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  • 1
    Electronic Resource
    Electronic Resource
    Preclinical pharmacology of cholera toxin (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 115-120 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cholera toxin ; Immunoassay ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cholera toxin was selected for pharmacologic evaluation by the National Caner Institute on the basis of antiproliferative activity against small-cell and non-small-cell lung-cancer cell lines. A feature common to the sensitive cell lines was abundant expression of GM1 ganglioside, the cellular receptor for cholera toxin. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to quantitate cholera toxin in biological fluids. A sigmoidal relationship was observed between the cholera toxin plasma concentration and the absorbance at 490 nm (OD490) of the product of horseradish peroxidase-catalyzed oxidation of o-phenylenediamine over the range of 6.25–1,600 ng/ml. Logit transformation of the OD490 data was linear over the entire concentration range and assay variability was less than 25%. Cholera toxin was stable in murine and human whole blood and plasma. Following i.v. administration of 1,500 μg/kg to male CD2F1 mice, cholera toxin plasma elimination was described by a two-compartment open model. The half-lives (t 1/2α, t 1/2β), plasma clearance, and steady-state volume of distribution were 0.7 min, 49 min, 24 ml min-1 kg-1 912 ml/kg, respectively. Cholera toxin was not detected in plasma following an s.c. dose of 1,500 μg/kg. Urinary recovery following intravenous drug administration was less than 0.1%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689194
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  • 2
    Electronic Resource
    Electronic Resource
    Comparative cytotoxicity and pharmacokinetics of antimelanoma immunotoxins containing either natural or recombinant gelonin (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 343-348 
    Details
    ISSN: 1432-0843
    Keywords: Key words Immunotoxins ; Gelonin ; Melanoma ; Recombinant toxins ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunotoxins are a class of targeted therapeutic agents under development by various research groups. The murine monoclonal antibody designated ZME-018 recognizes a high molecular weight glycoprotein present on most human melanoma cells and biopsy specimens and has been utilized for clinical imaging studies in patients with melanoma. The plant toxin gelonin is a ribosome-inactivating protein (RIP) with n-glycosidase activity similar to that of ricin A chain. In previous studies by our group, the gelonin toxin was sequenced, cloned and expressed in E. coli. The purified recombinant gelonin (RG) was found to have identical protein synthesis inhibitory activity to that of natural gelonin (NG). For comparative purposes, chemical conjugates of antibody ZME and either RG or NG were produced using the heterobifunctional crosslinking reagents SPDP and SMPT. The ZME-NG and ZME-RG immunotoxins were found to be 104- to 105-fold more cytotoxic to antigen-positive human melanoma cells than free toxin. NG toxin alone was cytotoxic to intact cells (IC50 = 100 nM) while RG was nontoxic to cells at doses up to 1 μM. Both ZME-NG and ZME-RG immunoconjugates were nontoxic to antigen-negative (Me-180) cells. ZME-RG immunotoxins constructed with the more stable SMPT reagent were slightly more effective in culture than conjugates made with SPDP. Tissue distribution studies in tumor-bearing nude mice demonstrated that tumor uptake of the ZME-RG immunotoxin was similar to that of the intact ZME antibody with reduced distribution to normal organs compared to an immunoconjugate produced with NG. Pharmacokinetic studies showed that the terminal-phase plasma half-life of ZME-RG was similar to that of ZME itself (42 h vs 50 h) and almost threefold higher than that of ZME-NG (11.5 h). The area under the concentration curve (Cxt) for ZME-RG was 50% lower than that for ZME due to an increased apparent volume of distribution (Vda) but was almost tenfold higher than the Cxt for ZME-NG. These studies suggest that immunoconjugates comprising RG demonstrate identical in vitro cytotoxic effects to immunoconjugates produced with NG and immunotoxins with RG display improved in vivo pharmacodynamics and tissue distribution compared to immunotoxins containing NG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050987
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  • 3
    Electronic Resource
    Electronic Resource
    Preclinical pharmacology of cholera toxin (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 115-120 
    Details
    ISSN: 1432-0843
