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  • 1
    Electronic Resource
    Electronic Resource
    Evaluation of methotrexate tissue exposure by in situ microdialysis in a rat model (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 297-301 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Microdialysis – Methotrexate – Tissue – Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The feasibility of using a microdialysis technique to obtain pharmacokinetic data on tissue exposure to methotrexate (MTX) was investigated. Microdialysis probes were implanted in the jugular vein, femoral muscle, and liver of anesthetized male Wistar rats. MTX (100 mg/kg) was given as a bolus injection through an indwelling venous catheter, and blood samples were obtained through a second venous access and by microdialysis for a total of 6 h. Heparinized plasma, ultrafiltered plasma, and microdialysis effluent from tissue and venous probes were analyzed by high-performance liquid chromatography. Centrifugal ultrafiltration of rat plasma spiked in vitro with MTX (1 – 100 μM) revealed a mean binding to plasma proteins of 21%. In vitro microdialysis of this spiked plasma resulted in 23% relative recovery of the unbound fraction. In rats receiving MTX, plasma protein binding was 23% and the relative drug recovery as assessed with venous microdialysis probes was 18%. Plotting of unbound (i. e., ultrafiltrate) MTX concentrations in the blood against venous microdialysis perfusate values in the blood gave a good linear correlation with a coefficient of correlation (r 2) of 0.98. There was also a linear correlation between the total MTX concentrations in venous blood and the drug levels in microdialysis samples from muscle and liver (r 2 = 0.93 and 0.74, respectively). Area under the curve estimations were consistent with an MTX exposure of 30% and 46% for the muscle and liver as compared with the circulation. The present study demonstrates that the microdialysis technique can provide reproducible data on tissue exposure to MTX in an animal model and indicates that the methodology is adaptable to clinical settings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686036
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Determination of extracellular methotrexate tissue levels by microdialysis in a rat model (1996)
    Springer
    Cancer chemotherapy and pharmacology 37 (1996), S. 394-400 
    Details
    ISSN: 1432-0843
    Keywords: Key words Microdialysis ; Methotrexate ; Tissue ; Recovery ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We used a microdialysis technique to determine tissue methotrexate (MTX) levels during steady state in a rodent model. Two different approaches were employed to measure the actual extracellular MTX concentrations in muscle, liver, and kidney tissues of anesthetized Wistar rats. With the reduced-perfusion-rate technique, the flow in the microdialysis perfusate was gradually decreased toward zero to permit calculation of zero-flow intercepts. Using the net change technique, microdialysis probes were perfused with different MTX concentrations to allow an assessment of equilibrium drug levels. For these two methods to be used, drug concentrations in the matrix to be analyzed must remain unchanged during the experimental procedure. In the animal model, steady state was attained after 1.5 h and maintained throughout the rest of the experiments by the administration of MTX as continuous infusions through a venous catheter. In vitro and in vivo, both the reduced-perfusion-rate and net change techniques gave reproducible data that permitted the estimation of extracellular drug concentrations in the dialyzed tissue compartments. The data suggest that the level of unbound MTX in the circulation is fairly similar to the extracellular concentrations in the muscle and liver. In the kidney, MTX levels were measured to be 3–8 times higher than those of unbound, circulating MTX, and a considerable discrepancy between the two methods used for estimations was apparent. These results demonstrate that both the net change and reduced-flow microdialysis techniques can produce reproducible and precise data. The results may constitute a basis for determining recoveries and, thus, true extracellular drug levels during in vivo microdialysis of MTX. This may be of importance in delineation of the relationship between tissue MTX levels and outcome in a variety of normally inaccessible compartments during cancer pharmacotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050403
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Quantition of cell-associated doxorubicin by high-performance liquid chromatography after enzymatic desequestration (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 197-202 
    Details
    ISSN: 1432-0843
    Keywords: Doxorubicin ; HPLC ; Cellular concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A method for measuring cellular concentrations of the anthracycline doxorubicin was developed. The assay involves cell lysis and protein degradation by detergent and proteinase K treatment followed by DNA hydrolysis using DNase I. Prior to high-performance liquid chromatography, samples are deproteinized by the addition of ZnSO4 and methanol. The assay is linear with respect to both the cellular drug content and the number of cells assayed over the ranges tested, and drug recovery is close to 100%. The method has a limit of detection of 50 fmol injected doxorubicin. Within run and between-day coefficients of variation have consistently been found to be in the 5% and 10% range, respectively, in different cell lines exposed to doxorubicin in vitro. The method has been evaluated in analyses of doxorubicin levels in mononuclear blood cells of patients. The assay offers several advantages over commonly used organic extraction techniques and may improve cellular drug monitoring during anthracycline therapy in patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685077
