Biology Reference
In-Depth Information
6 Combinatorial Therapies for the Future
PAD including IC is often caused by underlying arterial atherosclerosis, and is a
complex disease resulting from multiple molecular abnormalities. Thus, targeting a
single defect by highly specific drugs may be less effective than using more
promiscuous or “dirty” drugs in treating such complex diseases (Frantz
2005
).
Cilostazol may be an example of this latter category of drug because it has multiple
actions including inhibition of PDE3 (which targets platelets, VSMCs, and endo-
thelium), as well as increasing adenosine, prostaglandin, and NO concentrations.
Another advantage of multitargeted therapy is the possibility that potential unde-
sired side effects may be reduced through the interaction of different signaling
pathways. For example, in the case of cilostazol, increased adenosine accumulation
may reduce the positive cardiac inotropic and chronotropic effects caused by PDE3
inhibition (Liu et al.
2001
; Wang et al.
2001
).
A multitargeted approach can also be achieved through treatment of completely
different disease components. An on-going clinical trial is evaluating the effects of
combining cilostazol with
L
-carnitine (Clinicaltrials.gov) on walking distance in
patients with IC. Because cilostazol and
L
-carnitine may modify different aspects of
the disease, a combined therapy may have added benefits. Several studies have
investigated the effects of statins on walking distance and exercise performance
in IC patients. These studies reported either an improvement in walking distance
(Mohler et al.
2003a
; Mondillo et al.
2003
), or no effect (Bregar et al.
2009
). Statins
are unlikely to have a direct effect on platelet and vascular functions, but the
improvement in lipid profile by statins may reduce the progression of atherosclero-
sis, thus alleviating the symptoms of IC. Since cilostazol and statins target different
cellular mechanisms, it is possible that a combination therapy may provide added
benefit. Indeed, two studies provide support for such a combination: one demon-
strated that cilostazol and atorvastatin protect the ischemic heart in a synergistic
fashion (Manickavasagam et al.
2007
), and the other demonstrated that a combina-
tion of cilostazol and probucol, which lowers cholesterol by a different mechanism
from statins, was more effective in preventing atherosclerotic lesion formation than
the administration of each drug alone (Yoshikawa et al.
2008
).
7 Summary
Intermittent claudication is most commonly caused by atherosclerotic arteries in the
leg limiting the patient's ability to walk and exercise and severely reducing quality
of life. PDE3 is highly expressed in the cardiovascular system and inhibitors of
this enzyme have a plethora of effects that are beneficial for treatment of IC,
including the inhibition of platelet activation, relaxation of VSMCs, inhibition of
VSMC proliferation, and the modulation of lipid profiles. One of these inhibitors,
cilostazol, is approved for this indication as it significantly increases walking
