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Biomedical subjects

G Ehninger

Publications and source records attributed to G Ehninger.

306 records · Page 17Linked to original sources
PubMed1986

Appearance of an inherited porphyria cutanea tarda in a child after allogeneic bone marrow transplantation for chronic myelogenous leukaemia.

We report details of a 6 1/2-year-old girl who developed porphyria cutanea tarda after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. The results of studying porphyrin metabolism in the family members are described. Expression of the disease may have been induced by the cyclophosphamide and total-body irradiation in the conditioning regimen and/or by the administration of methotrexate for the prevention of graft-versus-host disease and meningeal leukaemia.

Bone Marrow Transplantation↗
PubMed1986

Combination therapy with mitoxantrone and etoposide in refractory acute myelogenous leukemia.

We have investigated the efficacy of mitoxantrone in combination with etoposide in patients with refractory acute myelogenous leukemia. The regimen consisted of 10 mg/m2/day of mitoxantrone given iv on Days 1-5; and 100 mg/m2/day of etoposide as short infusion, initially on Days 1-3 and extended to Days 4 and 5 as appropriate. Of the 26 patients treated with this combination, nine (34.6%) have achieved complete remission and two have achieved partial remission. The median duration of continuous complete remission was 85 days (range, 21-183+). Toxicity was mild and only one case of early death was observed. This combination seems to be an active regimen in refractory acute myelogenous leukemia, and its incorporation in front-line therapy seems warranted.

Adult↗
PubMed1986

Clinical pharmacology of mitoxantrone.

A pharmacokinetic study on mitoxantrone was performed within the framework of a phase II clinical trial. Serum concentrations and urinary excretion were measured using a high-performance liquid chromatography method. Four metabolites were separated in urine and three in serum. The two major metabolites cochromatographed with the synthesized monocarboxylic and dicarboxylic acids of mitoxantrone. Within 48 hours, 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as Metabolite 1, and 0.3% as Metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours and a volume of distribution of 2248 L/m2. The total-body clearance was 217 ml/min/m2 and the renal clearance was 15 ml/min/m2. These results suggest that mitoxantrone is sequestered in a deep tissue compartment and only slowly released.

Breast Neoplasms↗
PubMed1985

Detection and separation of mitoxantrone and its metabolites in plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method using ion-pair chromatography on reversed-phase C18 material was developed. After sample clean-up on XAD columns, mitoxantrone at concentrations below 1 ng/ml in serum and 0.2 ng/ml in urine were measurable with a coefficient of variation of less than 9.3% at a wavelength of 658 nm. Four metabolites were separated in urine. The two major metabolites co-chromatographed with the synthesized mono- and dicarboxylic acid derivatives of mitoxantrone. The method allowed the measurement of mitoxantrone and its metabolites in serum up to more than one week and in urine up to four weeks after administration of the drug.

Anthraquinones↗
PubMed1985

The pharmacokinetics and metabolism of mitoxantrone in man.

An HPLC method using paired-ion chromatography on RP C-18 material was developed. After sample clean up on XAD columns, mitoxantrone (Novantrone; dihydroxyanthracenedione) in concentrations below 1 ng/ml in serum and 0.2 ng/ml in urine were measurable with a coefficient of variation less than 9.3% at a wavelength of 658 nm. Four metabolites were separated in urine. The major metabolite cochromatographed with the synthesized dicarboxylic acid of mitoxantrone. Within 48 hours 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as metabolite 1 and 0.3% as metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours, and a volume of distribution (ss) of 3792 litres. The total body clearance was 358 ml/min and the renal clearance was 26.2 ml/min.

Anthraquinones↗
PubMed1985

Mitoxantrone in the treatment of relapsed and refractory acute leukemia.

Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.

Acute Disease↗
PubMed1985

Mitoxantrone in the treatment of relapsed and refractory acute leukemia.

Twenty-four patients with acute leukemia and blast crisis of chronic myelocytic leukemia in relapse or refractory to standard chemotherapy were eligible for treatment with mitoxantrone. Mitoxantrone was administered in a dose of 8-13 mg/m2 on five consecutive days. 5 of 20 evaluable patients were induced into complete remission, 1 patient achieved a partial remission. Side effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.

Acute Disease↗
PubMed1985

[Therapy of peritoneal carcinosis with intraperitoneal administration of cis-diamminedichloroplatinum and systemic sodium thiosulfate protection. Clinical results of a pilot study and pharmacokinetics].

Six patients with peritoneal carcinosis and ascites received 13 courses of ip cis-platinum (c-DDP). C-DDP (170-250 mg in 2L saline, dwell 4 h) was administered via Pig-Tail-Cordis catheter with concurrent infusion of sodium thiosulfate (bolus 7.5 g/m2 followed by 2.13 g/m2/h for 12 h). The patients received pre- and post-therapy hydration (250 ml/h) and mannitol-induced diuresis. Courses were given in 4 weekly intervals. With a dwell time of 4 h 27.0% +/- 14.6% (mean +/- SD) of platinum were recovered. Total serum platinum peaked at 3.1 +/- 1.0 microgram/ml. The peritoneal/serum ratio of platinum concentration was 49.5 +/- 12.6 after 1 h, 7.4 +/- 1.7 after 5 h and 4.2 +/- 1.7 after 12 h. Within 12 h 30.9% +/- 10.0% of the administered dose were excreted in urine. In 4 patients the ascites had disappeared lasting 14+, 15+, 5+, 3+ months. 2 patients died within 1 month caused by systemic tumor progression. Following toxicity was observed: 9/13 nausea and vomiting grade 1 (WHO), 2/13 hematological toxicity grade 2, 1/13 sterile peritonitis, no renal or neurological toxicity. This pilot study demonstrates a pharmacokinetic advantage of ip chemotherapy with c-DDP and an effectiveness against peritoneal carcinosis.

Adenocarcinoma↗
PubMed1985

[Perazine-induced agranulocytosis--case report and discussion].

A 22-year-old female patient developed agranulocytosis 26 days after starting single agent treatment with perazine. In accordance with the clinical and hematological picture this agranulocytosis is classified as antibody mediated with destruction of peripheral neutrophils. After cessation of perazine treatment and proper therapy of infection the patient recovered within two weeks. The diagnosis of agranulocytosis should be suspected in anyone on neuroleptic treatment who develops fever, malaise or objective evidence of an infection and in neutropenic patients the adequate treatment should be started immediately.

Adult↗
PubMed1984

Bone marrow transplantation for acute leukemia in second or subsequent remission.

Twenty-one patients with acute leukemia in second to fifth remission were treated with bone marrow transplantation: 19 patients with transplants from HLA-matched siblings and two with transplants from identical twins. Twelve patients survived from 15 to 1,625 days after transplantation: six of 11 in the ALL group and six of 10 in the AML group. Recurrence of leukemia after marrow transplantation occurred in five patients. The cause of death in five patients was infection, in two patients combined with graft-versus-host disease. Long-term disease-free survival can probably be achieved in 30%-35% of all patients with acute leukemia who receive a marrow transplant in second or subsequent remission.

Adolescent↗
PubMed1984

Mitoxantrone metabolism in the isolated perfused rat liver.

The hepatobiliary pharmacokinetics of mitoxantrone, a new anthracenedione derivative, was studied in the isolated perfused rat liver. Mitoxantrone was administered in doses of 0.2 and 0.4 mg/kg body weight. Multiple bile samples were obtained for 4 hours. Mitoxantrone and three metabolites were separated by high-performance thin-layer chromatography (HPTLC) and measured at 610 nm. Following 0.2 mg mitoxantrone/kg body wt, 25.8% +/- 2.6% of the administered dose was excreted in the bile during 4 h, the major metabolite M1 accounting for 80% of this. After 0.4 mg mitoxantrone/kg body wt the amounts excreted were lower and light microscopic examination showed disseminated areas of cell necrosis.

Animals↗
PubMed1984

Mitoxantrone and cyclophosphamide in patients with advanced breast cancer.

Twenty-eight patients with advanced breast cancer who had no prior chemotherapy received 14 mg/m2 of mitoxantrone iv on Day 1 and 600 mg/m2 of cyclophosphamide on Day 2, repeated every 4 weeks. Three patients (10%) achieved complete response and ten (36%) achieved partial response. The dose-limiting toxicity was leukopenia, and no septicemia occurred. Slightly greater than 50% of the patients had a wbc count nadir less than 2000/mm3. Based on the remarkably good tolerability, ie, mild nausea, rarely severe alopecia, and observed remission rate, this combination represents a positive addition to chemotherapy for advanced breast cancer.

Adult↗
PubMed1980

[The pharmacokinetics of adriamycin and adriamycin-metabolites (author's transl)].

A sensitive reproducible, nondestructive method for the determination of adriamycin and its metabolites in plasma, leukocytes and tissues has been developed. Apolar substances as adriamycinone (adm-one) were extracted at pH 2 with chloroform, polar ones as adriamycin (adm) and adriamycinol (adm-ol) at pH 8.8 with chloroform: methanol, separated by thin-layer-chromatography and quantitated by fluorescence spectrophotometry. The plasma levels of adm-ol and adm-one were lower in all patients compared to those of adm. Further metabolites were found in the bile. Toxic effects were found in patients with prolonged half-lives in the elimination phase. A delayed elimination was observed in a patient with an elevation of the bilirubin level, but also in patients without overt liver disease. The pharmacokinetics of adm showed considerable inter- and intraindividual fluctuations.

Chromatography, Thin Layer↗
PubMedDate not supplied

Detection and separation of the S-adenosylmethionine-decarboxylase inhibitor SAM486A in human plasma and urine by reversed-phase ion-pairing high-performance liquid chromatography.