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    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Quantitation of cell-associated doxorubicin by high-performance liquid chromatography after enzymatic desequestration (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 197-202 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Doxorubicin – HPLC – Cellular concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. A method for measuring cellular concentrations of the anthracycline doxorubicin was developed. The assay involves cell lysis and protein degradation by detergent and proteinase K treatment followed by DNA hydrolysis using DNase I. Prior to high-performance liquid chromatography, samples are deproteinized by the addition of ZnSO4 and methanol. The assay is linear with respect to both the cellular drug content and the number of cells assayed over the ranges tested, and drug recovery is close to 100%. The method has a limit of detection of 50 fmol injected doxorubicin. Within run and between-day coefficients of variation have consistently been found to be in the 5% and 10% range, respectively, in different cell lines exposed to doxorubicin in vitro. The method has been evaluated in analyses of doxorubicin levels in mononuclear blood cells of patients. The assay offers several advantages over commonly used organic extraction techniques and may improve cellular drug monitoring during anthracycline therapy in patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685077
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 5
    Electronic Resource
    Electronic Resource
    Evaluation of methotrexate tissue exposure by in situ microdialysis in a rat model (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 297-301 
    Details
    ISSN: 1432-0843
    Keywords: Microdialysis ; Methotrexate ; Tissue ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The feasibility of using a microdialysis technique to obtain pharmacokinetic data on tissue exposure to methotrexate (MTX) was investigated. Microdialysis probes were implanted in the jugular vein, femoral muscle, and liver ofanesthetized male Wistar rats. MTX (100 mg/kg) was given as a bolus injection through an indwelling venous catheter, and blood samples were obtained through a second venous access and by microdialysis for a total of 6 h. Heparinized plasma, ultrafiltered plasma, and microdialysis effluent from tissue and venous probes were analyzed by high-performance liquid chromatography. Centrifugal ultrafiltration of rat plasma spiked in vitro with MTX (1–100 μM) revealed a mean binding to plasma proteins of 21%. In vitro microdialysis of this spiked plasma resulted in 23% relative recovery of the unbound fraction. In rats receiving MTX, plasma protein binding was 23% and the relative drug recovery as assessed with venous microdialysis probes was 18%. Plotting of unbound (i.e., ultrafiltrate) MTX concentrations in the blood against venous microdialysis perfusate values in the blood gave a good linear correlation with a coefficient of correlation (r 2) of 0.98. There was also a linear correlation between the total MTX concentrations in venous blood and the drug levels in microdialysis samples from muscle and liver (r 2=0.93 and 0.74, respectively). Area under the curve estimations were consistent with an MTX exposure of 30% and 46% for the muscle and liver as compared with the circulation. The present study demonstrates that the microdialysis technique can provide reproducible data on tissue exposure to MTX in an animal model and indicates that the methodology is adaptable to clinical settings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686036
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    Paper (German National Licenses)
    Fulltext
  • 6
    Electronic Resource
    Electronic Resource
    A comparison of the effects of nine folate analogs on early and late murine hematopoietic progenitor cells in vitro (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 450-456 
    Details
    ISSN: 1432-0843
    Keywords: Key words Antifolates ; Colony-forming units in culture ; High proliferative potential colony-forming cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Since the clinical introduction of the antifolates aminopterin (AMT) and methotrexate (MTX) many promising analogs have been developed. A common feature of these compounds is their ability to induce bone marrow suppression. However, few studies have been undertaken on the effect of the folic acid analogs on the cells comprising the hematopoietic system. Methods: In this paper we describe the effects of the novel thymidylate synthase (TS) inhibitors raltitrexed (Tomudex, ZD1694), AG337 (nolatrexed, Thymitaq), and the two closely related analogs 5,8-dideazaisofolic acid (IAHQ2a) and 2-desamino-2-methyl 5,8-dideazaisofolic acid (IAHQ2c), the glycinamide-ribonucleosyl (GAR) transformylase inhibitor lometrexol (DDATHF), and the dihydrofolate reductase (DHFR) inhibitors MTX, AMT, trimetrexate (TMTX), and edatrexate (EDX) on purified populations of early and late murine hematopoietic progenitor cells. Results/Conclusion: All the antifolates inhibited bone marrow proliferation in suspension cultures and all drugs except DDATHF inhibited colony formation by more mature progenitor cells (CFU-C) in clonogenic assays. The lipophilic agents TMTX and AG337 were most toxic, totally abolishing CFU-C colony formation at high concentrations. When IAHQ2c, raltitrexed, DDATHF, and MTX were investigated further for effects on the immature high proliferative potential colony-forming cells (HPP-CFCs) in semisolid and limiting dilution cultures, none of these agents were found to be toxic to the HPP-CFC, but induced a reversible developmental arrest in the progenitor cell population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051018
