A series of studies were carried out using mice in an
ischemic hind limb model of PAD. As early as three days after
inducing ischemia, sodium nitrite was able to promote blood
flow into the damaged tissue with no effects observed in the
undamaged, normal limb. In contrast, a single acute injection
of sodium nitrite, such as those currently being used for
cyanide poisoning, congestive heart failure and stroke, had no
effect on angiogenesis. Importantly, the sodium nitrite is
effective when administered five days after the induction of
ischemia. This demonstrates that the compound’s mechanism of
action is to promote recovery as opposed to preventing injury.
This supports the idea that TV1001 will have similar efficacy
in patients with pre-existing PAD. From this work, it can be
demonstrated that:
- Chronic low dose sodium
nitrite therapy quickly restores
ischemic tissue blood flow, angiogenesis and arteriogenesis;
- Sodium nitrite therapy preferentially increases blood
flow
in ischemic tissue;
- Sodium nitrite therapy increases vascular density of
ischemic tissue and increases endothelial cell
proliferation;
- Delayed sodium nitrite therapy is effective in
promoting
recovery from pre-existing ischemia.
Importantly,
in all these studies no off target tissue or adverse effects
of treatment were observed. The figure at the right
illustrates the biological effects of continuous inorganic
nitrite therapy in an experimental model of chronic hind-limb
ischemia, which is a surrogate for experimental PAD. Dr. Kevil
found that daily nitrite therapy robustly increased blood
vessel density in ischemic tissues compared to control
treatments. Likewise, inorganic nitrite therapy had a profound
affect on preventing tissue necrosis in a model of diabetic
mice with chronic hind-limb ischemia.
