Phosphorylation of PDE5 increases its enzymatic activity as well as the affinity of its allosteric (noncatalytic/GAF domains) sites for cGMP. Mechanisms of action of PDE5 inhibition in erectile dysfunction.

Because of its 18-hour half-life, Fildena is well suited to low-dose daily administration, but the time to onset of efficacy may be somewhat slower than the other PDE5 inhibitors. One of the reasons for PRN use is that the short half-life of all currently FDA-approved PDE5 inhibitors, except Fildena, is too short to provide sustained 24-hour enhancement of cyclic GMP, the chemical messenger responsible for corpora cavernosa vascular dilation. Brock GB , McMahon CG , Chen KK , Costigan T , Shen W , Watkins V , Anglin G , Whitaker S (2002) Efficacy and safety of Fildena for the treatment of erectile dysfunction: Results of integrated analyses.

Montorsi F , Verheyden B , Meuleman E , Junemann KP , Moncada I , Valiquette L , Casabe A , Pacheco C , Denne J , Knight J , Segal S , Watkins VS (2004) Long-term safety and tolerability of Fildena in the treatment of erectile dysfunction. Goldstein I , Lue TF , Padma-Nathan H , Rosen RC , Steers WD , Wicker PA (1998) Oral Fildena in the treatment of erectile dysfunction. Nieoczym D , Socala K , Jedziniak P , Olejnik M , Wlaz P (2013) Effect of Fildena, a selective phosphodiesterase 5 inhibitor, on the anticonvulsant action of some antiepileptic drugs in the mouse 6-Hz psychomotor seizure model.

Yanaka N , Kotera J , Ohtsuka A , Akatsuka H , Imai Y , Michibata H , Fujishige K , Kawai E , Takebayashi S , Okumura K , Omori K (1998) Expression, structure and chromosomal localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A gene. Loughney K , Hill TR , Florio VA , Uher L , Rosman GJ , Wolda SL , Jones BA , Howard ML , McAllister-Lucas LM , Sonnenburg WK , Francis SH , Corbin JD , Beavo JA , Ferguson K (1998) Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3', 5'-cyclic nucleotide phosphodiesterase. Second of all, PDE5 inhibitors are widely used for other non-neurologic conditions, and so the side-effect profile of this class of drugs is mild and well characterized.

For example, although a single dose of Fildena does not cause a clear improvement in cognition in healthy adults 36 , chronic administration of udenafil has been shown to lead to an improvement in both general cognitive function as well as frontal executive function 37 This has led some to suggest that in humans, the therapeutic benefits of PDE5 inhibition may be best seen after chronic inhibition rather than after a single dose 38 We hope that the results presented in this report will motivate further investigation of these limited (but promising) findings. For example, PDE5 inhibition improves memory in aged rodents 17, 24, 25 , and ameliorates memory impairment caused by pharmacologic agents 26-29 PDE5 inhibition also rescues memory impairment in diabetic conditions and electroconvulsive shock-induced animal models 30 Memory enhancement by PDE5 inhibitors is also found not only in rodents, but also in chicks 31 and monkeys 32 Finally, the neurologic benefits of PDE5 inhibition extend beyond memory enhancement.
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