[Synthesis of 14C-azelastine hydrochloride]. / Synthese von 14C-Azelastin-hydrochlorid.

The synthesis of 4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone hydrochloride (14C-azelastine hydrochloride, Asta A 5610) is described Starting material was 14C-phthalic anhydride.

[Circulating immune complexes in bronchogenic carcinoma: relation to extent of disease and to therapy (author's transl)]. / Zirkulierende Immunkomplexe beim Bronchialkarzinom: Beziehungen zum Ausbreitungsstadium der Erkrankung und zur Therapie.

In sera of 72 patients with lung cancer, 20 patients with various benign lung diseases and 34 age matched controls circulating immune complexes were determined by column chromatography on Sepharose 6 B and subsequent testing of the eluate for macromolecular IgG as well as by inhibition of radiolabelled C1q binding to sensitized sheep erythrocytes. Whereas in both control and benign lung disease-sera complexes could be detected in less than 5%, sera of lung cancer patients showed macromolecular IgG in 83% and C1q reactive material in 53% at the time of diagnosis. Patients with metastases exhibited a significantly higher percentage of positive reactions than those without metastases (macromolecular IgG 93%/68%, C1q 71%/28%). The size of the complexes increased with the extent of disease. So far, no signficiant changes in circulating immune complexes could be demonstrated id pretherapeutic values were compared with those after X-ray-, chemo- or immunotherapy with one exception, which is an increase of C1q reactive material after radiotherapy.

In vitro sensitivity testing of cells of histologically typified ovarian carcinomas and carcinoma of corpus with 3H-cyclophosphamide-metabolites in the serum of man after massive dose therapy.

Cells of a carcinoma of the uterine corpus and of five ovarian carcinomas were cultured in vitro with monolayer and sandwich methods, respectively. After 24-hours-incubation with serum samples of patients treated with a massive dose of 3H-cyclophosphamide (60 mg/kg body weight i.v.)-the samples were taken at different times after application-these cultures with a chromatographically defined content of free metabolites were interpreted, guided by morphological criteria. Incubation of the cultures with serum samples taken 5 hours after application of the massive dose turned out to be a practical system for detection, before the start of therapy, of the sensitivity of malignant tumors to cyclophosphamide. Statements about the proliferation kinetics of the malignant cells, about the active ultimate form of the antitumor agent and its way of action, which are not guaranteed experimentally, are largely eliminated by this method. The justification for using 4-hydroxy- and 4-hydroperoxy-cyclophosphamide to test the sensitivity of malignant cells in vitro to cyclophosphamide was critically examined.

[Isoelectric focusing of an alkylating 3H-cyclophosphamide derivative from human bladder urine]. / Untersuchungen über einen alkylierenden 3H-Cyclophosphamidabkömmling des menschlichen Blasenurins unter Anwendung der isoelektrischen Fokussierung

1) A stable polar 3H-cyclophosphamide metabolite capable of alkylating 4-(p-nitrobenzyl) pyridine and relatively high concentrated in human bladder urine was isolated. The compound has the pI value 9.06. It is a phosphoramide mustard conjugate. 2) Determination of the isoelectric point was accomplished by means of a new thin-layer isoelectric focusing technique applicable for characterizing loaded parts of low molecular weight substance mixtures.

[Studies on the bioavailability of the individual components from a combination of dilazep and beta-acetyldigoxin (author's transl)]. / Uber die Bioverfügbarkeit der Einzelkomponenten aus einer Kombination von Dilazep und beta-Acetyl-digoxin

