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.

CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone-to-renin ratio, an indicator of sodium retention, in healthy volunteers.

Aims: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.

Methods: This randomized, double-blind, placebo-controlled study was conducted in two parts.

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.

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.

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.