomato-Chinese Chive (Allium tuberosum) Intercropping System (1999)
    Springer
    Journal of chemical ecology 25 (1999), S. 2409-2417 
    Details
    ISSN: 1573-1561
    Keywords: Allelopathy ; Allium tuberosum ; antibacterial activity ; biological control ; intercropping ; Lycopersicon esculentum Mill ; Pseudomonas solanacearum E. F. Smith ; root exudates ; soil-borne diseases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Tomato plants were grown alone or intercropped with Chinese chive plants, with or without the inoculation of Pseudomonas solanacearum. Chinese chive plants had no detrimental effects on the growth of tomato plants but significantly delayed and suppressed the occurrence of bacterial wilt of tomato. P. solanacearum population decreased faster in the soil grown with tomato alone than that in the soil grown with both tomato and Chinese chive. However, P. solanacearum population in bare soil was higher than that grown with Chinese chive. Root exudates of Chinese chive collected with a continuously trapping system were inhibitory to multiplication of P. solanacearum.
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    URL: http://dx.doi.org/10.1023/A:1020809805081
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    The Response of Phytoseiulus persimilis to Spider Mite-Induced Volatiles from Gerbera: Influence of Starvation and Experience (1999)
    Springer
    Journal of chemical ecology 25 (1999), S. 2623-2641 
    Details
    ISSN: 1573-1561
    Keywords: Herbivore-induced synomones ; infochemicals ; semiochemicals ; learning ; biological control ; prey location ; behavior ; Acarina ; Phytoseiulus persimilis ; Tetranychus urticae ; Gerbera jamesonii
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract When leaves of the ornamental crop Gerbera jamesonii are damaged by the spider mite Tetranychus urticae, they produce many volatile compounds in large quantities. Undamaged gerbera leaves produce only a few volatiles in very small quantities. In the headspace of spider mite-damaged gerbera leaves many terpenoids are present, comprising 65% of the volatile blend. In addition, a number of nitrogen containing compounds, such as oximes and nitriles, are produced. We studied the attraction of P. persimilis to the volatiles from spider mite-damaged gerbera leaves and how attraction is affected by starvation and previous experience. Phytoseiulus persimilis that were reared on spider mites (T. urticae) on Lima bean were not attracted to spider mite-induced volatiles from gerbera. Starvation did not influence the predator's response to these volatiles. In contrast, predators that were reared on spider mites on gerbera leaves were strongly attracted to volatiles from spider mite-infested gerbera. This was found also for predators that originated from a culture on spider mite-infested bean and were offered six days of experience with spider mites on gerbera leaves.
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    URL: http://dx.doi.org/10.1023/A:1020887104771
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    High-Performance liquid chromatographic determination of dibromomannitol in plasma (1998)
    Springer
    Chromatographia 48 (1998), S. 17-19 
    Details
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Dibromomannitol in plasma ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Myelobromol 1,6-dibromo-1,6-dideoxy-D-mannitol (dibromomannitol, DBM) is a bifunctional alkylating agent that has been in clinical use since 1963. It is currently included at high dose in preconditioning regimen for bone marrow transplantation (BMT) and is a main-stay of treatment for polycythaemia vera. A high-performance liquid chromatographic method was developed for the determination of DBM in the plasma. The basis of the assay is a derivatization with sodium-diethyldithiocarbamate at 42°C in the presence of 1-bromo-1-deoxy-3,6-anhydro-galactitol as internal standard (IS). The analysis was carried out on a 250×4mm Hypersil 5 CPS column equipped with a 20×4 mm Hypersil 10 CPS precolumn. The eluent consisted of heptane:isopropyl-alcohol: glacial acetic acid=600:76:80 w/w. The flow rate was 1.2 mL min−1. UV detection was performed at 254 nm. The calibration graph was linear in the concentration range of 2.5–260 μM of DBM in plasma. The limit of detection was 1.0 μM. The precision and accuracy of the method was between the good laboratory practice (GLP) required limits.
