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Biomedical subjects

K Mross

Publications and source records attributed to K Mross.

At least 55 records · Page 3Linked to original sources
PubMed1995

Dexverapamil to overcome epirubicin resistance in advanced breast cancer.

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

Adult↗
PubMed1995

Bone marrow transplantation for Philadelphia-chromosome-positive acute lymphoblastic leukemia.

The outcome of 14 bone marrow transplants (BMT) (autologous 4; allogeneic 10) for Philadelphia-chromosome (Ph1) positive acute lymphoblastic leukemia (ALL) was analyzed. Preparative regimens consisted of etoposide (VP16) (30 or 45 mg/kg BW) (n = 14), cyclophosphamide (CY)(120 mg/kg BW) (n = 14), and total body irradiation (TBI)(12 Gy) (n = 13) or busulfan (Bu)(16 mg/kg) (n = 1). All patients receiving autologous marrow were in complete remission (CR) (three patients in 1.CR, one patient in 2.CR) at the time of BMT. For allogeneic BMT (nine related, one unrelated donor), seven patients were in first CR, two patients in first refractory relapse, and one patient in second relapse. With a median follow-up of 503 days (range 93-1522 days), eight out of 14 patients are alive in remission (six out of 10 patients receiving allogeneic, and two out of four patients receiving autologous BMT). Disease-free survival for all patients is 46%. Causes of death were relapse (n = 3) and transplant-related toxicity (n = 3). All patients tested for the bcr/abl rearrangement by reverse transcriptase-polymerase chain reaction (RT-PCR) were negative 4 weeks post-BMT. Two of the three patients who subsequently relapsed were repeatedly RT-PCR positive prior to relapse (test not done in the third). Considering the negligible cure rate of Ph1-positive ALL with conventional chemotherapy regimens, our data support the concept of early (> or = 1 CR) BMT (allogeneic > autologous (purged) following triple therapy with TBI, VP16, and CY.

Adult↗
PubMed1994

Intravesical idarubicin--a phase-I study.

In the scope of a pharmacokinetic and dose-finding study 33 patients received instillations of idarubicin in 11 different doses 1 h before scheduled transurethral resection of bladder cancer. The dose was increased continuously from 5 to 30 mg and the concentration from 0.25-1.5 mg/ml. Idarubicin uptake into tissue was measured along with the serum level. The results showed a clear correlation of the tissue levels with dose and concentration. A significantly higher concentration of idarubicin was measured in the tumor in comparison with the mucosa. Absorption into the muscle was minimal and serum levels were low. Systemic toxicity was not observed, but there were signs of local toxicity in 50% of the subjects. Cytotoxic concentrations in the mucosa were reached at doses of over 15 mg and concentrations of over 0.5 mg/ml. A phase-II study is in preparation.

Administration, Intravesical↗
PubMed1994

Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.

PURPOSE: We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan. PATIENTS AND METHODS: Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system. RESULTS: All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI). CONCLUSION: The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.

Adolescent↗
PubMed1994

Pharmacokinetics of high-dose VP-16: 6-hour infusion versus 34-hour infusion.

