Ciclopirox (Loprox^®) Gel for Superficial Fungal Infections

A. K. Gupta, MD, PhD, FRCPC^1,2 and R. Bluhm, BSc (Hons), BA, MA<sup>2

1</sup>Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Centre (Sunnybrook site) and the University of Toronto, Toronto, Canada
²Mediprobe Laboratories Inc., London, Canada

ABSTRACT

Ciclopirox (Loprox^®) is a broad-spectrum antifungal medication that also has antibacterial and anti-inflammatory properties. Its main mode of action is thought to be its high affinity for trivalent cations, which inhibit essential co-factors in enzymes. Clinical trials have shown that ciclopirox gel is a successful treatment for seborrheic dermatitis of the scalp as well as for tinea pedis. Adverse effects are generally mild and include a skin-burning sensation, contact dermatitis, and pruritus. Ciclopirox is indicated in the US for the treatment of tinea pedis, tinea corporis, pityriasis versicolor, seborrheic dermatitis, and cutaneous candidiasis.
Key Words: ciclopirox, tinea, superficial fungal infection

Ciclopirox (Loprox^®, Medicis), a hydroxypyridone derivative, is the ethanolamine salt of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone.¹ Randomized controlled trials have demonstrated the efficacy and safety of ciclopirox in a number of indications in which the causative organism was a dermatophyte or a yeast.^2-4

Mechanism of Action

Unlike antifungals such as itraconazole and terbinafine, which affect sterol synthesis, ciclopirox is thought to act through the chelation of polyvalent metal cations, such as Fe3+ and Al3+. These cations inhibit many enzymes, including cytochromes, thus disrupting cellular activities such as mitochondrial electron transport processes and energy production.^1,5 Ciclopirox also appears to modify the plasma membrane of fungi,6 resulting in the disorganization of internal structures.⁷

Pharmacokinetics

Ciclopirox when applied to cadaverous skin has resulted in higher concentrations of the drug in the epidermis and dermis than the minimal inhibitory concentration (MIC) required for sensitive organisms.² Furthermore, in cadaverous skin, ciclopirox caused complete inhibition of T. mentagrophytes after both 4 and 24 hours of exposure.⁸

Loprox^® gel was applied for 14.5 days (15g/day) in a clinical study involving 16 men with moderate-to-severe tinea cruris. The mean (±SD) dose-normalized values of Cmax for total ciclopirox in serum increased from 100 (±42)ng/ml on day 1 to 238 (±144)ng/ml on day 15. Approximately 10% of the administered dose was excreted in the urine during the 10 hours after dosing on day 1.⁹

Antifungal, Antibacterial, and Anti-inflammatory Activity

Ciclopirox exhibits either fungistatic or fungicidal activity in vitro against a broad spectrum of fungal organisms, such as dermatophytes, yeasts, dimorphic fungi, eumycetes, and actinomycetes.³ In addition to its broad spectrum of action, ciclopirox also exerts antibacterial activity against many Gram-positive and Gram-negative bacteria.² Furthermore, the anti-inflammatory effects of ciclopirox have been demonstrated in human polymorphonuclear cells, where ciclopirox has inhibited the synthesis of prostaglandin and leukotriene.² Ciclopirox can also exhibit its anti-inflammatory effects by inhibiting the formation of 5-lipoxygenase and cyclo-oxygenase.^10,11

Clinical Trials

The efficacy of ciclopirox gel 0.77% in the treatment of seborrheic dermatitis of the scalp has been compared with its vehicle in a multicenter, randomized, double-blind study (n=178).12 The gel was applied twice daily for 28 days, with a final visit up to day 33. In the ciclopirox group, global evaluation scores were significantly better than those of the vehicle group at days 22 and 29, and at endpoint (p<0.01). The number of subjects with at least 75% improvement was significantly different from the vehicle after only 2 weeks of treatment up until the endpoint visit (p<0.01).¹²

