Review of phosphodiesterases in the urogenital system: new directions for therapeutic intervention.
BACKGROUND
With the success of Phosphodiesterase (PDE) type 5 inhibitors (i.e., sildenafil, tadalafil, vardenafil) in the treatment of erectile dysfunction (ED), PDEs are considered attractive targets for drug intervention in the urogenital tract.


OBJECTIVE
To review the role of PDEs, which exist as a superfamily of enzymes comprising 11 distinct families, in the urogenital system, focusing on anatomical locations, functions and dysfunctions, potential disorders that could be treated, and any promising new selective PDE inhibitors under development.


METHODS
Included are (i) abstracts from 2001, 2002, and 2003; (ii) a MEDLINE search from 1996 through December 2003; and (iii) a pipeline search for therapeutics in development. Data from animal experiments are presented when there is a paucity of human data, but with the caveat that the distribution of PDE isozymes in a specific tissue can vary between species.


RESULTS
PDE mRNA and protein have been localized throughout the normal human urogenital tract. Double-blind, placebo-controlled studies suggest possible new clinical roles for sildenafil, including prophylaxis to preserve penile smooth muscle and erectile function after radical prostatectomy, and treatment of ejaculatory delay secondary to serotonergic reuptake inhibitor antidepressant therapy. Open-label studies suggest a potential clinical role for: vinpocetine (a PDE1 inhibitor) in the treatment of incontinence and low-compliance bladder; and sildenafil in the treatment of premature ejaculation, prostate-related lower urinary tract symptoms, and in women who have had unsuccessful in vitro fertilization. Several new orally administered PDE5 inhibitors are in early clinical development for the treatment of ED. Potential indications for PDE inhibitors that are suggested by preclinical data include Peyronie's disease, ureteral colic, male and female birth control, and prevention of preterm labor.


CONCLUSIONS
Drug selectivity and differential PDE tissue distribution allow for potential targeted intervention for numerous disorders related to the urogenital tract.
Montorsi
Francesco
F
Department of Urology, Università Vita Salute San Raffaele, Milan, Italy. francesco.montorsi@hsr.it
Corbin
Jackie
J
Phillips
Stephen
S
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004542:Ejaculation / Q000187:drug effects; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines; D012333:RNA, Messenger / Q000235:genetics; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D000068581:Tadalafil; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014566:Urogenital System / Q000187:drug effects* / Q000378:metabolism*; D000069058:Vardenafil Dihydrochloride
D002243:Carbolines; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human