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  • DDATHF  (1)
  • Key words Etoposide  (1)
  • Metabolites  (1)
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  • 1
    Digitale Medien
    Digitale Medien
    Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 161-167 
    Details
    ISSN: 1432-0843
    Schlagwort(e): Key words Etoposide ; Pharmacology ; Breast cancer
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract  The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean±SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6± 2.5 μg/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R 2=0.77). All patients who had a day 1 AUC 〉2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R 2=98.9%). The equation AUCpr=−0.376+ 0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of −0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002800050382
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Digitale Medien
    Digitale Medien
    A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid (1996)
    Springer
    Investigational new drugs 14 (1996), S. 325-335 
    Details
    ISSN: 1573-0646
    Schlagwort(e): lometrexol ; lometrexol-toxicity ; lometrexol-clinical efficacy ; lometrexol and folic acid ; DDATHF
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00194536
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Digitale Medien
    Digitale Medien
    1H NMR studies of human urine: Urinary elimination of the anticancer drug carboplatin (1991)
    Chichester : Wiley-Blackwell
    Organic Magnetic Resonance 29 (1991), S. S125 
    Details
    ISSN: 0749-1581
    Schlagwort(e): 1H NMR ; Urine ; Metabolites ; Platinum anticancer drug ; Carboplatin ; Paraplatin ; CBDCA ; Chemistry ; Analytical Chemistry and Spectroscopy
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: Samples of urine from a patient obtained before and after treatment with 300 mg of the anticancer drug [Pt(II)(NH3)2(CBDCA)] (carboplatin, “Paraplatin”, where CBCDA is 1,1-dicarboxycyclobutane) have been analysed using 500 MHz 1D and 2D 1H NMR spectroscopy. Peaks for the intact drug and the free ligand CBDCA have been assigned and are present in a mol ratio of ca. 5:1. Only about one half of the total Pt in the sample was present as intact drug. Relative to creatinine and citrate, the excretion of hippurate increased by a factor of ca. 4 after drug treatment. This work suggests that NMR spectroscopy can play a valuable rǒle in studies of carboplatin metabolism.
    Zusätzliches Material: 2 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/mrc.1260291321
    Standort Signatur Einschränkungen Verfügbarkeit
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