VP-16 was administered in high doses (30-45 mg/kg) in combination with busulfan (BU) and cyclophosphamide (CY). The anticancer activity of VP-16 is thought to be schedule-dependent. We investigated a 6-h and a 34-h infusion of VP-16 to compare pharmacokinetic parameters and toxicity. Blood samples were taken from a total of 16 patients during infusion time (6 h and 34 h, respectively) and thereafter up to 2 days after bone marrow transplantation (BMT). VP-16 concentrations were measured in all plasma samples with HPLC technique and electrochemical detection and the results were analyzed with a pharmacokinetic data analysis system. All calculated pharmacokinetic parameters in the two patient groups were essentially similar. There were no statistically significant differences in half-lives, mean residence time, volume of distribution, total clearance and area under the curve. The treatment-related toxicity was not different between groups. The major difference was the maximal concentration in the case of 6-h infusions (122 +/- 35 micrograms/ml) and in the case of 34-h infusions (23.2 +/- 4.9 micrograms/ml) and the duration of VP-16 concentrations with > 10 and > 1 microgram/ml. Drug levels above these thresholds were always longer in case of 34-h infusions. In 8 of 16 patients VP-16 concentrations were measured in plasma samples at the time of BMT ranging from 80 to 820 ng/ml. The two different schedules for VP-16 administration, either given as a 6-h infusion or as a 34-h infusion, are bioequivalent in pharmacokinetic terms.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Determination of the new podophyllotoxin derivative NK 611 in plasma by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic method has been developed for the determination of the new podophyllotoxin derivative NK 611 in plasma samples. A solid-liquid extraction procedure with C18 extraction columns was used for extraction of plasma samples containing NK 611. The adsorbed NK 611 was eluted from the extraction columns with methanol-acetonitrile (50:50, v/v). The elution liquid was injected into a reversed-phase system consisting of a Chrompack C18 column. The mobile phase was acetonitrile-20 mM phosphate buffer, pH 7 (30:70, v/v). The UV detection mode allows sensitive determination of NK 611 in plasma within phase I trials. The limit of detection was 10 ng/ml, the limit of quantitation 35 ng/ml (for 1 ml of extracted plasma and 20-microliters injection volume). The calibration curve is linear within the concentration range 100-1000 ng/ml. The recovery of NK 611 from spiked plasma samples was approximately 80%.

Antineoplastic Agents↗
PubMed1993

Effects of verapamil on the pharmacokinetics and metabolism of epirubicin.

Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic interactions between these two drugs. Ten patients with advanced breast cancer were given EPI (40 mg/m2 in a daily i.v. bolus for 3 consecutive days), and five of them also received VPL (4 x 120 mg/daily p.o. for 4 consecutive days). The data indicated a significant interaction between these two drugs that affected their metabolism. The areas under the concentration-time curves (AUC) obtained for epirubicin glucuronide, epirubicinol glucuronide, and both of the 7-deoxy-aglycones were higher in the EPI + VPL group as compared with the EPI group. The AUC, terminal half-life, mean residence time, volume of distribution at steady state, and plasma clearance of EPI alone as compared with EPI + VPL did not differ significantly. These results suggest either an induction of enzymes necessary for drug metabolism or an increase in the liver blood flow, resulting in an enhanced generation of metabolites with time or in an inhibition of excretion processes. Comparisons of the AUC values obtained for EPI and its metabolites after the first, second, and third injections of EPI revealed a cumulative effect for the metabolites that was more pronounced in the EPI + VPL group, being significant (P < 0.05) for epirubicin glucuronide in both treatment groups and for epirubicinol glucuronide in the EPI + VPL group. Maximal concentrations of VPL and nor-VPL reached 705 +/- 473 and 308 +/- 122 ng/ml, respectively, with the steady-state concentrations being 265 +/- 42 ng/ml for VPL and 180 +/- 12 ng/ml for nor-VPL.

Chemotherapy, Adjuvant↗
PubMed1993

Monoclonal gammopathy of unknown significance in a bone marrow donor.

We report on a patient suffering from multiple myeloma, for whom allogeneic bone marrow transplantation was planned. Donor workup revealed monoclonal gammopathy of unknown significance. We discuss this finding and stress the importance of performing complete donor examinations.

Adult↗
PubMed1993

Randomized phase II study of single-agent epirubicin +/- verapamil in patients with advanced metastatic breast cancer. An AIO clinical trial. Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society.

