Cilostazol holds promise for treating lymphedema

Early research suggests that the FDA approved drug “Pletal” (cilostazol) may also have the potential to help treat lymphedema.

Cilostazol (sold under the brand name “Pletal”) is drug that inhibits platelet aggregation and increases peripheral vasodilation.  It is approved in the U.S. for the treatment of muscle pain during walking (intermittent claudication) in patients with peripheral artery disease.  Cilostazol is not yet approved by Health Canada.  Could this drug be useful for treating lymphedema as well?

Complex (Combined) Decongestive Therapy is currently the gold standard treatment for managing the symptoms of lymphedema.There is currently no cure for lymphedema, nor are there any medications available to help manage the symptoms, namely the chronic and progressive swelling and hardening of affected tissues. Unfortunately, there is also a dearth of promising drug candidates. This is not surprising since the underlying cause of the condition is damage, removal or malformation of lymph nodes and related lymphatic vessels. These anatomical structures are vital to maintain the appropriate circulation of lymph fluid, and there are no known medications that can help promote the regeneration of these tissues.

Would we expect cilostazol to help treat lymphedema?

At first blush, not really.  Cilostazol is an effective treatment for intermittent claudication because this condition arises from a narrowing or blockage of peripheral arteries in the legs, and cilostazol presumably counteracts these effects by promoting a widening (vasodilation) of arteries and a reduction in blood clotting through decreased platelet aggregation.  The cause of lymphedema is unrelated to that of intermittent claudication, but symptoms of lymphedema can be exacerbated by an increase in overall fluid load in the affected area, such as would result from vascular issues. So perhaps we could imagine cilostazol to provide some modest indirect benefit, but cilostazol would not be expected to act directly on the root cause of lymphedema.

Is there any precedent for treating lymphedema with cilostazol?

I have seen one report of clinicians testing cilostazol on a single patient with severe lymphedema caused by filariasis (a parasite infection) with some apparent success, but these results are entirely anecdotal [ref1], and so no conclusions can be drawn.

What does the latest research say?

A new rigorous study published this year investigated the effects of cilostazol in experimental mouse models of lymphedema, and directly on human lymphatic endothelial cells (the cells that line the walls of lymphatic vessels) [ref2].  The results are surprising. The authors of the study report that cilostazol had a positive effect on reducing mouse lympedema by improving lymphatic function directly – by promoting the development of new lymphatic vessels. Similarly, they found that cilostazol promoted the growth of human lymphatic endothelial cells in the laboratory, suggesting that it may have similar actions in humans. This evidence indicates that cilostazol may in fact have direct actions on damaged lymphatic pathways, an exciting possibility. The authors conclude:

“These results suggest that cilostazol would be a promising agent for the treatment of lymphedema.”

Conclusions

Unfortunately, the data so far is insufficient to support the use of cilostazol for treating lymphedema. The necessary human clinical studies have not been performed, and any potential benefit needs to be weighed against the known side effects of this drug. Much work still needs to be done.

But it is undeniable that cilostazol does show promise. Both indirect and direct mechanisms of action have been proposed, and early data is supportive.  We should also not underestimate the importance of the fact that cilostazol is already an FDA approved drug. It is much easier and less expensive for an existing drug to be approved for a new indication (or used “off-label” for a new indication) than it is for an entirely new compound to be approved for use. For these reasons, cilostazol appears to be a promising pharmaceutical candidate for treating lymphedema.

A variety of other pharmaceutical compounds and dietary supplements are also being investigated including selenium and Ubenimex. Ubenemix, a cancer drug that is currently used in Japan, may be the most promising drug to date for treating the symptoms of lymphedema. A clinical trial is currently underway.

References

1. Masuzawa M., Hara H., et al. Severe lymphorrhea and lymphedema caused by filariasis: the efficacy of oral treatment with cilostazol. Jpn J Dermatol. 2001;111:179-83.
2. Kimura T., Hamazaki T.S., et al. Cilostazol improves lymphatic function by inducing proliferation and stabilization of lymphatic endothelial cells. J Dermatol Sci. 2014 Jan 21. [Epub ahead of print].