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  • 1
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine whether long-term adriamycin (ADM) infusions resulted in cellular ADM concentrations at least comparable to those observed after bolus injections, ADM cellular and plasma concentrations were measured in 18 patients with leukemia. ADM was administered at 30 mg/m2 per day for 3 days, either as bolus injections or as 4-, 8-, or 72-h infusions. Negligible accumulation of plasma ADM was observed. Peak plasma ADM concentrations after bolus injections were 1640±470 ng/ml (n=7). Maximum levels were 176±34 ng/ml during 4-h infusion (n=5); 85±50 ng/ml during 8-h infusion (n=4); and 47±5 ng/ml (n=2) after 72-h infusion. ADM concentrations in nucleated blood and bone marrow cells correlated well (r=0.82, n=47). ADM accumulated in leukemic cells up to 30–100 times the plasma concentrations. The shorter the administration time-span, the higher the peak leukemic cell concentration and the greater the loss of drug immediately after the end of the administration. The final cellular ADM half-life was approximately 85–110 h. After long-term infusion and bolus injection of the same dose, similar areas under the curve for plasma or leukemic blast cell ADM concentrations were attained. Since comparable therapeutic efficacy was observed in all regimens, the antileukemic effect appeared not to be related to the peak plasma concentrations, while acute toxicity phenomena decreased with increasing duration of the infusion. Long-term ADM infusion deserves more attention in the treatment of patients with anthracyclines.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150–600 mg/m2), once a week (200 mg/m2 per week), or as 5 daily doses repeated every 28 days (60–180 mg/m2 per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9±2.1 h (n=18 doses). The volume of distribution was 3.4±2.6 l/kg and plasma clearance was 629±469 ml/min per m2. Several soluble analogues with similar antitumour activity are currently under investigation.
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  • 3
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of the duration of daunomycin (DNM) infusion on leukemic cell drug concentrations was evaluated. Cellular and plasma DNM concentrations were measured in 20 patients with acute non-lymphocytic leukemia. DNM 45 mg/m2 was administered either as a bolus injection or as a 4-, 8- or 72-h constant-rate infusion during 3 consecutive days. Peak plasma DNM levels amounted to 227±116 ng/ml after bolus injection and were only 16±6 ng/ml after 72-h DNM infusions. Terminal plasma DNM half-lives were 14±4 h. Peak leukemic cell DNM concentrations at the 3rd day of administration were 16810±2580 ng/109 cells (bolus injections) and 10310±5510 ng/109 cells (72-h infusions). The areas under the cellular curve were similar and independent of the duration of the DNM infusion. Peak leukemic cell daunomycinol (DNMol) concentrations were respectively 3500 ± 1600 ng/109 cells and 2850±1720 ng/109 cells. Cellular DNM terminal half-life was 13±4 h. DNM concentrations in nucleated blood and bone marrow cells correlated well (r=0.93, n=26). Long-term infusion produced less severe side effects. Therapeutic efficacy was maintained during long-term infusion.
    Type of Medium: Electronic Resource
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