Ciclopirox

Introduction

Ciclopirox is a hydroxylated pyridone, a unique substance in our topical treatment armamentarium. It first came to market in Europe and has been in use for a number of years (1). Worldwide it is or has been available as a spray, vaginal cream, powder, solution, cream, lotion, gel, and nail lacquer. The latter four are available in the United States at the time of this article. Ciclopirox gel differs from other formulations. It contains ciclopirox as a free acid, as opposed to an olamine salt. Superficial fungal infections and seborrheic dermatitis are two of the most common disorders seen in dermatology and indeed in medicine in general; ciclopirox is active against both, and literally may be used head to foot.

Mechanism

Ciclopirox differs structurally from other available anti-fungals and works differently. It has a unique and complex mode of action which mainly affects iron dependent enzyme systems (e.g. cytochromes, catalase, peroxidase) and cytoplasmic membranes (e.g. transport mechanisms) (2). It penetrates well into the stratum corneum (3). Ciclopirox may affect Malassezia furfur via damage to the cell membranes and disorganization of internal structures (2). Furthermore, with Candida albicans and Saccharomyces cerevisiae, ciclopirox may block the transmembrane transport of radiolabeled leucine (2). The other main classes of topical antifungals are the imidazoles, polyenes, allylamines, and benzylamines.

1) Imidazoles. Ciclopirox does not affect sterol biosynthesis, as do the azoles. The later are primarily fungistatic and work by inhibiting, ergosterol synthesis primarily affecting the cell wall.

2) Polyenes. These also work by binding to ergosterol, therefore disrupting the fungal cell membranes primarily in Candida.

3) Allylamines / benzylamines. These are closely related substances that suppress ergosterol at an earlier point than the azoles by inhibiting squalene epoxidase.

Spectrum of Activity

Antimicrobial Activity

Its uniformity of antimycotic activity distinguishes ciclopirox from most other topical antifungals (4). It has fungicidal and sporicidal activity in vitro (5). It can also be fungistatic at times (2). It is active against dermatophytes, yeasts and non-dermatophyte molds MIC range 0/9-3/9 g/ml (6,7). It has in vitro activity against many grain positive and gram negative bacteria including Proteus species, Psuedomonas species, Proprionibacteria aches, and Corynebacterium minutissimum (6).

Antiinflammatory Activity

Ciclopirox olamine may exhibit better antiinflammatory activity than 2.5% hydrocortisone (8). It may inhibit prostaglandin and leukotriene synthesis in human polymorphonuclear cells (2).

Clinical Uses

Seborrheic Dermatitis

About 3-4% of the population has or has had seborrheic dermatitis. Sebum-rich areas promote growth of lipophilic yeast like Pityrosporum ovale and Malassezia. It is effective against seborrheic dermatitis of the face and the scalp (9). It has been used in a shampoo form outside of the USA. Although there are no good studies to prove this, ciclopirox shampoo could be used empirically to decrease the chance of relapse and reinfection after tinea capitis is treated orally, as has been done empirically by clinicians with ketoconazole shampoo.

Tinea Versicolor

Clinical and mycologic cure rates have been recorded as high as 77% after two weeks of treatment (11).

Tinea Corporis/Cruris

At the end of 28 days with twice a day treatment, 2/3 of patients were clinically and mycologically cured (4).

Candidosis

Cutaneous candidosis was 83% clinically cured and 82% to 90% mycologically cured in one study (12). Vaginal candidosis was treated as an inserted cream, which cleared the condition 72% in one study (13) and as high as 91% in another (12).

Tinea Pedis

The drug is active against the common mycological causes of tinea pedis, Trichophyton rubrum and Trichophyton mentagrophytes. It also has antibacterial and anti-inflammatory properties that make it especially helpful in inflammatory conditions such as inflamed tinea pedis. One may experience mild transient burning after application. Ciclopirox powder may be used for drying as well as for its antimicrobial effect.

Onychomycosis

Lacquer is applied nightly to toenails. It has been shown to penetrate the nail plate. Cure is less than 10% (17). Other studies have been done with different formulations with varying results (15,16). Theoretically, especially in the lacquer form, it may be used to decrease relapse and reinfection of onychomycosis (18,19).

Safety

Ciclopirox olamine is pregnancy Category B (5). Safety and efficacy are unproven in lactating women (5). Ciclopirox olamine 1% cream is not associated with delayed hypersensitivity type contact sensitization, contact sensitizers, phototoxicity, or photo contact sensitization (2).

Discussion

The pedal complex (foot and nails) often acts as the reservoir for fungus to spread elsewhere. The author feels strongly that when seeing tinea on the body other than on the scalp, the pedal complex needs to be examined.

Some of the drawbacks of ciclopirox:

1) occasional contact burning

2) twice-a-day application

An ideal topical agent is broad spectrum, efficacious in low concentration, keratinophilic, and lipophilic, with a convenient dosing schedule, fungicidal activity, a reservoir effect in the stratum corneum, high mycologic and clinical cure rates, a lack of microbial resistance, low relapse rate, low incidence of adverse effects, and low cost (19). Cosmetic acceptability is another important criterion.

Conclusion

Ciclopirox olamine in its various forms is safe and effective. It appears to fulfill the criteria mentioned above as well as any other product on the market.

References

(1.) Dittmar W, Lohan G. HOE 296, a New Antifungal compound with a broad antimicrobial spectrum. Laboratory Results. Arzneim--Forsch Drug Res 1973; 23:670-676.

(2.) Gupta AK. Ciclopirox: An Overview. Intern J Dermatol 40:1-7, 2001.

(3.) Ceschin-Roques CG, Hanel H, Pruja-Bougaret SM, et al. Ciclopirox olamine cream 1%: In vitro and in vivo Penetration into the Stratum corneum. Skin Pharmacology 1991; 4:95-99.

(4.) Bogaert H, Cordero C, Ollague W, Sayin RC, et al. Multicentre Double-Blind Clinical Trials of Ciclopirox Olamine Cream 1% in the Treatment of Tinea Corporis and Tinea Cruris. J Int Med Res 1986; 14:210-216.

(5.) Loprox Cream package insert, 2002.

(6.) Gupta A. The Spectrum of Utility of Ciclopirox for the Treatment of Superficial Fungal &. Bacterial infection. Ann Dermatol Venereol 2002; 129:IS607-IS842.

(7.) Gupta A. Antifungal Susceptibility Testing of Dermatophytes, Yeasts and Non-Dermatophyte to Ciclopirox and other Antifungal agents. Ann Dermatol Venereol 2001; 129:IS607IS84201.

(8.) Rosen T, Schell BJ, Orengo I. Anti-inflammatory Activity of Antifungal Preparations. Internat J Dermatol 1997; 36:788-792.

(9.) Dupuy R, Maurette C, Amoric JC, et al. Randomized placebo-controlled, double-blind study on clinical efficacy of ciclopirox olamine 1% cream in facial seborrheic dermatitis. BR J Dermatol 2001; 144:1033-1036.

(10.) Wu YC, Chuan Mt, Lu YC. Efficacy of ciclopirox 1% cream in onychomycosis and tinea pedis. Mycoses 1991; 34:93-95.

(11.) Cailen SI, Frost P, Jacobson C. Treatment of Tinea Versicolor with a new antifungal agent, Ciclopirox Olamine Cream 1%. Clin Therapeutics 1985; 7:574-583.

(12.) Bagatell, FK, Bogaert, H, Cullen SL, et al. Evaluation of a New Antifungal Cream, Ciclopirox Olamine 1% in the Treatment of Cutaneous Candidosis. Clin Therapeutics 1985; 8:41-48.

(13.) Quciorz JL and Cymbalista NB. Estudo clinico com ciclopirox creme vaginal na candidiase vulvovaginal. Revista Brasileira Clinica e Terapuetica 1980; 37:479-483.

(14.) Peil HG. Offene Studie zur Wirksam Keit and vertragilich Keit cicloprox olamine bei vulvovaginaler candidose. Arzeimittel--Forshung 1981; 31: 1366-1372.

(15.) Jue SG. Dawson GW, Brogden RN. Ciclopirox Olamine 1% cream: A Preliminary Review of its antimicrobial activity and Therapeutic Use. Drugs 1985; 330-341.

(16.) Quadipur SA, Horn G, Hoehler T. Zur Lokalvirksamkeit von cicloproxolamin bei Naglemy Kosen. Arzneimittel--Forsch 1981; 31:1369-1372.

(17.) Penlac lacquer package insert, 2002.

(18.) Gupta AK, Daniel CR. Factors that may affect the response of onychomycosis to oral antifungal therapy. Australasian J Dermatol 1998; 59:222-224.

(19). Gupta AK, Daniel CR. Onychomycosis: Strategies to reduce treatment failure and recurrence. Curtis 1998; 62:189-101.

ADDRESS TO CORRESPONDENCE:

C. Ralph Daniel, MD

971 Lakeland Dr #659

Jackson, MS 39216

USA

F. EMILY BELL, MD, C. RALPH DANIEL, MD, MELISSA P. DANIEL, MCS

DEPARTMENT OF DERMATOLOGY, UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, JACKSON, MS

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