A reversed-phase ion-pairing high-performance liquid chromatography method for the detection and separation of SAM486A in human plasma and urine is described. Precipitation of proteins was used for plasma sample preparation. Enrichment of SAM486A on a 5 micro C18 column using 0.05 M NaH(2)PO(4) and 0.005 M pentan-sulfonic acid (pH 3.0) as eluent was followed by isocratic elution onto a 5 micro C18 analytical column using 0.01 M NaH(2)PO(4) and 0.005 M pentan-sulfonic acid (pH 3.0) as eluent. Analysis time was 23.0 +/- 0.1 min. The separation parameters were: capacacity factor = 6.21; plates/m = 15,002; peak tailing = 2.076. The method is linear between 5 ng/ml (detection limit) and 1000 ng/ml.

Adenosylmethionine Decarboxylase↗
PubMedDate not supplied

Fluconazole in the prophylaxis of fungal infection after bone marrow transplantation.

An open, non-comparative study was conducted to investigate the efficacy and safety of fluconazole in the prophylaxis of superficial or systemic fungal infections in patients having received bone marrow transplantation (BMT). The study population consisted of a total of 53 patients, including 10 children between the ages of 3 and 14 years who were scheduled for BMT. Fluconazole prophylaxis was initiated at 200 mg day-1 in adults and 100 mg day-1 in children. It was started at a mean of 7 days before treatment and continued for up to 112 days in the paediatric patients and 393 days in the adult patients. Apart from the baseline examination and the final evaluation, the patients were evaluated mycologically and serologically for the presence of fungal infections on a weekly basis, if feasible. Proven fungal infection, oesophageal candidosis or oropharyngeal candidosis was not found in any of the patients under study during the fluconazole prophylaxis. Thirteen of the adult patients developed unexplained fevers and had their treatment supplemented by antibiotic therapy and treatment with amphotericin B. In all 10 children, the prophylactic treatment proved successful. Adverse events were seen in 15 patients. In one case only, the event was judged to be causally related or possibly causally related to the study drug. Hence, fluconazole proves to be an effective and well-tolerated agent in the prophylaxis of fungal infections in recipients of bone marrow transplants.

Adolescent↗
PubMedDate not supplied

Evidence for oxidative activation of mitoxantrone in human, pig, and rat.

A new metabolite of mitoxantrone in human, rat, and pig urine has been discovered by means of HPLC. The metabolite has been isolated by preparative HPLC from patient urine and is characterized by tandem mass spectrometry and UV-visible spectroscopy as 8,11-dihydroxy-4-(2-hydroxyethyl)-6-[[2-[(2-hydroxyethyl)amino]ethyl] amino]-1,2,3,4,7,12-hexahydronaphtho-[2,3-f]-chinoxaline-7,1 2-dione. Final structural proof has been obtained by independent synthesis. The new metabolite is a product of the enzymatic oxidation of the phenylenediamine substructure of mitoxantrone. An important biological consequence of the oxidative biotransformation is the possibility of covalent binding to intracellular targets via a highly electrophilic intermediate. Thus, alkylation may be an important mode of action of mitoxantrone. Incubation of mitoxantrone with horseradish peroxidase/hydrogen peroxide in the presence of glutathione led to the formation of two glutathione conjugates of mitoxantrone. Their structures have been elucidated by combination of IonSpray (Sciex, Canada) ionization and tandem mass spectrometry. Radioactive mitoxantrone, synthesized from sodium [14C]cyanide, was used to determine interspecies variations between human and rat. The collected rat urine was analyzed by HPLC using a radioactivity monitoring detector and revealed significant differences in the biotransformation of mitoxantrone in rat compared to human. The main metabolites thus far described in human urine are not observed in rat urine.

Animals↗
PubMedDate not supplied

Detection and identification of human urinary metabolites of biantrazole (CI-941).

The anthrapyrazole derivative biantrazole (7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2- hydroxyethyl)amino]ethyl]amino]-anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride, CI-941) is currently under clinical investigation for the treatment of breast cancer. Up to now, pharmacokinetic data of the drug were acquired using an HPLC assay lacking the capability to detect and separate metabolites of CI-941. Therefore an HPLC separation procedure was developed that is compatible with the ionization methods used most frequently for coupling to mass spectrometry. Application of the HPLC analysis to the urine of a patient treated with biantrazole clearly demonstrated the presence of two more polar metabolites. The molecular masses of the metabolites were determined during an HPLC-MS coupling with ionspray ionization after injection of an extract of only 15 ml of patient urine. Both metabolites have the same UV-VIS spectra as biantrazole and exhibit collision-induced mass spectra typical for aminoalkylamino-substituted anthrapyrazoles. The daughter ion mass spectra acquired during the HPLC separation allowed the identification of the chemical structures of both metabolites. Metabolite 1 was identified as the oxidation product of CI-941 with both side chains oxidized at the hydroxymethylene groups to the corresponding dicarboxylic acid derivative, whereas metabolite 2 was shown to be the analogous monooxidation product. However, the unsymmetrical molecular structure of CI-941 did not allow us to distinguish between two possible isomers of metabolite 2. Quantitation of the drug and its metabolites in patient urine collected during a time period of 100 hr showed that 0.55% of the dose were excreted as metabolite 1, 0.34% of the dose as metabolite 2, and 7.8% of the dose as unchanged drug.

Anthraquinones↗