Biology Reference
In-Depth Information
a progressive modulation of the disease state. Thus far, no studies have investigated
the effect of cilostazol on muscle metabolism. While cilostazol can relieve symp-
toms associated with IC, it does not reverse or cure the disease and it has not been
associated with any improvement in mortality in the IC population (Beebe et al.
1999
; Hiatt et al.
2008
).
4.2 Pentoxifylline
Pentoxifylline was the first drug specifically approved for increasing walking
distance in IC patients and is a weak, nonselective PDE inhibitor (Table
1
).
Mega-analyses of clinical trials found a marginal but statistical significant improve-
ment in pain-free and maximal walking distance (Girolami et al.
1999
; Moher et al.
2000
). Little is known about the mechanisms involved, but some studies have
suggested that pentoxifylline and its metabolites improve the flow properties of
blood by decreasing its viscosity (Ambrus et al.
1984
; Berman et al.
1994
; Ehrly
1978
; Ferraresi et al.
1983
; Ohshima and Sato
1981
). This can theoretically increase
blood flow to the affected microcirculation and enhance tissue oxygenation in
patients with chronic PAD. However, in a more recent study, no such modification
of blood rheologic properties was found in patients treated with pentoxifylline
(Dawson et al.
2002
). Regardless of the mechanism of action, inhibition of PDEs
by pentoxifylline, which occurs with low potency and specificity, is unlikely to
provide a significant contribution to pentoxifylline's effects.
4.3 Other PDE3 Inhibitors Entering the IC Arena
Encouraged by the success of cilostazol, companies especially in Japan are devel-
oping new and more potent PDE3 inhibitors for IC. Nissan Chemical and Taisho of
Japan have evaluated NT-702 (NM-702, parogrelil, Fig.
4
) for the treatment of IC.
NT-702 inhibits PDE3 very potently. It also inhibits PDE5 and platelet TXA
2
synthase (Table
1
). In a rat femoral artery ligation model, NT-702 increased
walking distance (Ishiwata et al.
2007
). In a Phase II study, treatment with
NT-702 for 24 weeks was associated with improvement in walking distance
compared with placebo (Brass et al.
2006
). The improvement was very similar to
that observed with the use of cilostazol. As with cilostazol, there was no significant
bleeding risk associated with the use of NT-702 in this study (Brass et al.
2006
).
Another Japanese company, Kowa Pharmaceuticals, has developed a PDE3
inhibitor K-134 (OPC-33509, Fig.
3
) which is under Phase II trial for IC. This
compound is a derivative of cilostazol and its inhibitory potency for PDE3 is similar
to that of cilostazol (Koga et al.
1998
; Sudo et al.
2000
) (Table
1
). It is unknown
whether K-134 has any inhibitory effect on adenosine uptake, but it seems to
possess additional PDE-unrelated activity as one study found that it inhibited the