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    URL: http://dx.doi.org/10.1007/BF02467509
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    Determination of cisapride in human plasma by high-performance liquid chromatography (1998)
    Springer
    Chromatographia 47 (1998), S. 537-541 
    Details
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Cisapride in plasma ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary An HPLC method has been developed for the quantification of cisapride in plasma for pharmacokinetic studies. Clebopride was used as internal standard. Plasma samples were extracted at alkaline pH withtert-butyl methyl ether. The organic phase was then extracted with sulphuric acid to eliminate endogenous interferences, and cisapride and the internal standard were then extracted at alkaline pH intotert-butyl methyl ether. After evaporation oftert-butyl methyl ether, the residue was analysed by HPLC. Chromatography was performed at 20°C on a 250mm×4mm i.d. reversed-phase column selective for basic compounds. The isocratic mobile phase was 48∶52 (v/v) acetonitrile-water containing 0.05 M potassium dihydrogen phosphate and 0.04 M triethylamine, adjusted to pH 5.5; the flow rate was 1 mL min−1. Cisapride and the internal standard were detected by ultraviolet monitoring at 276 nm. The calibration graph was linear for quantities of cisapride from 1 to 200 ng mL−1. Intra- and inter-day precision (CV) did not exceed 13.98%. The limit of quantitation (LOQ) was 0.68 ng mL−1 for human plasma. The applicability of the method has been demonstrated in a pharmacokinetic study of normal volunteers who received 10 mg cisapride orally.
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    High-performance liquid chromatographic assay for simultaneous determination of tramadol and its active metabolite in human plasma. Application to pharmacokinetic studies (1998)
    Springer
    Chromatographia 48 (1998), S. 555-560 
    Details
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Tramadol andO-demethyl tramadol in plasma ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A sensitive liquid chromatographic assay for the quantitative determination of the opioid analgesic tramadol and its active metabolite is described. Fluconazole was used as internal standard. The assay involved a singletert-butyl methyl ether extraction and LC analysis with fluorescence detection. Chromatography was at 30°C pumping an isocratic mobile phase of acetonitrile-water (19∶81, v/v) containing 0.06M NaH2PO4 and 0.05M triethylamine, adjusted to pH 7.90, at 1 mL min−1 through a reversed-phase, 250×4 mm base-stable column. The limit of quantitation of tramadol and its active metabolite was 1 ng mL−1, only 0.5 mL plasma sample was required for the determination. The calibration curve was linear from 1–1000 ng mL−1. Intra and inter-day precision (C.V.) did not exceed 10%. Mean recoveries of 96.38% for tramadol and 96.62% forO-demethyltramadol with CVs of 0.43% and 1.46% were obtained. Applicability of the method was demonstrated by a pharmacokinetic study on normal volunteers who received 100 mg tramadol intravenously.
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    Rapid determination of ranitidine in human plasma by high-performance liquid chromatography (1998)
    Springer
    Chromatographia 47 (1998), S. 391-395 
    Details
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Ranitidine ; Plasma ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary An HPLC method has been developed for the quantification of rantidine in plasma for pharmacokinetic studies. Metoclopramide was used as internal standard. The method uses a simple and rapid sample clean-up procedure involving single-step extraction with organic solvent to extract ranitidine from plasma. After evaporation and reconstitution the samples are chromatographed on a 250 mm×4 mm base-stable reversed-phase column with 0.05 M ammonium acetate-acetonitrile, 75∶25 (v/v) as mobile phase and UV detection at 313 nm. The calibration graph was linear for quantities of ranitidine between 10 and 2000 ng mL−1. Intra- and inter-dayCV did not exceed 11.64%. The quantitation limit was 10 ng mL−1 for human plasma. The applicability of this method for pharmacokinetic studies of ranitidine after oral administration are described. Approximately 90 samples can be processed in 24 h.
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    URL: http://dx.doi.org/10.1007/BF02466469
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    Cytostatic and Apoptotic Effects of Paclitaxel in Human Ovarian Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 122-127 
    Details
    ISSN: 1573-904X
    Keywords: paclitaxel ; taxol ; ovarian cancer ; cytostasis ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The present study evaluated the cytostatic and apoptotic effects of a 24-hr paclitaxel treatment in ovarian tumors. Methods. Three-dimensional histocultures of surgical specimens from patients (n = 17) were used. The cytostatic effect was measured by inhibition of 96-hr cumulative DNA precursor incorporation and induction of apoptosis was determined by morphological changes. Results. Paclitaxel produced partial inhibition of DNA precursor incorporation in about 40% of tumors (maximum inhibition of ∼30%) and induced apoptosis in about 90% of tumors (maximum apoptotic index of ∼15%). In responsive tumors, maximum cytostatic and apoptotic effects were achieved at ≤1 μM with no further enhancement by increasing the drug concentration to 10 μM. In individual tumors, the apoptotic effect inversely correlated with cytostatic effect (r2 = 0.27, p = 0.031), and the maximal apoptotic index correlated with the LI for the untreated controls (r2 = 0.38, p 〈 0.01). More than 95% of apoptotic cells after paclitaxel treatment were labeled with DNA precursor. The incomplete cytostatic and apoptotic effects of paclitaxel and the link between DNA synthesis and apoptosis in ovarian tumors are similar to our previous findings in other human solid tumors. Conclusions. These findings suggest that (a) apoptosis is the major paclitaxel effect in advanced ovarian tumors, (b) tumor sensitivity to drug-induced cytostatic effect is opposite to sensitivity to apoptotic effect, (c) paclitaxel-induced apoptosis increases with increased cell proliferation and is completed after DNA synthesis, and (d) further increasing the dose to elevate plasma concentration beyond 1 μM may not improve treatment outcome.
