Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction.
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.
Kim
Noel N
NN
Department of Urology, Boston University School of Medicine, Massachusetts 02118, USA. nnkim@bu.edu
Dhir
Vinita
V
Azadzoi
Kazem M
KM
Traish
Abdulmaged M
AM
Flaherty
Elizabeth
E
Goldstein
Irwin
I
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
C412823:BMS 193884; D065128:Endothelin Receptor Antagonists; D010080:Oxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides