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  • 1
    Electronic Resource
    Electronic Resource
    Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 343-346 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00264202
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  • 2
    Electronic Resource
    Electronic Resource
    Taxol and taxotere in bladder cancer: in vitro activity and urine stability (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 460-464 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. In this study the antimicrotubular agents taxol, taxotere, and vinblastine were compared for their ability to inhibit the clonal growth of human bladder tumor cell lines using a soft-agar clonogenic assay. The stability of taxol and taxotere was evaluated by high-performance liquid chromatography over a range of pH in human urine. Both taxol and taxotere were shown to maximally inhibit the clonal growth of human bladder cell lines within 1 h of drug incubation. The most active agent in the panel of tumor lines was taxotere, with 6 of 12 lines being sensitive to the agent at 0.01 μM and all cell lines being sensitive at 0.1 μM. Taxol was active in 1 of 12 lines at 0.01 μM and in 11 of 12 at 0.1 μM. Only 2 of 12 cell lines were sensitive to vinblastine over the 0.01- to 0.1-μM dose range. Taxol and taxotere were found to be stable in human urine for 4 h over a pH range of 5–7. At least 85% of both drugs were present during this period of drug incubation. Our findings suggest that both taxol and taxotere may be clinically useful agents for systemic and intravesical use in bladder cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686501
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  • 3
    Electronic Resource
    Electronic Resource
    Taxol and taxotere in bladder cancer: in vitro activity and urine stability (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 460-464 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study the antimicrotubular agents taxol, taxotere, and vinblastine were compared for their ability to inhibit the clonal growth of human bladder tumor cell lines using a soft-agar clonogenic assay. The stability of taxol and taxotere was evaluated by high-performance liquid chromatography over a range of pH in human urine. Both taxol and taxotere were shown to maximally inhibit the clonal growth of human bladder cell lines within 1 h of drug incubation. The most active agent in the panel of tumor lines was taxotere, with 6 of 12 lines being sensitive to the agent at 0.01 μM and all cell lines being sensitive at 0.1 μM. Taxol was active in 1 of 12 lines at 0.01 μM and in 11 of 12 at 0.1 μM. Only 2 of 12 cell lines were sensitive to vinblastine over the 0.01- to 0.1-μM dose range. Taxol and taxotere were found to be stable in human urine for 4 h over a pH range of 5–7. At least 85% of both drugs were present during this period of drug incubation. Our findings suggest that both taxol and taxotere may be clinically useful agents for systemic and intravesical use in bladder cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686501
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  • 4
    Electronic Resource
    Electronic Resource
    Phase I and pharmacologic study of 7- and 21-day continuous etoposide infusion in patients with advanced cancer (1996)
    Springer
    Cancer chemotherapy and pharmacology 38 (1996), S. 459-465 
    Details
    ISSN: 1432-0843
    Keywords: Key words Chemotherapy ; Etoposide infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Purpose. This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. Methods. A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m2 per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m2 per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables. Results. Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m2 per day for schedule A and 40 mg/m2 per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was ≥1 μg/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r=0.56,  P=0.003). There were several marginal relationships in schedule B: PS versus Css (r=0.31,  P=0.058), PS versus AUC (r=−0.38; P= 0.058) and age versus CLp (r=−0.31, P=0.057). Conclusion. Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050511
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer (1992)
    Springer
    Cancer chemotherapy and pharmacology 31 (1992), S. 161-166 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 mg/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0–2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%–87%). The median survival was 8 months (range, 1–24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation: $$AUC = 15.45 + 3.86 \times C_2 + 7.10 \times C_4 ,$$ where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses: $$ANC_n = 0.399 + 0.024 \times E_{cl} ,$$ whereE cl represents the etoposide clearance expressed in milliliters per minute. Further studies are necessary to validate both models prospectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685105
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  • 6
    Electronic Resource
    Electronic Resource
    Clinical pharmacology of aminoglutethimide in patients with metastatic breast cancer (1987)
    Springer
    Cancer chemotherapy and pharmacology 20 (1987), S. 337-341 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacology of aminoglutethimide (AG) was studied in two subsequent trials without hydrocortisone supplementation. A total of 79 patients with metastatic breast cancer entered the study, and their plasma and urine samples were analyzed by high-performance liquid chromatography (HPLC). Thirty evaluable patients with a median age of 57 years (range, 37–79) were treated with the standard dose of 1000 mg/day, and 37 evaluable patients with a median age of 59 years (range, 35–79) received 500 mg/day. The median follow-up in the two groups was 5 months (range, 1–16) and 4 months (range, 1–21), respectively. After the first oral dose of 500 mg, peak plasma concentrations of AG were observed 1–4 h after administration in 15 patients. The elimination half-life was 10.1±1.7h (mean ±SD) after initial dosage; it decreased significantly to 6.9±1.2 h after 8 weeks of treatment. The area under the curve of AG concentrations was 92.5±14.2 μg/ml x h. The total clearance rate was 5.5±0.91/h and the volume of distribution was 80±11 l. About 23% of the drug was excreted unchanged in the urine. The major metabolite, N-acetyl-AG (AAG), had the same half-life as AG. A comparison on day 7 of treatment revealed that doses of 1000 and 500 mg yielded AG plasma concentrations of 9.0±1.2 and 4.5±0.5 μg/ml, respectively. After 1 month of treatment, however, AG plasma levels of 6–7 and 4–5 μg/ml were observed, respectively. A 50% reduction of dose, therefore, resulted in only 30% lower AG levels during continuous treatment. Apparently, the induction of metabolism is of greater importance in standard-dose than in lower dose treatment. The plasma concentrations of AG did not bear a relationship to the clinical response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262588
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  • 7
    Electronic Resource
    Electronic Resource
    Clinical pharmacodynamics of continuous-infusion etoposide (1990)
    Springer
    Cancer chemotherapy and pharmacology 25 (1990), S. 361-366 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Continuous-infusion etoposide was given to 15 patients with newly diagnosed small-cell lung cancer (extensive disease) and 10 patients with various refractory malignancies. The untreated patients with lung cancer received 200 mg/m2 etoposide over 24 h in combination with 100 mg/m2 cisplatin, and the pretreated patients received 400 mg/m2 etoposide over 36 h as monotherapy. Pharmacokinetic studies of etoposide were carried out in all patients. High-performance liquid chromatography (HPLC) was used to measure etoposide. All patients had normal hepatic and renal function tests and were followed weekly for hematologic toxicity after therapy. In all, 14 untreated and 9 pretreated patients were evaluable. Biostatistical analysis was done to correlate pharmacokinetic results to hematologic effects. Pearson correlation coefficients were calculated for continuous variables (i.e., blood counts), and Spearman correlation coefficients were calculated for ranked variables (i. e., toxicity grades). The values for the area under the plasma concentration vs time curve (AUC) and systemic clearance varied widely among patients. However, the AUC and clearance were significantly correlated (P〈0.05) with the WBC and platelet nadirs and the decrease in hemoglobin. The grade of leukopenia and total grade of hematologic toxicity were also correlated with AUC and clearance. Because the interpatient variability in etoposide pharmacokinetics correlates with the variable degree of hematologic toxicity, pharmacokinetic drug monitoring is suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686238
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  • 8
    Electronic Resource
    Electronic Resource
    Plasma concentrations of medroxyprogesterone acetate and megesterol acetate during long-term follow-up in patients treated for metastatic breast cancer (1988)
    Springer
    Journal of cancer research and clinical oncology 114 (1988), S. 186-190 
    Details
    ISSN: 1432-1335
    Keywords: Medroxyprogesterone acetate ; Megestrol acetate ; Plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A total of 32 patients with metastatic breast cancer responding with at least disease stabilization to treatment with two commercially available preparations of medroxyprogesterone acetate (MPA) or one preparation of megestrol acetate (MA) were followed for their plasma concentrations. The MPA and MA were measured by HPLC. MPA from Upjohn and Farmitalia was given to 12 patients (median age, 61 years; median follow-up, 20 weeks) and 8 patients (54 years, 16 weeks), respectively, on a schedule of 1000 mg daily i.m. for 10 days followed by 200 mg t.i.d.p.o. for the remainder of the treatment course. The peak concentrations (means, 163 vs 97 ng/ml), the time to peak levels (medians, 3 vs 10 weeks), and the areas under the concentration curves from time 0 to 24 weeks (means, 2400 vs 1868 ng/ml×weeks) were significantly different in the respective treatment groups (t-test; significance level, 0.05). MA from Bristol-Myers was administered orally in one daily dose of 160 mg throughout the treatment course in 12 patients (median age, 51 years; median follow-up, 20 weeks). A mean MA peak concentration of 218 ng/ml was reached after a median of 7 days. Plateau plasma levels were higher for MA than MPA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00417835
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  • 9
    Electronic Resource
    Electronic Resource
    Phase I study of pirarubicin (1988)
    Springer
    Journal of cancer research and clinical oncology 114 (1988), S. 91-94 
    Details
    ISSN: 1432-1335
    Keywords: Pirarubicin ; 4′-O-Tetrahydropyranyldoxorubiein ; Clinical study ; Phase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A Phase I trial of pirarubicin (4′-O-tetrahydropyranyl-doxorubicin) was undertaken to study its toxicity and to gain preliminary knowledge of its efficacy. The dose was escalated by increments of 10 from 30 to 70 mg/m2. Out of 20 patients, 19 were evaluable for toxicity and response to treatment. Hematologic toxicity was dose limiting and dose related. Other adverse effects included nausea and vomiting, hair loss, and stomatitis. No acute cardiotoxicity was encountered. In 2 patients with metastatic breast cancer who had not been pretreated with cytostatic agents, a partial remission was achieved lasting for 5 months. In 6 patients, tumor parameters did not change for a median of 3 months, and 11 patients suffered progressive disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00390491
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