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    Paper (German National Licenses)
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of different doses of methotrexate at steady state by in situ microdialysis in a rat model (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 283-289 
    Details
    ISSN: 1432-0843
    Keywords: Microdialysis ; Methotrexate ; Steady state Rat ; Tissues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We used a microdialysis technique to monitor extracellular methotrexate (MTX) levels during the steady state in a rodent model. Microdialysis probes were implanted in the muscle, liver, and kidney of anesthetized male Wistar rats. MTX (18.75–500 mg/kg) was given as a continuous infusion through a venous catheter, and blood samples were obtained through a second venous catheter. Heparinized plasma, ultrafiltered plasma, microdialysis effluent from tissues, and tissue samples (obtained at the end of experiments) were analyzed for MTX content by high-performance liquid chromatography (HPLC). Steady state was demonstrated in the blood and tissues from 2 h until the end of the experiments (6 h). Extracellular drug levels in muscle and liver displayed a linear correlation with doses, whereas kidney levels reached a plateau at an MTX dose of 150 mg/kg per 6 h. Microdialysis-fluid endpoint levels for muscle, liver, and kidney were positively correlated to the endpoint total tissue levels (r 2=0.80, 0.85, and 0.68, respectively). In the kidneys, the maximal relative tissue MTX accumulation was measured at a total dose of 75 mg/kg per 6 h. At higher doses, the relative drug sequestration declined to less than half of the values observed at this dose. This study demonstrates that the microdialysis technique can provide reproducible data on MTX tissue exposure in an animal model and that it offers a means of serial and reproducible monitoring of extracellular-tissue MTX levels at steady state and over a wide dose range. Pending additional studies, microdialysis may be a helpful technique for elucidating the kinetics of drug delivery to both targeted and toxicity-prone tissues during chemotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689044
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of different doses of methotrexate at steady state by in situ microdialysis in a rat model (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 283-289 
    Details
    ISSN: 1432-0843
    Keywords: Key words Microdialysis ; Methotrexate ; Steady state ; Rat ; Tissues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We used a microdialysis technique to monitor extracellular methotrexate (MTX) levels during the steady state in a rodent model. Microdialysis probes were implanted in the muscle, liver, and kidney of anesthetized male Wistar rats. MTX (18.75–500 mg/kg) was given as a continuous infusion through a venous catheter, and blood samples were obtained through a second venous catheter. Heparinized plasma, ultrafiltered plasma, microdialysis effluent from tissues, and tissue samples (obtained at the end of experiments) were analyzed for MTX content by high-performance liquid chromatography (HPLC). Steady state was demonstrated in the blood and tissues from 2 h until the end of the experiments (6 h). Extracellular drug levels in muscle and liver displayed a linear correlation with doses, whereas kidney levels reached a plateau at an MTX dose of 150 mg/kg per 6 h. Microdialysis-fluid endpoint levels for muscle, liver, and kidney were positively correlated to the endpoint total tissue levels (r 2=0.80, 0.85,  and 0.68, respectively). In the kidneys, the maximal relative tissue MTX accumulation was measured at a total dose of 75 mg/kg per 6 h. At higher doses, the relative drug sequestration declined to less than half of the values observed at this dose. This study demonstrates that the microdialysis technique can provide reproducible data on MTX tissue exposure in an animal model and that it offers a means of serial and reproducible monitoring of extracellular-tissue MTX levels at steady state and over a wide dose range. Pending additional studies, microdialysis may be a helpful technique for elucidating the kinetics of drug delivery to both targeted and toxicity-prone tissues during chemotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689044
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 9
    Electronic Resource
    Electronic Resource
    Chronic left atrial catheterisation in the rabbit (1972)
    Springer
    Pflügers Archiv 335 (1972), S. 167-172 
    Details
    ISSN: 1432-2013
    Keywords: Catheter ; Cardiac Output ; Microspheres
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A technique for chronic left atrial catheterisation in the rabbit is described and its advantages over other methods of access to the systemic circulation are discussed, particularly in relation to studies of cardiac output measurement and distribution. Evidence is presented which suggests that this procedure does not cause endocarditis and is followed by normal body growth and a rapid return to haemodynamic normality. Endothelialisation of the catheter within the atrium eliminates the risk of embolisation during implantation for several months. The uses of such a catheter in other areas of physiology are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00592043
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    Paper (German National Licenses)
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