BACKGROUND: Anthracyclines are the most active cytostatic agents in patients with metastatic breast cancer. Drug resistance and dose intensity are relevant issues in the treatment of cancer. METHODS: A randomized phase II study in 51 patients with advanced progressive metastatic breast cancer was performed. Twenty-six were treated with epirubicin (EPI) 120 mg/m2 i.v. bolus injection divided over three days combined with a daily dose of 480 mg verapamil (VPL) orally administered one day before and during EPI. Twenty-five patients received the same dose and schedule of EPI without VPL. Evaluation of response was carried out after three 21-day cycles. Study endpoints were objective response rate and overall survival. RESULTS: Among the 24 evaluable patients treated with EPI+VPL 1 CR (4%), 7 PR (29%), 9 NC (38%) and 7 PD (29%) were observed. Two patients were excluded because of toxicity. Among the 24 evaluable patients treated with EPI alone 8 PR (28%), 6 NC (24%) and 10 PD (40%) were observed, and one patient was excluded because of toxicity. Myelotoxicity was the major side effect followed by alopecia, stomatitis/mucositis and nausea. The patient group treated with VPL had lower blood pressure levels during therapy, with complete normalization after discontinuation of VPL. The median overall survival times were similar: 7.4 month in the EPI group and 8.9 month in the EPI+VPL group. CONCLUSION: In both treatment groups the objective response rate was about 30% and the overall survival rates were also the same. No clinical relevance could be demonstrated for the hypothesized resistance modifying action of VPL. Furthermore, VPL did not increase the toxicity of EPI.

Adult↗
PubMed1992

Tissue disposition and plasma concentrations of idarubicin after intravesical therapy in patients with bladder tumors.

We studied single doses of intravesical idarubicin (IDA) given as 1-h instillations to 33 patients with bladder tumors. The dose was escalated from 5 to 30 mg and the concentration, from 0.25 to 1.5 mg/ml for evaluation of the importance of both the total amount of drug and the drug concentration on the levels of IDA found in different tissues (tumor, mucosa and muscle). Additionally, plasma uptake over 24 h was studied. The results demonstrated that (1) the levels of IDA in extracts of bladder tumors were significantly higher than those in normal bladder tissue, (2) the incorporation of IDA into tumors depended on the total amount of drug instilled and on the concentration of drug in the instillation fluid, (3) cytotoxic concentrations of IDA were noted in all tumors when the total amount of drug instilled was greater than 15 mg and the drug concentration in the instillation fluid was greater than 0.33 mg/ml, and (4) plasma levels of IDA were negligible.

Administration, Intravesical↗
PubMed1992

Pharmacodynamic and pharmacokinetic aspects of iodo-doxorubicin.

Iodo-doxorubicin (I-DOX) is a new doxorubicin (DOX) analog presently in phase II clinical trials in Europe. This drug is similar to DOX in its metabolism but differs in its pharmacokinetics. We describe correlations between pharmacokinetic parameters and toxicity. There is a linear relationship between the dose in mg/m2 and the nadirs of the reduction in white blood cells (WBC), neutrophils (PMN), platelets (PLT), and hemoglobin (HB). Furthermore, a linear correlation exists between the dose in mg/m2 and the area under the curve (AUC) of I-DOX. The relationship between the AUC of I-DOX and the reduction of PMNs plotted on a logarithmic scale shows a sigmoidal curve, whereas no such correlation was found between I-doxorubicinol, the major cytostatic metabolite, and the reduction in PNMs. The variation in the AUC for I-DOX correlated with the relative amount of metabolism of I-DOX. A correlation existed between the relative amount of metabolism of I-DOX and the reduction in PNMs. These results may have an impact on the evaluation of I-DOX in phase II trials, since a sound understanding of the pharmacokinetic/pharmacodynamic relationships can yield important information for minimizing unacceptable toxicity during phase II, as well as phase III, trials.

Biotransformation↗
PubMed1990

Pharmacokinetics and metabolism of iodo-doxorubicin and doxorubicin in humans.

