Biomedical subjects
H Breithaupt
Publications and source records attributed to H Breithaupt.
The new antibiotics.
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Quantification of desferrioxamine, ferrioxamine and aluminoxamine by post-column derivatization high-performance liquid chromatography. Non-linear calibration resulting from second-order reaction kinetics.
Desferrioxamine B is widely used as therapeutic agent for removal of excess body iron and, more recently, for removal of aluminium. A HPLC-based method for direct sensitive and reliable determination of ferrioxamine, desferrioxamine, aluminoxamine and related metabolites has been developed for use in pharmacokinetic studies. The method consists of complete separation of the analytes by an optimized mobile phase avoiding conversion of desferrioxamine to ferrioxamine by the analytical system and overcoming problems due to peak tailing properties of desferrioxamine. A post-column derivatization reaction with colourless fluoro-complexed iron converts all iron free species to ferrioxamine and allows quantification at 430 nm avoiding interference of UV-absorbing coelutes. This reaction might be of interest for other analytical procedures concerning iron chelators. The influence of the post-column reaction system on the column plate number is characterized. As the reaction rate of desferrioxamine and aluminoxamine with iron(III) is of second-order kinetics, a quadratic calibration function is observed, resulting from a compromise between residence time and peak broadening. A solid-phase extraction procedure is presented for extraction of the analytes from plasma. Limits of detection (S/N ratio of 3) were determined as 1.95 ng for ferrioxamine, 3.9 ng for aluminoxamine and 15.7 ng for desferrioxamine, expressed as on-column load. A new iron-free metabolite was identified with fast atom bombardment-mass spectrometry as N-hydroxylated desferrioxamine.
Quantification of pyrazinamide and its metabolites in plasma by ionic-pair high-performance liquid chromatography. Implications for the separation mechanism.
Pyrazinamide, the amide of pyrazinoic acid, is one of the basic therapeutic agents currently used in combination for chemotherapy of tuberculosis. A reversed-phase high-performance liquid chromatography method based on ionic pair chromatography, was developed after solid-phase extraction of the analytes from plasma with prior addition of internal standard. The main metabolites, pyrazinoic acid, 5-hydroxypyrazinoic acid and 5-hydroxypyrazinamide, were included as well as uric acid and other purine derivatives to allow detailed study of the pharmacokinetics of the drug, especially in patients with impaired kidney function. Some interesting features of the chromatographic system giving some insight in the retention mechanism and of the solid-phase extraction are discussed in detail.
[Antibiotic therapy of septicemia--escalation or reduction?].
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Simultaneous quantification of cefotaxime, desacetylcefotaxime, ofloxacine and ciprofloxacine in ocular aqueous humor and in plasma by high-performance liquid chromatography.
Cefotaxime, given intravenously, is currently used as a broad-spectrum antibiotic for prophylaxis of intra- and postoperative infections in ocular lens surgery. A proposed therapeutic and economic alternative is the use of orally active fluoroquinolone ofloxacine as prophylactic agent. A HPLC method was developed for determination of both antibiotics in ocular aqueous humor and plasma in order to optimize dosage for safe surpassing minimal inhibitory concentration in the humor compartment. For plasma determinations a solid-phase extraction procedure was used with ciprofloxacine as internal standard. Detection limits for direct HPLC-analysis of ocular aqueous humor was 0.08 microg/ml for all compounds, whereas in plasma 0.31 microg/ml could be determined after solid-phase extraction.
[Calculated and controlled pharmacotherapy of problem infections in intensive care patients].
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Pharmacokinetic study of methotrexate, folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue.
The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g.m-2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL). The median steady-state concentration of MTX was 66 mumol.l-1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg.m-2.min-1. The 7-OHMTX level increased during each infusion and a Cmax of 19 mumol.l-1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8. The MTX metabolite APA was detected in concentrations less than 0.06 mumol.l-1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mumol.l-1 and 18 h following the last dose of LCV it was 0.44 mumol.l-1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mumol.l-1 with a median ratio of 5-MTHF to MTX of 2. Twenty infusions with 48 h MTX levels of less than 0.5 mumol.l-1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mumol.l-1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.
Kinetics of oral and intravenous mexiletine: lack of effect of cimetidine and ranitidine.
The pharmacokinetics of mexiletine, a Class I antiarrhythmic drug, was investigated in 6 healthy volunteers after single oral doses and 15 min intravenous infusions of 3 mg/kg. Cimetidine and ranitidine are commonly used H2-receptor antagonists, which interact adversely with many drugs, e.g. inhibition of the metabolism of Class I antiarrhythmics such as lidocaine and quinidine by cimetidine. To investigate the effects of the two drugs on the kinetics of mexiletine, cimetidine 800 mg.day-1 or ranitidine 600 mg.day-1 were administered orally for one week. Neither H2-receptor antagonist altered the distribution and elimination of mexiletine, nor did they affect its overall kinetics, or excretion of the metabolites para- and 4-OH-methylmexiletine after oral and intravenous administration of mexiletine.
Immune-mediated agranulocytosis related to drugs and their metabolites: mode of sensitization and heterogeneity of antibodies.
