Biology Reference
In-Depth Information
or vardenafil, with testosterone replacement therapy might be effective in hypogo-
nadal patients with ED when testosterone alone fails (or vice versa). Greco et al.
(
2006
), by means of an extensive MEDLINE search (2003-2006), reviewed rele-
vant data from basic and clinical studies regarding the efficacy of combined
testosterone replacement and PDE5 inhibitor therapy. Their analysis revealed
that, due to the molecular mechanisms of action of androgen hormones and its
receptor in the regulation of PDE5 expression in the human corpus cavernosum,
PDE5 inhibitors might be ineffective in hypogonadal men with ED. Thus, the
efficacy of this class of drugs might be enhanced by concomitant testosterone
administration whenever necessary. They concluded that screening for hypogonad-
ism in all men with ED is necessary to identify men with severe or moderate
hypogonadism, those who may be refractory to PDE5 inhibitor treatment and
who may benefit from testosterone supplementation (Greco et al.
2006
). These
considerations may improve the clinical management of patients who are unre-
sponsive to treatments with PDE5-selective inhibitors. The combination of cen-
trally acting agents, such as the dopaminergic agonist apomorphine, with PDE5
inhibitors has also been considered to be an attractive approach because the
two therapies target different signaling mechanisms (Sommer and Engelmann
2004
). However, no prospective randomized clinical trials with adequate numbers
of patients have yet been conducted to provide a scientific rationale for this
combination strategy.
4 Upcoming PDE5 Inhibitors
4.1 Udenafil (DA-8159)
Udenafil is an oral active PDE5 inhibitor currently available in South Korea for the
treatment of ED. Phase II clinical data demonstrated that in men with mild-to-
severe ED, the drug produced a significant improvement in erectile function after
12 weeks of treatment. Udenafil has been reported as being well tolerated. In
a rat model, the effects of acute treatment with DA-8159 were investigated on
erectile dysfunction associated with hypercholesterolemia or diabetes. In the
animals, the administration of DA-8159 (0.3 or 1 mg/kg) induced a dose- and
frequency-dependent increase in intracavernous pressure (ICP). Chronic treatment
with DA-8159 (20 mg/kg/day) over 5 months restored the erectile responses
induced by electric stimulation, improved endothelial function as assessed by
recording thoracic aorta relaxation in vitro in response to the cumulative addition
of acetylcholine to the bathing medium, and also significantly decreased plasma
levels of endothelin and asymmetrical dimethyl arginine (ADMA), an endogenous
inhibitor of nitric oxide synthase (NOS) activity (Kang et al.
2005
). These results
provided a rationale for the potential use of DA-8159 for treating ED secondary to
hypercholesterolemia.