    Keywords: Cholera toxin ; Immunoassay ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cholera toxin was selected for pharmacologic evaluation by the National Cancer Institute on the basis of antiproliferative activity against small-cell and nonsmall-cell lung-cancer cell lines. A feature common to the sensitive cell lines was abundant expression of GM1 ganglioside, the cellular receptor for cholera toxin. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to quantitate cholera toxin in biological fluids. A sigmoidal relationship was observed between the cholera toxin plasma concentration and the absorbance at 490 nm (OD490) of the product of horseradish peroxidase-catalyzed oxidation ofo-phenylenediamine over the range of 6.25–1,600 ng/ml. Logit transformation of the OD490 data was linear over the entire concentration range and assay variability was less than 25%. Cholera toxin was stable in murine and human whole blood and plasma. Following i.v. administration of 1,500 μg/kg to male CD2F1 mice, cholera toxin plasma elimination was described by a two-compartment open model. The half-lives (t 1/2α,t 1/2β), plasma clearance, and steady-state volume of distribution were 0.7 min, 49 min, 24 ml min−1 kg−1 912 ml/kg, respectively. Cholera toxin was not detected in plasma following an s.c. dose of 1,500 μg/kg. Urinary recovery following intravenous drug administration was less than 0.1%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689194
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    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    A phase I trial of 5-day continuous infusion cisplatin and interferon α (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 39-46 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cisplatin ; Interferon α ; Continuous infusion therapy ; Non-small cell lung cancer ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Combination therapy of cisplatin with interferon α (IFN) has been shown in several in vitro as well as in vivo models to be synergistic. In order to decrease toxicity seen with cisplatin, 5-day continuous infusions, in place of bolus administration, have been introduced. This led us to investigate the combination of 5-day continuous infusion cisplatin with repeated IFN dosing in a phase I cisplatin dose escalation study. A group of 17 patients were enrolled in this trial . The maximum tolerated dose (MTD) of cisplatin was 20 mg/m2 per day when combined with 3×106 units IFN given three times a week. The dose-limiting toxicities seen included thrombocytopenia, leukopenia, and nausea and vomiting. Pharmacokinetic analyses of free (unbound or ultrafilterable) platinum revealed that the decay curve fitted a monoexponential model. Pharmacokinetic parameters of cisplatin were found to correlate with toxicity. Both increases in the maximum concentration of cisplatin achieved (Cpmax) as well as the area-under-the-curve (AUC) for free platinum, correlated with the incidence of nausea and vomiting (both acute and delayed) and hematological toxicities (leukopenia and thrombocytopenia). None of the patients exhibited significant changes in renal function while on this study. The free platinum levels were higher than found in similar studies evaluating comparable cisplatin infusions alone. The enhanced toxicities seen in this trial may be explained by the results of an in vitro study using human plasma spiked with cisplatin and IFN that revealed decreased protein binding of cisplatin by 2.5–3.0-fold. Of the 17 patients treated, two non-small cell lung cancer patients obtained a partial response and one malignant melanoma patient obtained complete resolution of a malignant pleural effusion. Considering the acceptable toxicity seen in this trial, we recommend phase II trials be conducted with continuous infusion cisplatin with IFN in the treatment of non-small cell lung cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050365
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  • 5
    Electronic Resource
    Electronic Resource
    A pharmacokinetic study of trifluoperazine in two ethnic populations (1988)
    Springer
    Psychopharmacology 95 (1988), S. 333-338 
    Details
    ISSN: 1432-2072
    Keywords: Trifluoperazine ; Pharmacokinetics ; Population ; Kurtosis ; Skewness ; Blacks (negro) ; Whites (caucasian)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The single dose pharmacokinetics of trifluoperazine (5 mg, Stelazine) were investigated in black (n=25) and white (n=32) healthy male subjects. Plasma samples were harvested over 24 h and analysed by a GLC-MS method. There were wide intersubject variations in all pharmacokinetic parameters examined, including C max, AUC, apparent oral volume of distribution at steady state, and elimination half-life. For each of these parameters the distribution was positively skewed in both blacks and whites and the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean. In all pharmacokinetic parameters examined there was no significant difference detected between black and white subjects or between smokers and non-smokers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00181943
