Structural and clinical characterization of CYP11B2 inhibition by dexfadrostat phosphate.

Aldosterone synthase (CYP11B2) represents a promising drug target because its genetic dysregulation is causally associated with cardiovascular disease, its autonomous activity leads to primary aldosteronism, and its deficiency leads to salt wasting syndromes. The serendipitous discovery that the dextro-rotatory stereoisomer of the racemic aromatase (CYP19A1) inhibitor CGS16949A mediates potent CYP11B2 inhibition led to the purification and clinical development of dexfadrostat phosphate. To characterize the pharmacophore of dexfadrostat phosphate, structure-based enzyme coordination with CYP11B2, CYP11B1 and CYP19A1 was combined with steroid turnover upon in vitro and clinical treatment. Dexfadrostat, but not its 5S-enantiomer (5S-fadrozole), precisely coordinates with the catalytic heme moiety in the space of the CYP11B2 substrate binding pocket forming a tight and stable complex. Conversely, neither rigid nor flexible docking led to a plausible coordination geometry for dexfadrostat in steroid 11ß-hydroxylase (CYP11B1 - orthologue to CYP11B2) or in CYP19A1. The inhibitory preference of dexfadrostat was confirmed in vitro using an adrenal cortex-derived cell line. Dexfadrostat phosphate treatment of healthy subjects in the context of a clinical phase 1 study led to a dose-dependent decrease in urinary aldosterone secretion, accompanied by an increase in urinary corticosterone and deoxycorticosterone metabolites. Increased urinary corticosterone metabolites are indicative of CYP11B2 (18-oxidase) inhibition with clinical features reminiscent of patients with inborn corticosterone methyloxidase type II deficiency. An off-target effect on CYP19A1 was not observed as indicated by no clinical changes in testosterone and estradiol levels. Therefore, dexfadrostat exhibits the ideal structural features for binding and catalytic inhibition of CYP11B2 but not CYP11B1. Clinically, treatment with dexfadrostat phosphate leads to suppression of aldosterone levels by inhibiting predominantly one or both final CYP11B2-mediated reactions.

Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy.

CONTEXT: We describe the clinical investigation of the first generation aldosterone synthase inhibitor, LCI699, in patients with essential, uncontrolled, resistant, or secondary hypertension. LCI699 competitively reduced blood pressure at lower doses yet counterintuitive effects were observed at higher doses. OBJECTIVE AND METHOD: An extensive endocrine biomarker analysis was performed to better understand the pharmacological mechanism of the drug. RESULTS: The interference of LCI699 in the renin-angiotensin-aldosterone system occurred with limited target selectivity, as a dose-dependent compensatory stimulation of the hypothalamic-pituitary-adrenal feedback axis was discovered. Thus, LCI699 affected two endocrine feedback loops that converged at a single point, inhibiting the 11ß-hydroxylase reaction in the adrenal gland, leading to supraphysiological levels of 11-deoxycortiscosterone. The accumulation of this potent mineralocorticoid may explain the blunted blood pressure response to LCI699. CONCLUSION: Future aldosterone synthase inhibitors may improve their target selectivity by sparing the 11ß-hydroxylase reaction and preferentially inhibiting one of the two other enzymatic reactions mediated by aldosterone synthase.

Holmium laser enucleation of the prostate: morbidity in a series of 206 patients.

OBJECTIVES: To review the complications associated with 206 holmium laser enucleation of the prostate (HoLEP) procedures. HoLEP is a minimally invasive surgical treatment for benign prostatic hyperplasia. METHODS: A retrospective review was conducted of HoLEPs performed from April 1, 1999 to October 1, 2001. Patients with previous diagnoses of prostate carcinoma or who had undergone HoLEP after admission for unrelated problems were excluded. Demographic, intraoperative, and immediate postoperative data were recorded to determine the incidence of complications. Patients were also contacted by telephone or mailed surveys for documentation of longer term complications. RESULTS: The mean age and procedure time was 70.5 years (range 45 to 91) and 133.6 minutes (range 25 to 473), respectively. The mean specimen weight was 68.2 g (range 3 to 376), with 20 (9.7%) of 206 patients diagnosed with adenocarcinoma. The mean hospital stay was 1.1 days, with 86.9% of patients discharged after an overnight stay without a catheter. Two patients required postoperative transfusions (1.0%). No deaths, major complications (myocardial infarction or pulmonary embolism), or transurethral resection syndrome episodes occurred. Intraoperative complications consisted of three capsular perforations (1.5%), one bladder neck false passage (0.5%), four incomplete morcellations (1.9%), and four minor bladder mucosal morcellation injuries (1.9%). Of 206 patients, 173 (84.0%) provided follow-up data (mean 19.0 +/- 8.4 months), allowing documentation of longer term complications, including five clot retention episodes (2.4%), five urethral strictures (2.4%), eight bladder neck contractures (3.9%), and 16 patients requiring re-catheterization (7.8%). CONCLUSIONS: HoLEP can be performed with minimal complication risks and blood loss. Patients can expect an overnight hospital stay and discharge without an indwelling catheter.

Holmium laser enucleation of prostate (HoLEP): the Methodist Hospital experience with greater than 75 gram enucleations.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) effectively removes obstructive prostate tissue in minimally invasive fashion. We present our large enucleation outcomes (greater than 75 gm retrieved). We examined post-procedural prostate specific antigen (PSA) and transrectal ultrasound (TRUS) volume changes to assess tissue removal completeness. MATERIALS AND METHODS: We retrospectively reviewed HoLEPs performed from April 1, 1999 through September 30, 2002 to identify all enucleations greater than 75 gm. Demographic, laboratory, operative and pathological data were obtained. Patients were surveyed to document longer term complications. RESULTS: The cohort of 108 patients had a mean age and specimen weight of 71.5 years (range 53 to 90) and 120.6 gm (range 75.3 to 376), respectively. Average procedural time and hospital stay were 166.8 minutes (range 75 to 473) and 1.2 days (range 0 to 4), respectively. No deaths or episodes of transurethral resection syndrome occurred. Postoperative complications included transfusion in 2 cases, a clot retention episode in 3, capsular perforation in 2, morcellator blade malfunction in 4, minor bladder mucosal injury in 1 and bladder neck contracture in 1. American Urological Association symptom scores reassessed in 53 patients without chronic retention an average +/- SD of 10.6 +/- 7.1 months postoperatively showed a mean decrease from 20.3 +/- 6.4 to 4.7 +/- 3.8. PSA in 48 patients a mean of 5.0 +/- 4.1 months postoperatively had decreased an average of 91.7%. In 10 patients TRUS data revealed a mean post-procedural volume decrease of 85.9%. CONCLUSIONS: HoLEP can be performed on extremely large prostates with minimal risk or need for secondary interventions. Most patients are discharged home after an overnight stay. Postoperative decreases in PSA and TRUS volumes support the completeness of enucleation that can be achieved.