Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity.

A series of new cortexolone-related derivatives has been synthesized and investigated for potential anti-androgenic activity. Among the steroids evaluated, 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04) was the most promising one. The compound displayed a strong local antiandrogenic activity in hamster's flank organ test, and it was also found to be effective in the rat after subcutaneous injection. When compared to other well known androgen antagonists, the rank order of topical anti-androgenic activity in that test was: cyproterone acetate (CAS 427-51-0) > or = CB-03-04 > finasteride (CAS 98319-26-7) > flutamide (CAS 13311-84-7). In addition, the steroid had selective antigonadotropic activity, when injected into parabiotic rats, and was about as active as progesterone. The activity of CB-03-04 was ascribed mainly to its ability to compete with the stimulating effects of testosterone and dihydrotestosterone and, concurrently, to inhibit the gonadotropins hypersecretion. This bimodal mechanism of action could be predictive for the clinical usefulness of the steroid in the treatment of prostate cancer and benign prostate hypertrophy.

Visualizing the vitreous body in the anterior chamber using 11-deoxycortisol after posterior capsule rupture in an animal model.

OBJECTIVE: To develop a new technique to visualize vitreous body prolapsed in the anterior chamber using 11-deoxycortisol. STUDY DESIGN: Experimental study. METHODS: An animal model of posterior capsule rupture was developed to investigate the usefulness of 11-deoxycortisol, a precursor of cortisol without steroid activity. After the intentional creation of posterior capsule rupture, the suspension of 11-deoxycortisol was injected into the anterior chamber of rabbit eyes. After gentle irrigation and aspiration, the vitreous body that had prolapsed into the anterior chamber was removed using an anterior vitrectomy cutter. To investigate the safety of 11-deoxycortisol, the biomicroscopic appearance, intraocular pressure (IOP), corneal endothelial count, and microstructure of the corneal endothelium were examined in the rabbits that received injections of 11-deoxycortisol in the anterior chamber. RESULTS: In our posterior capsule rupture model, the vitreous in the anterior chamber became clearly visible, with 11-deoxycortisol showing white particles entrapped on its surface. The injection of 11-deoxycortisol facilitated the complete removal of the vitreous body from the anterior chamber. In intact rabbit eyes, most of the injected 11-deoxycortisol had disappeared from the anterior chamber by 12 hours after injection. The injection of 11-deoxycortisol had no effect on IOP, corneal endothelial density, or the microstructure of the corneal endothelium. CONCLUSIONS: The injection of 11-deoxycortisol in the anterior chamber is useful in visualizing the vitreous body and has no significant side effects. This technique might reduce the intraoperative and postoperative complications of anterior vitrectomy after posterior capsule rupture.

Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.

The aim of this study was to investigate the antiandrogenic activity of a new monoester of cortexolone, cortexolone 17alpha-propionate (CAS 19608-29-8, CB-03-01). Although the compound displayed a strong local antiandrogenic activity in hamster's flank organ test, it did not exhibit antiandrogenic activity in rats after subcutaneous injection, nor did it affect gonadotropins hypersecretion when injected to parabiotic rats. As topical antiandrogen, the steroid resulted about 4 times more active than progesterone (CAS 57-83-0) and, when compared to known antiandrogen standards, it was about 3 times more potent than flutamide (CAS 13311-84-7), about 2 times more effective than finasteride (CAS 98319-26-7) and approximately as active as cyproterone acetate (CAS 427-51-0). Its pharmacological activity seemed to be primarily related to its ability to antagonistically compete at androgen receptor level; nevertheless its primary pharmacological target needs to be further investigated. Its topical activity, along with the apparent absence of systemic effects, anticipates this compound to have the potential of representing a novel and safe therapeutic approach for androgen-dependent skin disorders.

Be13, a human T-leukemia cell line highly sensitive to dexamethasone-induced cytolysis.

A unique human T-leukemia cell line highly sensitive to dexamethasone-induced lysis is described. The cell line designated Be13 is killed readily within 24 hr by 10(-9) M dexamethasone. No lysis is induced by nonglucocorticoid steroids. The lysis is mediated via specific cytoplasmic receptors and is efficiently blocked by the antagonist cortexolone. The inhibiting effect of actinomycin D and cycloheximide on the lytic process suggests the involvement of gene activation and destruction of the cells by an "autolytic protein." Kinetic studies imply that the lytic process is induced during a distinct phase of the cell cycle. Dexamethasone, however, does not cause an arrest in a distinct phase of the cell cycle. The Be13 cell is a unique human cell line killed directly by glucocorticoids, and it may serve as a suitable in vitro model for studying the lytic effect of glucocorticoids on the proliferating compartment of human leukemias.