title: Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction.
abstract: Endothelins have been postulated to be important regulators of penile erectile function. The endothelin-A receptor antagonist BMS-193884 was evaluated as a treatment for mild-to-moderate erectile dysfunction in an animal model and in human volunteer subjects. In laboratory studies, organ bath preparations of rabbit and human penile cavernosal tissue strips were incubated with BMS-193884 and exposed to increasing concentrations of endothelins. In rabbit tissue, 1 microM BMS-193884 significantly inhibited contraction to ET-1, ET-2, and ET-3 by 34.5%, 42.9%, and 100%, respectively. In human tissue, 1 microM BMS-193884 inhibited contraction to ET-2 by 44.4%. In rabbit tissue strips contracted with 20 nM of ET-1 or ET-2, BMS-1 93884 caused dose-dependent relaxation with EC50 values of 107.2 +/- 32.3 nM and 1.7 +/- 0.5 nM, respectively. In anesthetized male rabbits, intravenous administration of BMS-193884 (systemic plasma concentration approximately 50 and 100 nM) increased the duration of pelvic nerve-stimulated penile erection. To further assess the safety and efficacy of BMS-193884, 53 men diagnosed with mild-to-moderate erectile dysfunction were administered oral placebo or 100 mg BMS-193884 in a double-blind fashion. Evaluations were based on 1) erectile function testing during 2 in-office visits and 2) diary and questionnaire data of 4 intercourse attempts over 2-4 weeks of home use. Although the drug was well tolerated, BMS-193884 did not significantly improve erectile function during office visits or home use when compared to placebo. Thus, BMS-193884 facilitated cavernosal smooth muscle relaxation ex vivo and prolonged penile tumescence in vivo. In contrast, a pilot clinical study failed to show enhancement of erectile response in men with mild-to-moderate erectile dysfunction. The disparity between the laboratory and clinical studies suggests that there may be differences between species with regard to the role of endothelin in erectile function.
authors.affiliation: Department of Urology, Boston University School of Medicine, Massachusetts 02118, USA. nnkim@bu.edu
authors.forename: Noel N
authors.initials: NN
authors.lastname: Kim
authors.forename: Vinita
authors.initials: V
authors.lastname: Dhir
authors.forename: Kazem M
authors.initials: KM
authors.lastname: Azadzoi
authors.forename: Abdulmaged M
authors.initials: AM
authors.lastname: Traish
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Flaherty
authors.forename: Irwin
authors.initials: I
authors.lastname: Goldstein
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage*; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000502:physiology; D010865:Pilot Projects; D011817:Rabbits; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C412823:BMS 193884; D065128:Endothelin Receptor Antagonists; D010080:Oxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides