Biology Reference
In-Depth Information
counteract the degradation of this cyclic nucleotide by binding to the catalytic site
of PDE5 and blocking access by the substrate, cGMP. Hereby, enhancement of NO-
initiated relaxations of cavernous erectile tissue can be obtained (Kalsi and Kell
2004
). The efficacy of the PDE5 inhibitors has been evaluated in myriad clinical
trials involving thousands of male subjects with different causes of impotence:
psychogenic, with no identifiable organic cause, as well as patients with diabetes
and histories of spinal cord injury and pelvic surgery (radical prostatectomy). In all
trials, men receiving a PDE5 inhibitor more often reported erections sufficient for
sexual intercourse than did those who received placebo (Fink et al.
2002
; Stief et al.
2004
; Eardly and Cartledge
2002
). However, the action of PDE5 inhibitors requires
some degree of neuronal input to the corpus cavernosum as well as the intact
cavernous endothelial structures. The most common side effects that are reported
following the use of PDE5 inhibitors include headache (18%), flushing (11%),
dyspepsia (7%), nasal congestion (5%) and are related to the presence of PDE5 in
tissues other than the corpus cavernosum (K
uthe et al.
2000
). With regard to the
cardiovascular safety, it has been shown that PDE5 inhibitors do not affect the
ability of patients with coronary artery disease to maintain a level of exercise
similar to that required for sexual activity and that patients do not experience
significant side effects from the use of these medications. Studies to evaluate the
interactions between PDE5 inhibitors and organic nitrates demonstrated only modest
synergistic effects on the nitrate-induced reduction in mean systolic and diastolic
blood pressure (Mazzu et al.
2001
; Thadani and Mazzu
2002
; Emmick et al.
2002
).
Nevertheless, due to their mechanisms of action, that is the enhancement of cGMP
accumulation due to increased synthesis and decreased cGMP breakdown, the use
of PDE5 inhibitors is contraindicated in ED patients taking nitrates.
€
3 Treating ED by Combining PDE5 Inhibitors
with Other Drugs
Since several classes of drugs with different modes of pharmacological action
demonstrate efficacy in treating ED, this creates the potential for therapeutic
combination of some of these drugs. Currently, only the combined application of
sildenafil and alprostadil (PGE1) has been studied comprehensively despite other
possibilities. In a placebo-controlled cross-over study, 40 patients with ED, who
had experienced unsatisfactory erections with both 50 and 100 mg of sildenafil,
were treated for 4 weeks with intracavernous injections of PGE1 (20
m
g) (two per
week given in the clinic and then provided with either placebo or 50 mg sildenafil
for use at home). In a subset of 26 subjects (65%), the IIEF-Erectile Function
domain score, the main outcome measure, was found to be considerably higher with
the combined PGE1/sildenafil (50 mg) treatment than with PGE1/placebo or
sildenafil (50 or 100 mg) alone (Gutierrez et al.
2005
). There is also evidence that
the combination of an orally effective PDE5 inhibitor, such as sildenafil, tadalafil,