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of long-acting injectable neuroleptic drugs: clinical implications (1989)
    Springer
    Psychopharmacology 98 (1989), S. 433-439 
    Details
    ISSN: 1432-2072
    Keywords: Schizophrenia ; Neuroleptics ; Pharmacokinetics ; Long-acting neuroleptics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The authors review the literature regarding the pharmacokinetics of long-acting injectable neuroleptic drugs (LINS). There are important differences between LINS and oral neurolepties that affect their pharmacokinetics. By avoiding first pass metabolism in gut and liver, LINS result in lower circulating concentrations of metabolites than are found after oral administration. In addition, LINS take more time to reach a stable steady state than their oral counterparts. The clinical significance of these pharmacokinetic properties is discussed. The authors recommend that when patients are being changed from oral neuroleptics to LINS, that this conversion be done gradually over several months.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00441937
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cyclosporin in children with stable renal transplants (2000)
    Springer
    Pediatric nephrology 15 (2000), S. 167-170 
    Details
    ISSN: 1432-198X
    Keywords: Key words  Cyclosporin ; Renal transplant ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Fourteen children, aged between 5 and 17 years, with stable renal graft function and stable cyclosporin A (CSA) trough levels (Cmin) were studied. They had been taking CSA 12-hourly since their transplant 1.5–9 years previously, with the average dose of Neoral being 6.4 (range 4.4–8.4) mg/kg per day. CSA whole blood levels were measured at 0, 20, and 40 min, and at 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h following the morning dose using the Abbott TDx fluorescence polarization immunoassay. The area under the concentration time curve (AUC), clearance adjusted for bioavailability (CL/F), and steady-state volume of distribution adjusted for bioavailability (Vss/F) were determined using model-independent pharmacokinetic analysis. Delay time (Tdel), peak concentration (Cmax), time to peak concentration (Tmax), and Cmin were also determined and correlated with AUC and other parameters. The Tdel in absorption varied from 0.3 to 1.6 (mean 0.73) h, resulting in a similarly variable time to Tmax of 1–2.4 h (mean 1.59). Tmax was related to the age of the patient (Tmax=0.027age+1.41, r 2=0.56, P〈0.005). The AUC showed good correlation with Cmax (Cmax=0.25AUC+423.32, r 2=0.96, P〈0.0005). Cmax appears to be a more-suitable measure of exposure to CSA than Cmin. Prediction of Tmax from the age of the child may help to overcome the problem of when to collect blood for peak levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670000325
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  • 8
    Electronic Resource
    Electronic Resource
    Variation in the single dose pharmacokinetics of fluphenazine in psychiatric patients (1988)
    Springer
    Psychopharmacology 96 (1988), S. 206-211 
    Details
    ISSN: 1432-2072
    Keywords: Fluphenazine ; Pharmacokinetics ; Interpatient variation ; Kurtosis ; Skewness ; Blacks (negro) ; Whites (caucasian) ; Biliary recycling ; Fluphenazine conjugates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The single dose pharmacokinetics of fluphenazine (2 × 5 mg tablets, Prolixin) were studied in 21 drug free male psychiatric patients (12 black, 9 white). Plasma samples were harvested over a period of 48 h while the patients were on a strictly controlled diet. The results showed wide interpatient variations in all pharmacokinetic parameters including Cmax, AUC, apparent oral clearance, and elimination half-life. It was determined for each of these parameters that the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean and the distribution was skewed and leptokurtotic. There was no significant difference between blacks and whites in any pharmacokinetic parameter examined. Considerable variations and marked undulations in the elimination portion of the plasma concentration versus time profiles were evident, possibly indicating biliary recycling of the drug. These undulations made it difficult to determine elimination rate constants for several of the patients. Hydrolysis or plasma samples from one patient demonstrated that the conjugate(s) of fluphenazine was present in three to four times the concentration of the unchanged drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00177561
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