In vitro binding of 16-methylated C18 and C19 steroid derivatives to the androgen receptor.

The binding of androgens and structurally related analogues to the androgen receptor was studied. The in vitro experiments were carried out with cytosol of castrated rat prostate, using [3H]R1881 (methyltrienolone) as radioligand. The binding parameters measured were Kd = 1.25 x 10(-10) M and Bmax = 111 fmol (mg protein)-1. Ligand specificity was confirmed by competition experiments with known androgen, oestrogen and progestogen ligands. The receptor binding of substituted steroids was studied. The RBAs (relative binding affinities) of our recently synthetized 16-alkyl steroids were low. The only exception was the 17 beta-hydroxy-16 beta-methylestr-4-en-3-one, which exhibited the remarkable RBA of 22.9%.

In vitro inhibitory effects of 16-methyl-substituted steroids on 5 alpha-reductase in rat and human prostates.

The inhibitory effects (IC50) of 16-methyl steroids on 5 alpha-reductase were studied. The in vitro experiments were carried out with homogenates of rat and human prostates. The investigated 16-methyl steroids were found to be weak inhibitors. In comparison with the known 5 alpha-reductase inhibitor 4-MA (17 beta-N, N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one), the relative IC50 values of the studied compounds are 4.7 times or more greater than 4-MA in human prostate and 23.5 times or more greater than 4-MA in rat prostate. The IC50 values increase in the sequence 16 alpha-, 16 beta- and 16,16-dimethyl derivatives. In human prostate homogenates IC50 varies between 0.6 and 120, while in rat it ranges from 1.6 to 1000 microM. This shows that the enzyme of the human prostate is more sensitive than that of the rat prostate to the methyl-substituted compounds.

[In vitro inhibitory effects of 16-methyl-substituted steroids on 5 alpha-reductase in rat and human prostates]. / 16-metil-szubsztituált szteroidok in vitro gátló hatása az 5 alpha-reduktáz aktivitására patkány- és emberi prosztatában.

The inhibitory effects (IC50) of 16-methyl steroids on 5 alpha-reductase were studied. The in vitro experiments were carried out with homogenates of rat and human prostates. The investigated 16-methyl steroids were found to be weak inhibitors. In comparison with the known 5 alpha-reductase inhibitor 4-MA, the relative IC50 values of the studied compounds are 4.7 times or more greater than 4-MA in human prostate and 23.5 times or more greater than 4-MA in rat prostate. The IC50 values increase in the sequence 16 alpha, 16-beta- and 16,16-dimethyl derivatives. In human prostate homogenates IC50 varies between 0.6 and 120, while in rat it ranges from 1.6 to 1000 microM. This shows that the enzyme of the human prostate is more sensitive than that of the rat prostate to the methyl-substituted compounds. Acylation of the 17-hydroxy group significantly increases the IC50 values (cf. 8,11: from 4.8 to 23.5 and from 0.52 to 0.62;9,12: from 26.0 to 170.0 and from 0.58 to 1.4;15,17: from 3.9 to 35.0; and 16,18: from 5.6 to 58.0 microM). Whereas lack of a 19-CH3 group improves the inhibitory effect in the 16-unsubstituted compounds (1,19;14,22), the reverse hold in the 16-methylated derivatives (9,20; 10,21; 15,23; 16,24).

Steroids 35: synthesis of 16,16-dimethyl-17 beta-hydroxysteroids.

The reaction of 16-methylene-17-ketosteroids (Ia), (Ic) and (Ie) with methyl magnesium iodide yields 16-methylene-17 alpha-methyl-17 beta-hydroxysteroids (IIa), (IIb) and (IId). These are subjected to the addition of hypobromous acid and the subsequent anionotropic rearrangement to convert them into 16 alpha-methyl-16 beta-bromomethyl-17-ketosteroids (Va), (Vb) and (Vd). These were reduced with LiA1H4 to obtain 16,16-dimethyl-17 beta-hydroxysteroids (VIa), (VIb) and (VId). Compounds (VIIa) and (VIIe) were selectively deacetylated yielding (VIIb) and (VIId); these were then oxidized and hydrolyzed to convert them into (VIf) and (VIg).

[Significance of plasma-protein paracoagulation test in the diagnosis of thromboembolic the disease]. / Die Bedeutung des Plasma-Protamin-Parakoagulationstests zur Erkennung thromboembolischer Erkrankungen

Fibrinogen degradation products were examined by plasma protamine paracoagulation test in 235 cases. The test was positive in about 60% of thrombosis of deep veins, pulmonary embolism, and myocardial infarction cases examined. The test was also positive in 23,4% of women taking oral contraceptives who were free of complaints and symptoms. Because of its easy applicability the test is recommended for screening.

[Clinical studies on kinking of the neck-vessels]. / Klinische Beobachtungen bei Kinking der Halsgefässe

A survey is given of the clinical course of 273 patients hospitalised at one of the departments for internal diseases of a general hospital because of cerebral lesions of different pattern and origin. By means of angiography carried out on 60 patients kinking of the extracranial arteries was proved in 18 cases. Ten patients were submitted to reconstructive vascular surgery: 7 of them are symptom-free. Signs, symptoms and possibilities of surgical or conservative treatment are discussed.