In a multicenter, double-blind, clinical study, ciclopirox gel 0.77% has been shown to be more effective than its vehicle in the treatment of tinea pedis.13 A total of 374 subjects with interdigital tinea pedis were enrolled and they applied either ciclopirox 0.77% gel or the vehicle gel twice daily for 28 days, with a final visit up to day 50. At day 43, 2 weeks post-treatment, the pooled data revealed that 85% of ciclopirox subjects were mycologically cured (negative KOH and culture), compared to only 16% of vehicle subjects (p=0.05). At endpoint, 60% of the ciclopirox subjects achieved treatment success, defined as mycological cure with Ž75% clinical improvement, compared to 6% of the vehicle subjects (p=0.05).¹³

Adverse Effects

In clinical trials, 140 of 359 subjects (39%) treated with ciclopirox gel reported adverse experiences. The most frequent complaint was a skin-burning sensation upon application, which occurred in approximately 34% of seborrheic dermatitis patients and 7% of tinea pedis patients. Also, reports of contact dermatitis and pruritus occurred in 1-5% of the subjects. Other reactions that occurred in less than 1% included dry skin, acne, rash, alopecia, pain upon application, eye pain, and facial edema.⁹

Dosage and Administration

Ciclopirox gel should be gently massaged into the affected areas and surrounding skin twice per day, in the morning and evening, immediately after cleaning or washing the areas to be treated. A 4-week, twice daily application has been used in the treatment of interdigital tinea pedis, tinea corporis, and scalp seborrheic dermatitis with ciclopirox gel.⁹

Conclusion

Superficial fungal infections caused by dermatophytes and yeasts have been successfully and safely treated with ciclopirox. The gel formulation is beneficial in the treatment of fungal infections due to its antifungal, antibacterial, and anti-inflammatory properties.

References

1. Sakurai K, Sakaguchi T, Yamaguchi H, Iwata K. Mode of action of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone ethanolamine salt (Hoe 296). Chemotherapy 24(2):68-76 (1978).
2. Abrams BB, Hanel H, Hoehler T. Ciclopirox olamine: a hydroxypyridone antifungal agent. Clin Dermatol 9(4):471-7 (1991 Oct-Dec).
3. Gupta AK. Ciclopirox: an overview. Int J Dermatol 40(5):305-10 (2001 May).
4. Korting HC, Grundmann-Kollmann M. The hydroxypyridones: a class of antimycotics of its own. Mycoses 40(7-8):243-7 (1997 Nov).
5. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part I. J Am Acad Dermatol 30(5 Pt 1):677-98 (1994 May).
6. Gasparini G, Contini D, Torti A, Guidarelli C, Lasagni A, Caputo R. The effect of ciclopiroxolamine investigated by means of the freeze-fracture technique. Mykosen 29(11):539-44 (1986 Nov).
7. Del Palacio-Hernanz A, Guarro-Artigas J, Figueras-Salvat MJ, Esteban-Moreno J, Lopez-Gomez S. Changes in fungal ultrastructure after short-course ciclopiroxolamine therapy in pityriasis versicolor. Clin Exp Dermatol 15(2):95-100 (1990 Mar).
8. Kligman AM, McGinley KJ, Foglia A. An in vitro human skin model for assaying topical drugs against dermatophytic fungi. Acta Derm Venereol 67(3):243-8 (1987).
9. Loprox® Gel (ciclopirox) 0.77% Package insert. 2000. Phoenix, AZ, Hoechst Marion Roussel Deutschland GmbH.
10. Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol 43(4 Suppl):S57-69 (2000 Oct).
11. Hanel H, Smith-Kurtz E, Pastowsky S. [Therapy of seborrheic eczema with an antifungal agent with an antiphlogistic effect]. Mycoses 34 Suppl 1:91-3 (1991).
12. Aly R, Katz HI, Kempers SE, et al. Ciclopirox gel for seborrheic dermatitis of the scalp. Int J Dermatol 42 Suppl 1:19-22 (2003 Sep).
13. Aly R, Fisher G, Katz HI, et al. Ciclopirox gel in the treatment of patients with interdigital tinea pedis. Int J Dermatol 42 Suppl 1:29-35 (2003 Sep).

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