The pharmacokinetics of doxorubicin (DOX), iodo-doxorubicin (I-DOX) and their metabolites in plasma has been examined in five patients each receiving 50 mg/m2 of both anthracyclines as a bolus injection. Terminal half-life, mean residence time (MRT), peak plasma concentration Cmax, and area under the curve (AUC) appeared smaller for I-DOX, whereas its plasma clearance (CLP) and volume of distribution at steady state (Vss) were larger than for DOX. The major metabolite of I-DOX was iodo-doxorubicinol (I-AOL) followed by doxorubicinol aglycone (AOLON). The AUC of I-AOL was 6-times larger than that of its counterpart AOL, which is the major metabolite of DOX. AOLON generated after I-DOX administration is a further important metabolite, as its AUC was 10-times larger than that of AOLON generated from DOX. The other aglycones, such as doxorubicin aglycone (AON) and the 7-deoxy-aglycones were only minor metabolites after either I-DOX or DOX injection. The ratio AUCI-AOL/AOL/AUCI-DOX/DOX was 27 in the case of I-DOX and 0.4 after DOX. The terminal half-lives of the cytostatic metabolites I-AOL and AOL were similar, although a longer MRT for AOL was calculated. Both metabolites had much longer MRTs than their parent drugs. The MRTs of the aglycones AOLON and AON were greater than those of the 7-deoxy-aglycones after both I-DOX and DOX. Approximately 6% DOX and less than 1% I-DOX were excreted by the kidneys during the initial 48 h. About 5% of I-DOX was excreted via the kidneys as I-AOL. Aglycones were not detected in significant amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

A phase II study of intensive-dose epirubicin/verapamil as induction therapy followed by intensive-dose ifosfamide for advanced breast cancer.

Preliminary data of an ongoing phase II-study in metastatic breast cancer patients are presented. Patients with metastatic breast cancer entered the study after hormone therapy had failed; prior treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was also allowed. The patients were treated with three cycles of 40 mg/m2 epirubicin i.v. on days 1-3 and 4 x 120 mg oral verapamil on days 0-3, given every 3-4 weeks. After three chemotherapy courses, ifosfamide was given as a short infusion of 3 g/m2 on days 1-3. Mesna (20% of the total ifosfamide dose) was given 0, 4 and 8 h after ifosfamide administration. Response was evaluated after three cycles of epirubicin/verapamil and after the last (third) cycle of ifosfamide. The side effects of this treatment were tolerable. The epirubicin/verapamil combination was no more toxic than epirubicin alone. Despite the high dose of verapamil, systolic blood pressure remained above 80 mm Hg, and patients never had a period of strict bed rest. Alopecia was almost complete after induction therapy with epirubicin/verapamil, and nausea and vomiting were absent or mild during epirubicin/verapamil chemotherapy and were easily controlled by antiemetics during ifosfamide treatment. Stomatitis and mucositis, the main toxic effects, could be ameliorated by intensive mouth-washing procedures. The haematological toxicity was greater after epirubicin/verapamil treatment than after ifosfamide therapy, but neither bleeding nor infections due to thrombocytopenia or leucopenia were observed.

Adult↗
PubMed1990

Toxicity, pharmacokinetics and metabolism of iododoxorubicin in cancer patients.

25 patients, mostly pretreated, received 55 courses of iododoxorubicin as a single intravenous bolus every 2 weeks. The starting dose was 2 mg/m2 with seven steps to reach the dose-limiting toxicity level. 3 patients treated with 90 mg/m2 had WHO grade 4 myelotoxicity; 2 of these patients had not had cytostatic chemotherapy. 3 of 7 patients treated with 75 mg/m2 had grade 3-4 myelotoxicity; 4 had grade 1-2. Non-haematological toxicities were minor. Acute cardiotoxicity and objective tumour responses were not observed. Plasma and urine levels of iododoxorubicin and five metabolites were assayed in 16 patients. Metabolism to iododoxorubicinol was rapid and plasma clearance was dose-dependent and rapid. Plasma levels and the area under the curve for iododoxorubicin increased with dose. The mean residence time was 3.9 h in patients without liver metastasis and 10.4 h in patients with liver metastasis. Renal excretion was minor. The maximally tolerated dose was 90 mg/m2.

Adult↗