Biomedical subjects
Publications and source records attributed to W Hiddemann.
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In spite of its broad clinical application in the treatment of malignant disorders, the pharmacokinetics of mitoxantrone are still not fully understood and warrant further investigation. Information is also limited about interindividual differences in the plasma AUC infinity (area-under-the-curve concentration to time infinity) and renal elimination of mitoxantrone and its main metabolites, mono- and dicarboxylic acid. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m2 in 18 patients undergoing combination therapy with mitoxantrone and high-dose cytosine arabinoside for acute myeloid leukemia. Plasma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases with chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m2 mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed for plasma and urine pharmacokinetics. Plasma AUC infinity for mitoxantrone differed approximately 13-fold between individual patients and varied between 80-1030 ngh/ml. The corresponding values for mono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml, respectively. The median terminal half-life for mitoxantrone was similar to that of the mono- and dicarboxylic acid and was 75 h. Cumulative renal elimination ranged from 670-1950 micrograms for mitoxantrone, from 366-852 micrograms for monocarboxylic acid, and from 792-3420 micrograms for dicarboxylic acid. Renal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabolites were 57 and 67 ml/min. In contrast to the great interindividual differences in pharmacokinetic results, a low intraindividual variability was observed upon repeated determinations of renal elimination of mitoxantrone and its metabolites at weekly intervals in five patients. These data provide new insights into the pharmacokinetic of mitoxantrone and its main metabolites revealing substantial differences in drug metabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicity and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.
The current study investigated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine (araC) in leukemic cells of 45 patients with acute myeloid leukemia (AML). AML blasts from bone marrow (BM) (n = 39) and peripheral blood (PB) (n = 17) were incubated for 48 h with or without GM-CSF (100 U/ml) followed by a concurrent treatment with increasing concentrations of araC (0.06-100 microM) for an additional 24 h. After GM-CSF a 1.5-8.4-fold (median 2.3) increase in 3H-araC incorporation into the DNA was observed in ten of 14 peripheral blast specimens and in 23 of 28 bone marrow samples, 18 of whom also showed an enhanced 3H-TdR incorporation (1.5-8.5-fold, median 2.0-fold). Four different types of response were identified when analyzing 3H-araC incorporation into the DNA of bone marrow samples in relation to the applied araC dose: (i) 8/28 cases had increases of the araC incorporation at all araC dose levels applied (0.06-100 microM), (ii) 12/28 at low araC concentrations only (0.06-1.0 microM), (iii) 3/28 at high araC concentrations only (10-100 microM), and (iv) 5/28 showed no increase at any dose level given. Hence, 20 of the 23 responding patients revealed a GM-CSF induced enhancement of araC incorporation at low or conventional doses of araC (0.06-1.0 microM). Fourteen of the 18 cases with concomitant rises of 3H-TdR and 3H-araC incorporation into the DNA after GM-CSF had elevated DNA polymerase alpha activity (16-531%, median 72%) and in ten cases overall DNA polymerase activity was enhanced (10-70%, median 22.5%). In contrast, thymidine kinase (TK) and deoxycytidine kinase (dCK) activity were elevated after GM-CSF in only ten and five patients, respectively. An increase in the fraction of cells in S phase was found in 11/21 bone marrow specimens and in 5/9 peripheral blast samples. However, no correlation was observed between increases in the proportion of cells in S phase and enhancements in enzyme activities. In 13 cases the cytotoxicity of araC with and without GM-CSF was assessed by means of a blast cell colony assay. Preincubation with GM-CSF increased the araC mediated cytotoxicity in ten of 13 patients by a median of 3.2-fold (range 2.2-229-fold). The respective LD50 values for araC were reduced from 0.45 to 0.19 microM on average.(ABSTRACT TRUNCATED AT 400 WORDS)
A 36-year-old man developed progressive pain in the left thorax radiating to the shoulder, associated with weight loss as well as axillary and supraclavicular lymph-node swellings, and a left Horner's syndrome. The radiological diagnosis was Pancoast tumour. Computed tomography of the thorax revealed that the tumour had almost completely infiltrated the left lung and hilus. Sonography demonstrated metastases in the liver and retroperitoneum. Histological examination of an excised axillary lymph-node metastasis showed an undifferentiated small-cell tumour. Immunohistochemical tests revealed expression of protein S 100 and neurofilamental proteins, i.e. evidence of a peripheral malignant neuroectodermal tumour. The tumour also expressed vimentin. Treatment consisted of two chemotherapy cycles according to the EVAIA scheme (daily three times 235 mg etoposide, 2 mg vincristine, three times 0.8 mg actinomycin D, three times 3.2 g ifosfamide, three times 30 mg doxorubicin, and three times 12 mg dexamethasone), without any effect on the rapid progression of the disease. He died 17 weeks after the diagnosis had been made.
BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.
We describe a new high-performance liquid chromatographic method using electrochemical detection for the determination of buprenorphine and norbuprenorphine in plasma and urine. The minimum concentration for detection of buprenorphine and norbuprenorphine is 40 pg/ml. The intra-assay coefficient of variation (C.V.) in plasma and urine samples ranges from 6 to 17% depending on the drug concentration. At a plasma concentration of 500 pg/ml the inter-assay C.V. is 8% for buprenorphine and 9% for norbuprenorphine. The analysis duration is 16 min. After solid-phase extraction and evaporation a valve-switching system with two Rheodyne valves enables sample enrichment, optimal sample cleaning and rapid elution of long-retained substances.