Original tablets of Cormelian [= 50 mg 1,4-bis[3-(3,4,5-trimethoxybenzoyl-oxy)-propyl]-perhydro-1,4-diazepine (dilazep)] and Cormelian-Digotab (= 50 mg dilazep + 0.2 mg beta-acetyl-digoxin) were produced with 3H-dilazep as prescribed in the special galenic technique. After application of a single oral dose of two tablets dilazep to 9 patients serum concentration was analysed at different times up to 24 h p.a.; the renal excretion rate of dilazep and metabolites was determined up to 48 h. Two tablets of the combination were given to 4 of these patients 4 days after application of dilazep and the corresponding analysis were repeated; in the serum of these patients the concentration of glycoside was determined by radioimmuno assay. The following results were obtained. 1. Differences in serum concentrations and renal excretion rates of dilazep and metabolites were not observed after application of the mono- and combination product. In comparison to results after oral application of pure dilazep in gelatin capsules the serum concentrations 1 h after application of Cormelian and Cormelian-Digotab were statistically significantly higher. With reference to comparable total absorption rates these results may be representative for a possibly retarded absorption rate of dilazep given as pure substance. An influence of the different galenic techniques on the intensity and direction of metabolites could not be substantiated. 2. By large dispersions of the single values high absolute and relative concentrations of beta-acetyl-digoxin were found in the serum of all the 4 patients after application of combination. Contrary to two commercial products, applied to each of 10 test persons under comparable conditions, statistically higher serum concentrations of glycoside were analysed 1 h after application of the combination. The results of these studies confirm a positive influence of the galenics on the biological availability of both the components in the combination drug Cormelian-Digotab.

[Osteopathies and calcium absorption in chronic liver diseases]. / Osteopathien und Kalziumresorption bei chronischen Lebererkrankungen

Enteral calcium absorption was determined in 18 patients with non-obstructive liver disease (16 with liver cirrhosis, 2 with chronic hepatitis). There was no significant difference in comparison with healthy persons. Osteoporosis in patients with chronic liver disease probably is not due to impaired calcium absorption but to other complications of liver disease as immobility, muscle atrophy, chronic pancreatitis, alcoholism and malnutrition. Osteomalacia on the other hand, is a complication of long standing obstructive liver disease. In these cases vitamin D treatment is indicated.

[Radiochromatography studies on the metabolism of 3H-cyclophosphamide in sheep]. / Radiochromatographische Untersuchungen zur Frage der Metabolisierung von 3H-Cyclophosphamid beim Schaf

Radiochromatic analyses were made in serum and urine sample fractions as well as in extracts of different organs of a ewe and a ram up to 5 and 14 days, resp., after a single oral dose of 30 mg 3H-cyclophosphamide/kg bodyweight. In a polar and an unpolar system cyclophosphamide (CPM) and up to 7 more hydrophilic and up to 5 more lipophilic metabolites could be characterized by their typical Rf-values. The following results were obtained: 1. At the maximum (1 h p.a.) CPM only showed 25 percent of the total serum concentration and a very short half-life (t 1/2) in the fall of concentration of about 1 h. It was to be analysed up to 48 h. The intensive metabolism was confirmed by a low renal excretion of about 1 percent of the dose. The lipophilic metabolites showed very low concentrations in serum except of 4-keto-CPM, which was analysed over a limited time with higher concentrations but a short half-life; 3 and 8 percent, resp., of dose were excreted in form of this metabolite with urine. 2. 1 or 2, resp., more hydrophilic metabolites with alkylating activity are the chief breakdown products of CPM in sheep. Their part of the total serum concentration falls from 50 percent at the maximum to 25 percent after 24 h. 40 percent of the oral dose were eliminated with urine in form of these metabolites. NH-mustard was found in very low concentration in serum and urine. The course of concentration of these alkylating substances (t 1/2 2 h) corresponds very well with the concentration of the total alkylating activity (NBP-test). 3 mainly hydrophilic metabolites were analysed in all serum and urine samples. 3. More than 90 percent of the residual concentrations found in the organs and tissues after killing the animals were due to alkylating reactions with biologically active metabolites. The analysed more lipophilic breakdown products in the extracts of organs seem to be metabolized to inactive, more hydrophilic substances. CPM was found in smallest concentrations (mug/kg) only in lungs and thymus of the ewe and in kidneys and muscle of the ram. The alkylating main metabolite was questionably analysed only in liver and lung of the ewe. The alkylating reactions reach their maximum at about 2 h p.a. and may be terminated by 48 h p.a.