Assessing The Potential Wound Healing Abilities Of Ciclopirox

By Gary L. Dockery, DPM, FACFAS

What Studies Reveal About Ciclopirox

   Let’s take a closer look at the ciclopirox studies by Linden, et al.4    • Does ciclopirox induce angiogenesis in a mouse skin model? In this study, investigators confirmed their earlier observation of reddening of the skin of rabbits where a 1% solution of ciclopirox had been applied. They created punch-through ear holes of 2 mm in diameter in mice and treated them daily with a cream containing 1% ciclopirox on one ear and an identical, ciclopirox-free cream on the other ear. The ciclopirox caused reddening of the wound margin, which was never observed on the healthy skin of the same ear. Four of 10 animals showed similar effects and none had more pronounced reddening on the placebo-treated wound margin than the ciclopirox-treated wound margin.    • Do iron chelators ciclopirox, deferoxamine (DFX) and 2,2’ dipyridyl (DP) have an effect on HIF-1-dependent proliferation/viability? The researchers also studied the effects of ciclopirox on cell proliferation and HIF-1 induction, and compared ciclopirox with two other iron chelators, the hydrophilic DFX and the lipophilic DP, both well known for their HIF-1 inducing capabilities.15-17 They stably transfected Chinese hamster ovary cells with a luciferase reporter gene, which allows for the rapid determination of HIF-1 activity.18,19 All three iron chelators induced HIF-1 dependent reporter gene expression by 25- to 40-fold under normoxic conditions.    Whereas ciclopirox was maximally active at 16 µM, the optimal concentrations of DFX and DP were approximately 10-fold higher at 150 µM in this cell line. Exposure to hypoxia did not result in an additional increase of reporter gene activity at these concentrations. All three iron chelators similarly reduced cell proliferation/viability by 30 to 40 percent at concentrations that were below those for optimally inducing reporter gene activity. Researchers observed no further decrease of proliferation/viability within the range of iron chelator concentrations that induced reporter gene activity.    • Does ciclopirox induce VEGF gene expression? As ciclopirox is known for its antiinflammatory properties, the investigators suspected this reddening represented enhanced angiogenesis during wound healing rather than inflammation. Therefore, they were interested in whether ciclopirox can cause induction of VEGF.4    The authors subsequently investigated whether ciclopirox also induces endogenous HIF-1 target genes, including VEGF. Consistent with the reporter gene studies, the same range of ciclopirox concentrations strongly induced the HIF-1a protein in normoxic HepG2 hepatoma cells.    • What about estimating the iron affinity of ciclopirox? DFX has a very high affinity for Fe3+ with a stability constant of 10-31.20 Apart from its higher lipophilicity, allowing better penetration of the cytoplasmic membrane, an unusually high iron affinity of ciclopirox might contribute to the efficiency with which ciclopirox can induce HIF-1. Investigators estimated the iron affinity of ciclopirox semi-quantitatively by comparing it with the iron affinity of DFX. The data from this study suggest ciclopirox binds iron with an even higher affinity than DFX.    • Is there a lack of HIF-1 target gene induction by ciclopirox in the isolated, perfused rat kidney? It has been reported previously that systemically administered DFX can induce ubiquitous HIF-1 stability and kidney-specific erythropoietin expression in mice.16 Regarding a potential topical application of ciclopirox for therapeutic angiogenesis, it is conceivable that a fraction of the applied ciclopirox might reach the bloodstream. To test the effects of ciclopirox delivered by the bloodstream, researchers perfused isolated rat kidneys for three hours under normoxic conditions with increasing concentrations of ciclopirox. However, ciclopirox did not induce the mRNA levels of the HIF-1 target genes VEGF, Glut-1 or aldolase.

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