Hans-Walter Fritsch

Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters with clinical conditions

SummaryThe pharmacokinetic parameters of etoposide were established in 35 patients receiving the drug parenterally within the framework of different polychemotherapy protocols. A total of 62 data for 24-h kinetics were analysed. After sample extraction and high-performance liquid chromatography (HPLC) or thin-layer cromatographic (TLC) separation, etoposide was measured by means of [252Cf]-plasma desorption mass spectrometry (PDMS). This highly specific detection system proved to be very practicable and reproducible. The present study comprised two parts that were absolutely comparable in terms of clinical and pharmacokinetic parameters. In part II of the study, sensitivity was improved by modifying the analytical technique. After the exclusion of patients who had previously been given cisplatin or who exhibited renal impairment and of one patient who showed extremely high levels of alkaline phosphatase, γ-GT and SGPT, the mean values calculated for the pharmacokinetic parameters evaluated were: beta-elimination half-life (t1/2β), 4.9±1.2 h; mean residence time (MRT), 6.7±1.4 h; area under the concentration-time curve (AUC), 5.43±1.74 mg min ml−1; volume of distribution at steady state (Vdss), 6.8±2.7 l/m2; and clearance (Cl), 18.8±5.3 ml min−1 m−2. The pharmacokinetic parameters were correlated with 12 different demographic or biochemical conditions. Impaired renal function, previous application of cisplatin and the age of patients were found to influence etoposide disposition to a statistically significant extent. We suggest that the dose of etoposide should be reduced in elderly patients and/or in individuals with impaired renal function, especially in those exhibiting general risk factors such as reduced liver function with regard to the polychemotherapy.

Pharmacokinetics of high-dose etoposide after short-term infusion

SummaryThe pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m2 divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m2 cytosine arabinoside (ara-C), 300 mg/m2 carmustine (BCNU), or 1,200 mg/m2 carboplatin. Plasma etoposide concentrations were determined by252Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2β, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629μg min ml−1 (normalized to a dose of 100 mg/m2); volume of distribution at steady state (Vdss), 6.6±1.2l/m2; and clearance (CL), 20.4±2.4 ml min−1 m−2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m2). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 μg/ml, all patients exhibited undelayed hematopoietic reconstitution.

Quantitative matrix assisted plasma desorption mass spectrometry

Abstract The development of optimized sample preparation methods accompanied the history of successful applications of 252Cf-PDMS. Studying the pharmacokinetics of the antineoplastic agent etoposide serum samples from cancer patients were labelled with the homologeous compounds teniposide as internal standard for the quantitative PDMS analysis. Sample purification by chloroform extraction and by thin layer chromatography turned out to be insufficient to guarantee a satisfying final PDMS result. Embedding the purified sample into a matrix of suitable substances on the target reduced the negative influence of impurities, raised the signal-to-noise ratio of molecular ions and improved the reproducibility of calibration. This preparation method was again successfully employed for the quantitative analysis of the cytostatic drug doxorubicin. The application of a different matrix optimized for the preparation of this anthracycline and its homologeous compound daunorubicin, improved the sensitivity, linearity and detection limit.

Complex dynamics variables for molecules and molecular clusters

Abstract We describe a method to analyse dynamic properties of molecules and molecular clusters. The model involves the change in lifetimes of collective, quasi-stationary excited states of the system under consideration by low energy electron local excitations. Probabilities of desorption-ionisation processes and cluster decomposition are also estimated. The model is based on the quantum multi-particle theory and the exciton or excimol theory for condensed matter and molecules. The energies of excitation have complex values which permit us to take into account the unharmonic character of bond vibrations and the relaxation process. We apply a perturbation theory for excitation analysis describing the possible deviation of molecules or molecular clusters from regular structures. The wave-functions can be taken in their asymptotic form and the dilatation method is used for the complex energy states.

Application of 252Cf plasma desorption mass spectrometry in dental research

Abstract Topically applied fluorides introduced in dental hygiene products elevate the concentration levels of fluoride in oral fluids and thus also affect chemical reactions of enamel de- and remineralisation. The chemical reactions on the surface of tooth enamel still are a subject of controversy. Here 252 Cf-plasma desorption mass spectrometry and argon ion etching are used to analyse the molecular structure of the upper layes of enamel. The mass spectrum of untreated enamel is characterised by a series of cluster ions containing phosphate. It is evident that under certain conditions the molecular structure of the surface enamel is completely transformed by treatment with fluorides. The result of the degradation and precipitation processes is reflected by a total replacement of the phosphate by fluoride in the measured cluster ion distribution. Stepwise etching of the upper layers by Ar + ions reveals the transition from a nearly pure CaF 2 structure to the unchanged composition of the enamel mineral.

Gridless Ion Acceleration Systems for Time-of-Flight Mass Spectrometry.

Pointlike ion sources allow the application of gridless acceleration systems in time-of-flight mass spectrometry (TOF/MS). When ions are extracted from large sample areas according to the applied ionization method and sample geometry, the application of electrostatic lenses for acceleration seems to be difficult. Inhomogeneous extraction fields are likely to induce acceleration time variations for ions emerging from different locations on the sample. We investigated gridless acceleration systems with the help of computer simulations. An appropriate solution for TOF/MS was found and experimentally tested, combining the features of compactness and a wide-acceptance aperture with simple principles of construction. nt]mis|Dedicated to Ronald D, Macfarlane on the occasion of his 60th birthday.

Persistent segmental perfusion defect in an intermediate-probability lung scan

A perfusion defect persisting for 11 years in a 37-year-old woman is described. This area demonstrated a V/Q mismatch but was not caused by pulmonary embolism.

Huge necrotic liver metastases in advanced pancreatic carcinoma visualized on bone scans.

A 49-year-old man had a histologically confirmed pancreatic carcinoma with several huge necrotic metastases in the liver. Many cases of increased radionuclide uptake in liver metastases have been reported, but in this case the radionuclide uptake was missing.

Imaging of Parathyroid Adenomas Using Technetium-99m-Sestamibi in an Endemic Goiter Area

Double-phase single radionuclide parathyroid scintigraphy with Tc-99m-Sestamibi was performed in 26 patients with primary and in 9 patients with secondary hyperparathyroidism. The Tc-99m-Sestamibi-scan identified and localized 21 of 26 adenomas in the 26 patients with pHPT. In only 6 of the 9 patients with parathyroid hyperplasia a focally increased uptake was found. The cause of one false positive result in 5 control patients was an increased Tc-99m-Sestamibi-uptake in a follicular adenoma of the thyroid gland. Parathyroid scintigraphy using Tc-99m-Sestamibi as a single radiotracer is at least as sensitive in detecting and localizing parathyroid adenomas as TI/Tc-scintigraphy.