Assessing The Potential Wound Healing Abilities Of Ciclopirox

   Ciclopirox has been well documented as a broad-spectrum antifungal agent with additional antibacterial and antiinflammatory properties.1-3 However, in recent studies reported by Linden, et al., ciclopirox has also demonstrated potent angiogenic activity, which suggests that the drug may have certain wound-healing properties.4 If this is borne out by larger studies in the future, ciclopirox may possess a significant advantage in treating fungal infections in high-risk patients.    These high-risk patients may include those who suffer from diabetes mellitus and peripheral vascular disease, as well as those with autoimmune disorders such as AIDS or HIV infection. Other high-risk patients include the elderly, particularly those in nursing homes, those with poor hygiene, substance abusers and those on long-term therapies with antibiotics, corticosteroids, chemotherapy or radiation.5    Given that this population exhibits a greater tendency for serious lower-extremity complications from foot infections and chronic ulcers, clinicians may want to re-evaluate treating fungal infections (both simple and complex) with ciclopirox in light of these new findings regarding the drug’s potential for wound healing.    In earlier studies addressing the cutaneous effects of a 1% ciclopirox solution on rabbit skin, Linden, et al., observed occasionally transient reddening of healthy skin and persistent reddening of experimentally wounded skin. This observation prompted their investigation of the capability of ciclopirox to induce angiogenesis.4    Therapeutic angiogenesis, whether it occurs via recombinant angiogenic growth factors or by gene therapy, has become an important treatment modality during the past few years.6-8 The hypoxia-inducible factor (HIF)-1 is a physiological regulator of vascular endothelial growth factor (VEGF) expression. The Linden studies explored the possibility that ciclopirox activates endogenous HIF-1 target genes — including VEGF — in in vitro cell culture and in vivo organ models. These studies uncovered a potent angiogenic activity of ciclopirox.4     (In ongoing human clinical trials, researchers have applied VEGF gene therapy in the treatment of critical limb ischemia and myocardial ischemia. In experimental investigations, researchers have looked at VEGF therapy for treating gastric and duodenal ulcerations, as well as in dermal ulcers, cultured skin substitutes and skin excision wounds.9-14)

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.    • Does ciclopirox induce angiogenesis in the chicken chorioallantoic membrane (CAM)? Based on the investigators’ observations that ciclopirox induced VEGF expression in cell culture, they analyzed its angiogenic capacity in an in vivo model of angiogenesis. At day nine of development, researchers overlaid the chicken CAM with inert polymer discs containing various concentrations of ciclopirox or solvent only. After two days of incubation, researchers observed no signs of angiogenesis with the solvent control discs.    In contrast, polymer discs containing 50 µM ciclopirox consistently induced CAM angiogenesis, as evidenced by numerous, newly formed, radially arranged vessels. A total of 10 CAMs treated with 50 µM ciclopirox showed similar angiogenesis and all seven control CAMs lacked any signs of angiogenesis. Investigators noted that the 1% ciclopirox concentration in dermal cream equals a molar concentration of 37 µM, which is close to the concentration found to be angiogenic in these CAM assays.

What One Can Draw From The Linden Studies

   The Linden studies demonstrate that ciclopirox functionally activates HIF-1 and induces VEGF transcription as well as angiogenesis. The authors observed that wound healing in the skin may be complicated by microbial invasion, inflammation and ischemia, leading to ulceration. As ciclopirox is lipophilic, antimicrobiotic, antiinflammatory, angiogenic and does not affect healthy tissue, it might be beneficial for the topical treatment of skin wound tissue.4    The implications of potential wound-healing properties in the antifungal ciclopirox are especially noteworthy for podiatrists who are all too familiar with the various simple and complex infections that can lead to chronic wounds (see “Understanding The Connection Between Common Infections And Chronic Wounds” below). These infections result from a combination of factors including disease, injury, neuropathy, vascular impairment and inefficient wound healing. Severe complications leading to wounds in the feet and lower leg occur as a result of chronic infections, pathogenic resistance to drugs and lack of treatment.21,22

Understanding The Connection Between Common Infections And Chronic Wounds

   The incidence of severe and chronic wounds among patients with diabetes has risen dramatically in the United States. Type 1 and 2 diabetes afflict an estimated 17 million people and up to 15 percent of those patients will undergo lower-extremity amputation.23,24 Public health officials estimate 800,000 new cases of diabetes are diagnosed annually. Diabetes patients will undergo lower-extremity amputations at an increasing rate, with approximately 80 percent of those amputations primarily caused by chronic foot ulcers.23-25    Similar to patients with diabetes, those with peripheral vascular disease and those who are immunocompromised frequently suffer lower extremity complications because of fungal and bacterial infections.    Three of the most common clinical presentations podiatrists see are tinea pedis, onychomycosis and paronychia. Dermatophytes are commonly the underlying basis for tinea pedis and other fungal and bacterial infections.26 Although nail infections are preceded by a dermatophyte, the symptomatic patient may have a more complex infection, complicated by pyogenic bacteria or other fungal species.27    Currently, ciclopirox is indicated for topical treatment of a broad range of dermal fungal infections including: tinea pedis, tinea cruris and tinea corporis due to Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum and Microsporum canis; candidiasis due to Candida albicans; and tinea versicolor due to Malassezia furfur.1,28 Ciclopirox also has in vitro activity against many Gram-positive and Gram-negative bacteria including Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Staphylococcus and Streptococcus species.2 There is also evidence that ciclopirox may exhibit better antiinflammatory activity than 2.5% hydrocortisone.3

In Conclusion

   Timely and satisfactory management of any fungal or bacterial infection in the high-risk patient is the key to preventing the development of more complex, difficult-to-treat conditions that can lead to chronic, non-healing wounds, lower-extremity amputations or even death. Given its antifungal, antibacterial and antiinflammatory properties, ciclopirox has an established record of efficacy in the treatment of infections caused by dermatophytes and yeasts.    The additional discovery of the potential wound healing properties of ciclopirox by Linden, et al., strengthens the rationale for using ciclopirox not only to treat lower-extremity infections, but to help prevent the unfortunate cascade of events one often sees among high-risk patients with lower extremity ulcers. Dr. Dockery (shown here) is a Fellow of the American Society of Podiatric Dermatology and the American College of Foot and Ankle Surgeons. He is the Founder and Director of Scientific Affairs of the Northwest Podiatric Foundation Education and Research, USA in Seattle. Dr. Steinberg (pictured) is a faculty member of the Department of Surgery at the Georgetown University School of Medicine in Washington, D.C.
 

References:

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