Biology Reference
In-Depth Information
mechanism resulting in elevation of cGMP by cilostazol is via inhibition of PDE5.
Inhibition of PDE5 expressed in insect cells (IC
50
of 4.4
m
M) has been reported
for cilostazol (Sudo et al.
2000
). However, we did not observe an inhibitory effect
of cilostazol on recombinant human PDE5 expressed in mammalian cells (unpub-
lished observation). If indeed cilostazol elevates cGMP in cells involved in athero-
sclerosis, either via NO release or PDE5 inhibition, this effect could potentially
contribute to its therapeutic efficacy, as cGMP has very broad biological effects
(Kemp-Harper and Schmidt
2009
; Tsai and Kass
2009
), with some of these effects,
including vasodilation, antiplatelet and endothelium protection, being similar to
those of cAMP. Furthermore, cross-talk between cAMP and cGMP signaling path-
ways may also be involved in modulating these cellular functions (Zaccolo and
Movsesian
2007
). Section
5
discusses the attempts to evaluate potential benefits of
cGMP elevation for the treatment of IC.
4.1.4 Minimal Bleeding Risk with Cilostazol
Thrombosis and hemostasis share many similar molecular events. Thus, antiplatelet
therapies are usually associated with increased risk of bleeding. Cilostazol seems to
be an exception. Clinical studies have demonstrated no increase in bleeding risk in
patients treated with cilostazol, and no added risk if co-administered with other
antiplatelet agents, such as aspirin and clopidogrel (see review by Goto
2005
). The
lack of effect on bleeding is important as an increase in such events is associated
with major ischemic complications in PAD patients (van Hattum et al.
2009
). There
is no obvious explanation for this unique property of cilostazol. Further studies are
warranted to understand this unique feature of cilostazol so the knowledge can be
applied in future drug development.
4.1.5 Class Effect of PDE3 Inhibitor on the Heart
The development of PDE3 inhibitors has been hindered by the observation that
some inhibitors including milrinone worsen mortality in heart failure patients [more
details in Movsesian and Kukreja (
2011
)]. Because of this, patients with heart
failure with any severity were excluded in clinical trials for cilostazol, and its use
has been contraindicated in patients with heart failure. All cause and cardiovascular
mortality were compared in IC (excluding those with heart failure) patients taking
cilostazol or placebo in a phase IV study (Hiatt et al.
2008
). No indication of
increased mortality was associated with the use of cilostazol in these patients. The
finding that cilostazol elevates extracellular adenosine has been suggested to
alleviate any potentially toxic effects arising from excessive cAMP elevation
caused by PDE3 inhibition in the heart (Wang et al.
2001
). This can be explained
by the predominance of adenosine A
1
receptors, which inhibits AC via the stimula-
tion of Gi, in cardiac myocytes (Kambayashi and Liu
2007
).