Two major unresolved problems in drug-related immune agranulocytosis are understanding the mechanism by which sensitization takes place in vivo, and verification of the diagnosis. Using a sensitive, competitive enzyme-linked immunoassay (ELISA) we were able to characterize the causative antibodies in 13 patients with drug-related agranulocytosis [metamizole (n = 5), penicillin (n = 5), dimethylaminophenazone (n = 1), propyphenazone (n = 1) and diclofenac (n = 1)]. Irrespective of the causative drug, the majority of patients appear to have developed autoantibodies (aab) in addition to drug-dependent antibodies (ddab) of the IgG and/or IgM classes. In all cases related to metamizole, and in the single case related to diclofenac, the ddab appeared to recognize only metabolites of the drug since they were reactive in the presence of ex vivo antigens (urine from individuals receiving therapeutic levels of the drugs), but not the native drugs. Only a few ddab were reactive with granulocytes pretreated with the drug (cell-drug complexes); the majority of ddab could not be detected unless the drug or ex vivo antigen was added to the incubation mixture as well as the solution used for subsequent washes. Our results indicate that drugs and/or their metabolites interact with target cells and thereby directly function as immunogenic haptens, even when the drugs do not bind tightly to the cells.
[Treatment with mexiletine. Clinical and pharmacokinetic studies].
Pharmacokinetics of the antiarrhythmic agent mexiletine were found to be highly variable. Ineffective or toxic doses can be avoided by monitoring mexiletine concentrations in patients plasma. However, the success of antiarrhythmic therapy is mainly determined by the severity of the underlying disease. Therefore, the efficacy of treatment with mexiletine should be controlled by Holter monitoring.
High dosage desferrioxamine therapy in a female patient with acquired aplastic anaemia and transfusion siderosis.
A 32 year old woman with severe aplastic anaemia required frequent transfusions and consequently developed hyperferrioxaemia (54 microMol/l) and hyperferritinaemia (1,700 ng/ml). For the treatment of transfusion siderosis she was given 18 high dose courses each comprising 35 g of desferrioxamine. Because of pre-existing thrombocytopenia (platelet count 5 X 10(9)/l) the iron chelating agent was given by continuous intravenous infusion over 3 1/2 days. High dose desferrioxamine had to be abandoned because of severe bone pain. The desferrioxamine infusions achieved a negative iron balance, iron loss after each infusion being 100 to 200 mg in the urine and 400 mg in the faeces. Serum iron and ferritin concentrations fell almost to normal. This report shows that faecal iron excretion must be taken into account in assessing the balance of iron input and output during desferrioxamine treatment.
[Results of therapy with high-dose cytosine arabinoside].
Four patients with acute leukemias resistant to various ARA-C containing regimens and one patient with rapidly progressive malignant nonseminomatous tumor of the testis, who failed to conventional therapy were treated with HD ARA-C from december 1979 to september 1980. The drug was monitored by HPLC in plasma and in CSF. The first patient received only one course of HD ARA-C, developed fever and died of septicemia ten days later. The leucocyte count of her AML (FAB 2) decreased from 120,000/microliter to 30,000/microliter on the third day after HD ARA-C. Patient 2 reached CR criteria of the bone marrow for 23 days, then resistant AML (FAB 2) recurred. A male patient of 30 years was treated for recurrent acute undifferentiated leukemia (AUL) with a high cumulative dose of 176 gs of ARA-C. The repeated courses of treatment included a period of 50 days of CR. Toxicity was remarkable including pulmonal and cerebral dysfunction. A fourth patient with monocytic leukemia did not respond to HD ARA-C, neither did the patient with the malignant teratoma. Adverse reactions were tolerable. Only the third patient suffered from severe toxicity, pneumonitis, blurring vision, cerebral dysfunction and dermatitis. His pretreatment regimen had included X-ray prophylaxis to the skull. Since there was no possibility to prolong the remission duration in 1980, we decided not to treat further patients with HD ARA-C. Nowadays bone marrow transplantation offers some patients a capability of eradication of the leukemic disease.(ABSTRACT TRUNCATED AT 250 WORDS)
[Treatment of hypertension (V)].
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Kinetics of methotrexate, dacarbazine and 5-fluorouracil during isolated liver perfusion.
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[Therapeutic response of various histological osteosarcoma subtypes to high-dose methotrexate treatment].
The successful or unsuccessful chemotherapy of osteosarcoma has given rise to the division of these tumors into responders and non responders from the clinical point of view. In order to work out drug sensitive tumor components we studied 9 osteosarcomas by a histological subdivision of the osteosarcoma tissue into 6 subtypes. Seven of the 9 osteosarcoma patients had developed lung metastases under adjuvant high dosage methotrexate (HDMTX) therapy. The aim was to identify the components of the primary tumors which had endured HDMTX-therapy as lung metastases. As HDMTX-sensitive histologic differentiation form of osteosarcoma tissue we regarded the no matrix producing-subtype (III), because it did not occur in the lung metastases. The classical subtype (IV) seems to be only partially sensitive because the corresponding lung metastases showed a higher osteoblastic differentiation with increased osteoid production. No therapeutic effect could be observed in the chondromatous (I) and in the sarcomatous (II) subtypes as well as in the two subtypes with intensive osteoid production being termed trabecularly sclerosing (V) and massively osteoid producing subtypes (VI).
High-dose methotrexate for osteosarcoma: toxicity and clinical results.
9 patients with osteosarcoma were treated with a total of 122 infusions of high-dose methotrexate (MTX; 140-350 mg/kg) followed by leucovorin rescue. Plasma kinetics of MTX and 7-hydroxymethotrexate (7-OH-MTX) has been routinely monitored. Due to inadequate hydration and alkalinization, 1 of the 122 high-dose MTX infusions was followed by delayed disappearance of MTX and 7-OH-MTX from plasma with subsequent development of severe mucositis. Serious hepatotoxicity repeatedly developed in another patient with inconspicuous MTX kinetics. The benefit of monotherapy with high-dose MTX for adjuvant treatment of osteosarcoma remains questionable, since 6 of 8 patients with primary osteosarcoma developed pulmonary metastases within 4-12 months (median 5 months), 2 have been disease-free and alive for 25 and 53 months.
[Treatment of hypertension (IV)].
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