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    A Novel Podophyllotoxin-Derived Compound GL331 Is More Potent than Its Congener VP-16 in Killing Refractory Cancer Cells (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 997-1002 
    Details
    ISSN: 1573-904X
    Keywords: GL331 ; VP-16 ; apoptosis ; cytotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. GL331 is a new homolog of VP-16, and has demonstrated more efficacious anti-cancer activity in both the in vitro and in vivo lymphoma systems. To extensively explore GL331's clinical value, we furthermore evaluate the cytotoxicity and apoptosis-inducing activity of GL331 in several human cell lines from cancers that are not normally treated with VP-16. Methods. By MTT and clonogenic survival assays, the cytotoxicities of GL331 and VP-16 were evaluated in a variety of cell lines including nasopharyngeal, hepatocellular, gastric, colon, cervical, and neuro-blastoma cancer types. Western blot analysis was performed to detect the MDR-1 level in these cell lines. By Annexin V-staining flow cytometry and detection of DNA ladders, the apoptosis-inducing activities of GL331 and VP-16 were also evaluated. Results. GL331 showed more efficacy than its congener VP-16 in killing cancer cells. The estimated ID50 of GL331 were 2.5 to 17-fold lower than those of VP-16. GL331 possessed more cell-killing activity even in MDR-1-overexpressing cell lines such as HCC36 and SW620. Its higher cytotoxicity could be attributed by the elevated ability to induce apoptotic cell death. Conclusions. GL331's overriding drug resistance and higher cancer cell-killing activity suggest its superiority in clinical cancer therapy.
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    Effects of Arbekacin and Vancomycin on Release of Lactate Dehydrogenase and Fragmentation of DNA in LLC-PK1 Kidney Epithelial Cells (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1132-1135 
    Details
    ISSN: 1573-904X
    Keywords: arbekacin ; vancomycin ; cisplatin ; apoptosis ; toxicity ; LLC-PK1 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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    URL: http://dx.doi.org/10.1023/A:1011919306412
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    The Geometric and Thermodynamic Properties of Grain Boundary Junctions (1999)
    Springer
    Interface science 7 (1999), S. 251-271 
    Details
    ISSN: 1573-2746
    Keywords: triple junctions ; taxonomy ; dimensionality ; structure ; energy ; segregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Abstract We provide an overview of the properties of triple junctions and quadruple points. It is shown that these junctions may exhibit distinct behaviors that imply that they have and thermodynamically distinct properties in the same way that grain boundaries can be considered as thermodynamically distinct phases, separate from the material that they inhabit. It is shown that the treatment of triple junctions as thermodynamically distinct defects is a natural extension of the treatment of grain boundaries, and that it can be further extended to other junctions such as quadruple nodes. Equilibrium dihedral angles under conditions of anisotropic interfacial energy are explored, and it is found that the dihedral angles may be variable under a range of different conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008769209265
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  • 83
    Electronic Resource
    Electronic Resource
    New antitumor leads from a peptidomimetic library (1999)
    Springer
    International journal of peptide research and therapeutics 6 (1999), S. 325-333 
    Details
    ISSN: 1573-3904
    Keywords: antiproliferative effect ; apoptosis ; combinatorial library ; isosteric structures ; oxaniloyl hydrazides ; peptidomimetics ; substrate-binding site ; tyrosine kinase inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60c-src enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c-src PTK showed that the energy-minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008994116275
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  • 84
    Electronic Resource
    Electronic Resource
    New antitumor leads from a peptidomimetic library (1999)
    Springer
    International journal of peptide research and therapeutics 6 (1999), S. 325-333 
    Details
    ISSN: 1573-3904
    Keywords: antiproliferative effect ; apoptosis ; combinatorial library ; isosteric structures ; oxaniloyl hydrazides ; peptidomimetics ; substrate-binding site ; tyrosine kinase inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60c−src enzyme. The new structures were based on kown PTK inhibtors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c−src PTK showed that the energyminimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02443428
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