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Non-responders To PDE-5 Inhibitors: What Is Next?
Alvaro Morales - Kingston, Canada
Until the early 1980s there was very faint promise for the introduction of non-hormonal pharmacological treatments for erectile dysfunction (ED). Innovative reports in 1982 and 1983 (Virag and Brindley) change this dismal outlook. Their pioneering studies open the doors to truly understand the mechanisms of cavernosal smooth-muscle cell relaxation and the first specific, effective, albeit somewhat invasive, pharmacological approaches for the treatment of ED: intracavernosal injection of vaso-active drugs. The second revolution was marked by the introduction of sildenafil in 1988. Other compounds in the same family (tadalafil and vardenafil) made their appearance a few years later. This is not the place to discuss the merits and drawbacks of these agents. Suffice to say that they are safe and effective but that their efficacy leaves much room for improvement.

Due to the cost of these drugs and the fierce competition among manufacturers, it is common practice to supply men complaining of ED with a few samples and, hopefully, pertinent instructions (not infrequently without additional investigations). For the 30-40% that return claiming lack of efficacy, what is next?

The obvious: a. review the mode of administration to ensure it is correctly done; b. consider increasing the dose (there is significant latitude on this); c. consider and alternative PDE-5; d. make sure that a hormonal abnormality has been ruled out. When all this has failed we might have to revert to older, less palatable alternatives (injectables, vacuum constriction, prosthetics).

Predictions in medical progress are notoriously inaccurate: A systematic approach to foresee the future in this field would be easier by considering the therapeutic taxonomies of erectile dysfunction:

  • For Central Initiators: new delivery forms for apomorphine and melanotans.
  • For Peripheral Initiators: not a clear break-through
  • Central Conditioners: improved delivery forms for testosterone, perhaps other androgens (DHEA) or, more exciting, Selective Androgen Receptor Modulators (SARMS). Perhaps better (shorter acting) SSRIs will come to light.
  • Peripheral Conditioners: There always will be room for improvement of current PDE-5Is: less side effects, improved efficacy, prompter and longer action. Would an intracavernosal or intra-urethral PDE-5I be develop for those failing the oral administration? Better therapies for Peyronie's disease and premature ejaculation most likely will enter the armamentarium
The Holy Grail of therapy for ED, of course will be an acceptable cure. There is a ray of hope with gene therapy and perhaps stem cells. But I dream. Back to reality: the changes will not be dramatic within the first decade of this new century.