¹Division 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).

¹Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Centre (Sunnybrook site) and the University of Toronto, Toronto, Canada
²Mediprobe Research, London, Ontario, Canada
³University of Western Ontario, London, Ontario, Canada

ABSTRACT

Seborrheic dermatitis is a common inflammatory skin disease, affecting between 1% and 3% of immunocompetent adults. While its cause is unknown, a number of predisposing factors have been reported, including the implications of Malassezia yeasts. Various treatment options are available, such as ciclopirox shampoo, which combines anti-Malassezia activity with an anti-inflammatory action. This agent has been shown to be an effective and safe treatment for seborrheic dermatitis of the scalp.
Key Words: ciclopirox, seborrheic dermatitis

Clinically, seborrheic dermatitis presents as red, flaking, slightly greasy-looking patches, which are located primarily on the scalp, nasolabial folds, ears, eyebrows and chest. The degree of flaking and erythema can vary markedly between patients.¹ The exact cause of seborrheic dermatitis is not known, however, a number of predisposing factors have been reported. Such endogenous host factors include nutritional,² environmental,^3,4 and immunological⁵ factors, as well as the presence of Malassezia yeast.⁶

While there is some controversy with regard to the relationship between seborrheic dermatitis of the scalp and dandruff, it has been argued that dandruff is a mild form of seborrheic dermatitis.^7,8 Furthermore, the relationship between Malassezia yeasts and the effective treatment of seborrheic dermatitis with antifungal agents helps to support the claim that these yeasts are the primary cause of seborrheic dermatitis.⁹

Due to the fact that there is an increased prevalence of seborrheic dermatitis in HIV-positive and AIDS patients,^10,11 it is thought that the disease may be caused by an abnormal immune response to Malassezia. However, it is unclear exactly what this immune response might be. Many individuals without seborrheic dermatitis have antibodies to Malassezia yeasts and while some authors have found that the level of IgG antibodies to the yeasts is increased in patients with seborrheic dermatitis,^5,12 others¹ have found no difference in the number of antibodies produced by patients with seborrheic dermatitis and controls.

It has recently been suggested that the reaction by seborrheic dermatitis patients to Malassezia is best characterized as an irritant response¹³ involving an inflammatory reaction and that reduction of Malassezia yeast on the skin reduces the clinical signs of seborrheic dermatitis.

Treating Seborrheic Dermatitis

The two main classes of treatment for seborrheic dermatitis are topical corticosteroids and antifungal agents. Corticosteroids reduce inflammation, thus resulting in clinical improvement of seborrheic dermatitis. However, prolonged treatment with topical steroids may result in adverse effects on the skin, such as atrophy, telangiectasia, or perioral dermatitis¹⁴ and, especially in the case of higher potency, fluorinated topical steroids, to dysfunction of the adrenal cortex.¹⁵ Because of the adverse effects associated with topical steroids, there has been a shift in treatment strategies for seborrheic dermatitis with an increased interest in antifungal agents. Several antifungal agents have been found to be effective in the treatment of seborrheic dermatitis. These include non-specific agents (e.g., zinc pyrithione, selenium sulfide, propylene glycol, lithium succinate), hydroxypyridones (e.g., ciclopirox), azoles (e.g., bifonazole, fluconazole, itraconazole, ketoconazole, miconazole, metronidazole), and the allylamines (e.g., terbinafine).

Ciclopirox

Ciclopirox is the ethanolamine salt of 6-cyclohexyl-I-hydroxy-4- methyl-2(IH)-pyridone.¹⁶ The empirical formula of ciclopirox is C12H17NO2, with a molecular weight of 207.27.17 Ciclopirox shampoo 1% is a colorless, translucent solution,¹⁷ which has been used in the treatment of seborrheic dermatitis. In addition to its effect on Malassezia yeasts, ciclopirox has been shown to decrease inflammation. Rosen et al.¹⁸ found that the anti-inflammatory activity of ciclopirox was greater than that of several azole agents or hydrocortisone. Ciclopirox appears to exert its anti-inflammatory effect via several pathways, including the inhibition of 5-lipoxygenase and cyclo-oxygenase.^19,20

Clinical Trials of Ciclopirox

Vardy et al.²¹ conducted a double-blind, randomized, placebocontrolled clinical study of ciclopirox olamine 1% shampoo to determine its effectiveness in the treatment of scalp seborrheic dermatitis. One hundred and two patients were randomly selected to apply either ciclopirox olamine 1% shampoo or the vehicle shampoo to the scalp for 5 minutes, twice per week for 4 weeks. Signs and symptoms of erythema, scaling, and pruritus were assessed at the end of the study, which revealed that 93% of the ciclopirox shampoo-treated patients had significantly improved or cleared compared to 41% in the placebo group (P<0.00001). Another double-blind, randomized, vehicle-controlled study was conducted to assess the efficacy of 1% ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp.²² Subjects were randomly selected to 5ml (10ml for shoulder-length hair or longer) of either 1% ciclopirox or vehicle shampoo twice per week for 4 weeks. Grading of erythema, scaling, and the overall status of seborrheic dermatitis was performed at week 4, using a 6-point rating scale (0=none, 1=slight, 2=mild, 3=moderate, 4=pronounced, and 5=severe). Effective treatment was defined as a score of 0 (or 1 if baseline score was ≥3) for the combined rating of global status, erythema, and scaling. It was reported that 26% of the ciclopirox-treated patients were effectively treated compared to 13% of the vehicle group (P=0.0001).²²

Adverse Effects

Ciclopirox shampoo 1% was used twice a week in 626 patients.¹⁷ Increased itching was the most frequent adverse event found in 1% of the subject population. Furthermore, application reactions, such as burning, erythema, and itching also occurred in 1% of the subjects.¹⁷

Dosage and Administration

After wetting hair, apply approximately 1 teaspoon (5ml) of ciclopirox shampoo 1% to the scalp.¹⁷ If the patient has long hair, it is recommended to use up to 2 teaspoons (10ml). Lather and leave on for 3 minutes before rinsing. Treatment should be repeated twiceper week for 4 weeks, with a minimum of 3 days between each application.¹⁷

Conclusion

Evidence suggests that an abnormal or inflammatory immune system reaction to Malassezia yeasts may be the cause of seborrheic dermatitis. An available treatment for this disease is ciclopirox shampoo, which is an antifungal agent that also has antibacterial and anti-inflammatory properties. The proven efficacy and safety of ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp makes it an important addition to the treatment options available.

References

1. Parry ME, Sharpe GR. Seborrhoeic dermatitis is not caused by an altered immune response to Malassezia yeast. Br J Dermatol 139(2):254-63 (1998 Aug).
2. Brenner S, Horwitz C. Possible nutrient mediators in psoriasis and seborrheic dermatitis. I. Prevalence, etiology, symptomatology, histological and biochemical features. World Rev Nutr Diet 55:153- 64 (1988).
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4. Wahlberg JE, Liden C. Is the skin affected by work at visual display terminals? Dermatol Clin 6(1):81-5 (1988 Jan).
5. Bergbrant IM, Johansson S, Robbins D, Scheynius A, Faergemann J, Soderstrom T. An immunological study in patients with seborrhoeic dermatitis. Clin Exp Dermatol 16(5):331-8 (1991 Sep).
6. Faergemann J. Seborrhoeic dermatitis and Pityrosporum orbiculare: treatment of seborrhoeic dermatitis of the scalp with miconazolehydrocortisone (Daktacort), miconazole and hydrocortisone. Br J Dermatol 114(6):695-700 (1986 Jun).
7. Bulmer AC, Bulmer GS. The antifungal action of dandruff shampoos. Mycopathologia 147(2):63-5 (1999).
8. McGrath J, Murphy GM. The control of seborrhoeic dermatitis and dandruff by antipityrosporal drugs. Drugs 41(2):178-84 (1991 Feb).
9. Shuster S. The aetiology of dandruff and the mode of action of therapeutic agents. Br J Dermatol 111(2):235-42 (1984 Aug).
10. Berger RS, Stoner MF, Hobbs ER, Hayes TJ, Boswell RN. Cutaneous manifestations of early human immunodeficiency virus exposure. J Am Acad Dermatol 19(2 Pt 1):298-303 (1988 Aug).
11. Marino CT, McDonald E, Romano JF. Seborrheic dermatitis in acquired immunodeficiency syndrome. Cutis 48(3):217-8 (1991 Sep).
12. Midgley G, Hay RJ. Serological responses to Pityrosporum (Malassezia) in seborrhoeic dermatitis demonstrated by ELISA and western blotting. Bull Soc Fr Mycol Med 17:267-76 (1988).
13. Faergemann J, Bergbrant IM, Dohse M, Scott A, Westgate G. Seborrhoeic dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory cells and mediators in the skin by immunohistochemistry. Br J Dermatol 144(3):549-56 (2001 Mar).
14. Guin JD. Complications of topical hydrocortisone. J Am Acad Dermatol 4(4):417-22 (1981 Apr).
15. Morman MR. Possible side effects of topical steroids. Am Fam Physician 23(2):171-4 (1981 Feb).
16. 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).
17. Loprox® Shampoo (ciclopirox) 1% Package Insert. MEDICIS Pharmaceutical Corp., Scottsdale, AZ (2003 Feb).
18. Rosen T, Schell BJ, Orengo I. Anti-inflammatory activity of antifungal preparation. Int J Dermatol 36(10):788-92 (1997 Oct).
19. 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).
20. Lassus A, Nolting KS, Savopoulos C. Comparison of ciclopirox olamine 1% cream with ciclopirox 1%-hydrocortisone acetate 1% cream in the treatment of inflamed superficial mycoses. Clin Ther 10(5):594-9 (1988).
21. Vardy DA, Zvulunov A, Tchetov T, Biton A, Rosenman D. A doubleblind, placebo-controlled trial of a ciclopirox olamine 1% shampoo for the treatment of scalp seborrheic dermatitis. J Dermatol Treat 11:73-7 (2000).
22. Lebwohl M. A multicenter, randomized, double-blind, vehiclecontrolled study of the efficacy and safety of 1% ciclopirox shampoo in the treatment of seborrheic dermatitis of the scalp. Int J Dermatol. In Press (2004).