[Hyperthyroidism, eosinophilia, and fever in a 64-year-old patient]. / Hyperthyreose, Eosinophilie und Fieber bei einem 64-jährigen Patienten.

We report on a male patient suffering from loss of weight, fatigue, fever, eosinophilia, and hyperthyreoidism. The echocardiogram revealed a left atrial mass originating from the posterior mitral leaflet. In combination with the constitutional symptoms a left atrial myxoma was diagnosed. The tumor was surgically removed. Postoperatively therapy with corticosteroids and thiamazole was stopped. During follow-up, eosinophilia and hyperthyreodism could no longer be detected.

[Effective levels of cyclophosphamide and metabolites in pleural effusions during intravenous therapy (author's transl)]. / Wirkspiegel von Cyclophosphamid und Metaboliten in malignen Pleuraergüssen bein intravenöser Therapie.

Levels of cyclophosphamide (CP, Endoxan) and metabolites were determined in blood and pleural effusions of 5 cancer patients receiving 20 mg/kg CP i.v. The pleural concentrations of CP and its stable deactivated metabolites as 4-keto-CP and carboxyphosphamide increased slowly and even after 4 to 6 an equilibrium with plasma levels was not achieved completely. Plasma peak levels of activated CP (4-hydroxy-CP + aldophosphamide) determined after conversion into the stable derivative 4-(S-benzyl)sulfido-CP or by a fluorometric test were in the range of 1 to 2 nmol/ml. Using these techniques, as two independent methods, amounts of activated CP in pleural effusion were found to be below the limit of detection (0.1-0.2 nmol/ml). Also the alkylating rates of proteins in the pleural effusions were only 20% of those measured in blood samples. The relatively short plasma half-life (approx. 15 min) of 4-hydroxy-CP, when compared with the slow passage of CP-metabolites from blood to the pleural space, is assumed to be the reason for the failure of detection of activated CP and low levels of alkylating material observed in the pleural effusions.

[Leukocyte-adherence-inhibition reactivity in patients with colorectal and pancreatic cancer (author's transl)]. / Immunreaktivität bei Patienten mit kolorektalen Tumoren und Pankreaskarzinomen im Leukozytenadhärenz-Inhibitionstest.

The immunoreactivity of patients with colorectal or pancreatic cancer was investigated by a modified leukocyte adherence inhibition test (LAI). The microcapillary-LAI-test was easy to practise and measurements had a low intra-assay coefficient of variation. The number of false positive results was low, only 1 of 39 patients with benign disease and not one of 13 healthy volunteers reacted in the presence of colorectal carcinoma extracts. In 43 patients with colorectal cancer 17 of 25 (68%) with Dukes' B & C and 15 of 18 (83%) with Dukes' D cancer were LAI positive. Of the 19 patients with colon polyps 6 positive results were observed, exclusively in case of large villous adenomas, polyposis coli and one polyp with a focal carcinoma. 10 of 11 patients with pancreatic cancer reacted in the test. Leukocytes from patients with limited cancer of other source, when tested with colorectal or pancreatic carcinoma extracts, showed a negative LAI response. However, in case of metastatic diseases some crossreactions were observed, which resulted in false positive tests. Following our results, the LAI test could be of value in the diagnosis of gastrointestinal carcinoma.

Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test.

The activated metabolites of ifosfamide and cyclophosphamide (4-hydroxy-ifosfamide and 4-hydroxy-cyclophosphamide) were analysed fluorometrically by condensation of liberated acrolein with m-aminophenol yielding 7-hydroxyguinoline. Interfering fluorescence of blood and urine was eliminated by extraction with dichlormethane and determination of blanks in which the liberated acrolein reacted with hydrazine to non-fluorescent pyrazoline. The modified test proved effective in identifying low levels of activated metabolites in man. After i.v. injection of 20 mg/kg cyclophosphamide or ifosfamide peak levels of activated cyclophosphamide (4.7 nmol/ml) and the area under the curve (c.t = 16.7 nmol.ml/h) showed mean values three times higher than those found for activated ifosfamide. One per cent of the applied dosis of cyclophosphamide vs. 0.3% of ifosfamide was excreted as activated metabolites. Due to the high stability of activated cyclophosphamide and ifosfamide in urine a low liberation rate of acrolein was found, the concentration of which in urine was below 0.5 nmol/ml. Acrolein, which was directly liberated from activated cyclophosphamide or ifosfamide, does not seem to play an important role in the urotoxicity of these cytostatics.

[Effect of damaged liver parenchyma, renal insufficiency and hemodialysis on the pharmacokinetics of cyclophosphamide and its activated metabolites]. / Einfluss von Leberparenchymschäden, Niereninsuffizienz und Hämodialyse auf die Pharmakokinetik von Cyclophosphamid und seinen aktivierten Metaboliten.

Patients with impaired liver function have a reduced biotransformation rate of the cytostatic agent cyclophosphamide. With pathologically reduced serum cholinesterase activity the half-life of the drug increases from normally 4.3 h to 6.7 h. These patients show significantly lower peak levels of activated cyclophosphamide (4-hydroxy-cyclophosphamide + aldophosphamide). Because of the low renal clearance of cyclophosphamide (16 ml/min) and equally low renal excretion of activated cyclophosphamide amounting to only 1% of the applied dose more than 80% of the drug is still metabolized and the area under the curve of activated cyclophosphamide (cXt) remains relatively constant. No change in the pharmacokinetics of cyclophosphamide and its activated metabolite is observed in an anuric patient. However, an accumulation of toxic, directly alkylating metabolites with a fourfold alkylation rate of plasma proteins is found in this case. Hemodialysis sufficiently eliminated the toxic alkylating metabolites without a measurable influence on the pharmacokinetics of activated cyclophosphamide.

[Blood level and urinary excretion of activated cyclophosphamide and its deactivation products in man (author's transl)]. / Uber Blutspiegel und Urin-Ausscheidung von aktiviertem Cyclophosphamid und seinen Deaktivierungsprodukten beim Menschen.

Blood levels and urinary excretion of cyclophosphamide and its metabolites were determined in cancer patients receiving cyclophosphamide. Activated cyclophosphamide (4-hydroxycyclophosphamide aldophosphamide) was assayed by TLC after derivatisation to stable 4-(S-benzyl)-sulfido-cyclophosphamide. Twenty minutes after injection of 10(20) mg/kg cyclophosphamide mean peak levels of activated cyclophosphamide were found to be 1.4(2.6) nmol/ml. The rate constant for biotransformation (=activation) of cyclophosphamide in man (km = 0.132 h-1) was only 1/50 of the value found in the mouse whereas the elimination rate constant of activated cyclophosphamide (ke[M] approximately 6.78 h-1) was much higher equalling that of laboratory animals. 4-ketocyclophosphamide, carboxyphosphamide, and phosphoramidemustard reached their peak levels between 4 and 6 h after cyclophosphamide injection. Increasing quantities of cyclophosphamide metabolites were bound to plasma proteins reaching a constant level after 24 h lasted for several days. Fifty per cent of those metabolites were reversibly bound to plasma proteins. Within 24 h, the cumulative excretion of cyclophosphamide and its metabolites amounted to 50% of the dose applied. The main metabolites excreted were phosphoramide-mustard and carboxyphosphamide whereas only 2% consisted of activated cyclophosphamide. The significance of the different pharmacokinetics of cyclophosphamide in laboratory animals and man for the therapeutic index is discussed.