Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.
Saphenous ablation using 808-nm laser by variable retraction speed, combined with saphenofemoral interruption, leads to sufficient vein wall injury to assure venous occlusion. Full thickness thermal injury or perforation is infrequent. Optimal results can be obtained in veins <10 mm in diameter.
Although a large number of immunohistochemical markers that can facilitate the differential diagnosis between epithelioid pleural mesothelioma and lung adenocarcinoma involving the pleura have proven to be valuable, no single antibody has demonstrated absolute sensitivity and/or specificity in making this distinction. Using immunohistochemical analysis with h-caldesmon, a specific marker for smooth muscle tumors, we examined 70 cases of epithelial mesotheliomas and 70 cases of lung adenocarcinomas. In addition, immunohistochemistry for muscle markers, such as desmin, alpha-smooth-muscle actin, muscle-specific actin, myoglobin, myogenin, myosin, and MyoD-1, was performed on all mesothelioma cases. Reactivity for h-caldesmon was obtained in 68 (97%) of the 70 epithelial mesotheliomas, but in none of the adenocarcinoma cases. All mesothelioma cases were found to be negative for the other muscle markers examined. We conclude that h-caldesmon is a highly sensitive and specific marker and suggest its inclusion in the immunohistochemical panel for the differential diagnosis of epithelioid mesothelioma versus lung adenocarcinoma.
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