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We determined the concentration and effusion/serum ratio of mucin-like carcinoma-associated antigen (MCA) in comparison to carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, and cancer antigen 15-3 in 80 sera and 99 effusions from 64 patients with histologically confirmed malignancies (4 patients out of this group showed various effusions simultaneously, which were analyzed separately) and 31 patients with various nonneoplastic diseases. Tumor cells were detected by cytological examination in 41 effusions (60.3%) from patients with neoplastic diseases, while in another 27 cases this method failed to demonstrate the malignant origin of the effusion. Of the cytological "positive" malignant effusions 90% were also correctly identified by an elevated MCA concentration at a cutoff level of 10 U/ml, whereas only one effusion of benign origin (3%) showed a slightly elevated MCA concentration of 10.5 U/ml. In 33% of cytologically "negative" effusions of patients with neoplastic diseases, the MCA concentration was also elevated, with a maximum of 453 U/ml. Increased MCA levels in cytologically confirmed malignant effusions were not restricted to metastatic breast cancer. All 17 cytologically "positive" "non-breast cancer" effusions were correctly identified by their MCA concentrations. None of the other tumor markers reached this high sensitivity at the same level of specificity. The ratio of effusion/serum concentration of all tumor markers as well as the concentration of cancer antigen 125 in effusions was of little diagnostic value. Our results indicate that the MCA concentration in an effusion correlates very closely with its malignant origin and is superior to all the other antigens tested.(ABSTRACT TRUNCATED AT 250 WORDS)
The present study was designed to determine whether Filgrastim, a neutrophil-specific hematopoietic growth factor, could be administered simultaneously with intensive induction chemotherapy for adult acute lymphoblastic leukemia (ALL). The effect of Filgrastim on the severity of chemotherapy-induced neutropenia, fever, and infections was assessed in 15 patients treated according to the protocol of the German multicenter ALL (GMALL) trial 04/89. Filgrastim (5 micrograms/kg/day) was given concurrently with successive cycles of cyclophosphamide, cytosine-arabinoside (ara-C), 6-mercaptopurine (6MP), prednisone (PRD), intrathecal methotrexate, and prophylactic cranial irradiation. During the study period the median total duration of severe neutropenia (< 0.5 x 10(9)/l) in 13 evaluable patients was 8 days, individual periods of neutropenia typically were short. Infections occurred in six patients; seven patients remained fever-free during treatment with Filgrastim. We conclude that simultaneous treatment with Filgrastim and chemotherapy in this specific setting is feasible and well tolerated. The efficacy of this treatment approach in terms of overall treatment results requires further testing in a randomized trial.
Determination of nuclear DNA by flow cytometry of skeletal muscle biopsies of three unrelated male patients with centronuclear (myotubular) myopathy demonstrated, in two patients, a normal pattern and, in one case, a near haploid DNA content in c. 60% of all nuclei, indicating muscle tissue mosaicism.
After a first study showed that GM-CSF following chemotherapy effectively accelerated neutrophil recovery and reduced early mortality in high risk patients with AML, a second study was begun in which GM-CSF was applied preceding chemotherapy and continuing until neutrophil recovery in the initial 5 chemotherapy courses for patients with newly diagnosed AML. The CR rate in patients of 16-75 (median 50) years was 75% in GM-CSF patients and 84% in controls. GM-CSF patients showed a trend to more frequent rapid blast clearance and fewer persistent leukemias and a significantly superior remission duration as of this update two-and-a-half years after the study started. It should be shown later by this study whether GM-CSF multiple course priming and longterm administration adds to the cure rate of patients with AML.
193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of either 3.0 versus 1.0 g/m2 in pts. < 60 years of age or 1.0 versus 0.5 g/m2 in older pts. Mitox was given to all cases at a dose of 10 mg/m2/d on days 3, 4, and 10, 11. Randomization was stratified for primary refractoriness against induction therapy and the length of first remission in relapsed cases (< 6 mths., 6-18 mths., > 18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates being 52% and 44% for the 3.0 versus 1.0 g/m2 AraC regimens in pts. < 60 years and 48% and 45% after 1.0 versus 0.5 g/m2 AraC in older pts. No differences between the respective regimens emerged either for the time to CR (median 46 days) nor remission duration (median 4.5 mths). Analysis of treatment failures, however, demonstrated a significantly higher rate of NR after the lower dose regimens in both age groups of 41% and 32% versus 11% and 14% in pts. receiving AraC at higher doses (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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In a phase II study, 45 patients with advanced low-grade non-Hodgkin's lymphomas (NHLs) who had failed on or had relapsed after first-line chemotherapy were treated with a 5-day regimen of fludarabine, 25 mg/m2/d, by a 30-minute infusion. All patients were pretreated and had received one to 11 preceding regimens (median, three regimens). Histologic subtypes included 17 centrocytic/centroblastic NHLs, three centrocytic NHLs, 23 lymphoplasmocytoid immunocytomas, and one case each of peripheral T-cell and lymphocytic lymphoma. From 38 presently evaluable patients, 12 (31%) cases responded (five [13%] complete and seven [18%] partial remissions). Treatment-associated toxicity was mild to moderate, with myelosuppression comprising the major side effect. From the 12 complete and partial response patients, seven are currently in unmaintained remission for more than 12 months. These data indicate a high activity of fludarabine in heavily pretreated patients with low-grade NHL. Further investigations are warranted to assess the most appropriate usage for this highly promising agent at earlier stages of low-grade NHL therapy.
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