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Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the United States.

Gupta AK.

Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site), and the University of Toronto.

BACKGROUND: Recently a novel topical nail lacquer, ciclopirox solution 8%, has been approved for the treatment of onychomycosis. OBJECTIVE: This was undertaken to determine the most cost-effective treatment for the treatment of dermatophyte onychomycosis of the toes in the United States in 2000. METHODS: The nature of the problem was defined. The drug comparators were ciclopirox nail lacquer, terbinafine, itraconazole (pulse), itraconazole (continuous), fluconazole, and griseofulvin. A decision analytic model that reflected the manner in which pedal tinea unguium is managed was produced. Studies that have evaluated the efficacy of the nail lacquer and the oral antifungal agents for this indication were identified. Appropriate studies were used in a meta-analysis to determine the mycologic and clinical response rates when the drug comparators are used for the treatment for toe dermatophyte onychomycosis. For each drug comparator a cost of regimen analysis was carried out. This is the sum of the drug acquisition cost, the cost of medical management, and the cost of managing adverse effects. Next, the expected cost of management was calculated, disease free days were determined, and a sensitivity analysis was conducted. RESULTS: For each comparator the meta-analytic average mycologic cure (MC) rate and clinical response (CR) rates were: ciclopirox nail lacquer (MC: 52.6 +/- 4.2%, CR: 52.4 +/- 9.0%), griseofulvin (MC: 41.1 +/- 20.4%, CR: 33.7 +/- 14.1%), itraconazole (continuous) (MC: 66.3 +/- 4.2%, CR: 70.3 +/- 4.2%), itraconazole (pulse) (MC: 70.8 +/- 5.7%, CR: 73.6 +/- 4.6%), terbinafine (MC: 77.2 +/- 4.0%, CR: 75.3 +/- 2.9%), and fluconazole (MC: 65.6 +/- 7.1%, CR: 66.5 +/- 11.7%). The cost of regimen for the drug comparators was: ciclopirox nail lacquer $325.2, griseofulvin $1413.1, itraconazole (continuous) $1410.2, itraconazole (pulse) $811.7, terbinafine $890.1, and fluconazole $966.8. The cost/mycologic cure rate and expected cost/expected symptom free day were, ciclopirox nail lacquer ($618.2, 1.69), griseofulvin ($3438.2, 5.3), itraconazole (continuous) ($2126.9, 3.52), itraconazole (pulse) ($1146.4, 2.01), terbinafine ($1153.0, 2.14), and fluconazole ($1473.7, 2.10). The relative cost-effectiveness was ciclopirox nail lacquer 1.00, itraconazole (pulse) 1.19, fluconazole 1.24, terbinafine 1.27, itraconazole (continuous) 2.08, and griseofulvin 3.13. Sensitivity analysis indicated that ciclopirox nail lacquer was a cost effective alternative compared with the oral regimens of terbinafine, itraconazole (continuous), and griseofulvin when clinical response rate was used as the primary efficacy parameter. CONCLUSION: Ciclopirox nail lacquer solution 8% is a recent addition to the armamentarium of therapies available to the physician and patient for the treatment of onychomycosis. The nail lacquer is a cost effective agent compared with the oral antifungal therapies, terbinafine, itraconazole, fluconazole, and griseofulvin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11002199&dopt=Abstract ciclopirox Penlac



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[Studies on the pharmacology and toxicology of ciclopiroxolamine (author's transl)]

[Article in German]

Alpermann HG, Schutz E.

Pharmacological studies with 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt (ciclopiroxolamine, Cic, Hoe 296, Batrafen) have been carried out in various test animal species and in isolated organs. The studies did not reveal any indication of effects on the central nervous system or an metabolic functions such as body temperature, urinary and biliary excretion, blood coagulation and acute inflammatory processes. Blood pressure and heart rate were slightly decreased. In the isolated ileum of the guinea pig, slight antagonism towards Ba2+, histamine, carbachol and nicotine was observed. With the doses of ciclopiroxolamine used in local therapy, no systemic pharmacological effects can be expected. Short-term toxicity studies carried out in the usual species of test animals produced oral LD50 values in the range of g/kg of body weight. A 4-week oral administration of 30 mg/kg body weight was virtually symptom-free and the corresponding dose in a 3-month administration was 10 mg/kg. The compound revealed a favourable therapeutic index. As anticipated, the cutaneous tolerance was dependent on animal species, pharmaceutical preparation, concentration of pure drug and duration of the application. The same applies to the tolerance in the vaginal mucosa of the dog. Studies on reproduction toxicology, mutagenicity, carcinogenicity and phototoxicity of ciclopiroxolamine produced no prohibitive findings.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7197539&dopt=Abstract ciclopirox Penlac



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[Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration]

[Article in German]

Kellner HM, Arnold C, Christ OE, Eckert HG, Herok J, Hornke I, Rupp W.

1. Following the dermal application of the carbon-14 labelled broad spectrum antimycotic 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt (ciclopiroxolamine, Hoe 296, Batrafen) in the form of a 1% aqueous cream to healthy human dorsal skin (penetration time: 6 h; occlusive dressing for 5 h), percutaneous absorption accounted on average for 1.3% of the dose applied. Excretion occurred via the kidney, with biological half-lives of 1.7 h. As can be seen from penetration studies of cadaverous skin, the horny layer contained the highest concentrations, with values of 2300-4500 microgram/cm3. The levels determined in the corium were still above the minimum inhibitory concentrations. These concentrations were already obtained at the first test stage (1.5 h after application) and did not change virtually at all over the longer penetration period. According to studies using histoautoradiography, ciclopirox can penetrate the skin via the epidermis and the hair follicles. When ciclopirox-14C-olamine aqueous cream was spread on the surface of fingernails, the radioactive-labelled compound penetrated right through the nail. The percutaneous absorption in dogs was higher, at 5-15% of the dose, than it was in humans. 2. After vaginal application (1 mg/kg) of ciclopirox-14C-olamine in the form of a 1% aqueous cream to bitches, between 42 and 97% of the dose (depending on the animal) was recovered in the urine and faeces, the remainder having penetrated into the tampon used to close the vagina. 3. Ciclopirox is excreted by dogs and man in the urine, primarily as a glucuronide. In humans another glucuronide with properties similar to those of the original substance was detected. Two conjugated, relatively non-polar metabolites were also present in small amounts. The metabolite patterns after oral and dermal application were similar. The binding of ciclopirox to serum proteins in humans was 96 +/- 2% in a concentration range of 0.01-11.0 microgram/ml. 4. Placental transfer was low in the rats studied. Though there was good absorption by the mother animal, the radioactivity in the foetal tissues was always lower than that of the maternal blood.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7197541&dopt=Abstract ciclopirox Penlac



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Ciclopirox nail lacquer solution 8% in the 21st century.

Gupta AK, Baran R.

Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site), and the University of Toronto, and the Nail Research Center, Cannes.

Ciclopirox nail lacquer solution 8% has been shown to be effective in the treatment of dermatophyte onychomycosis of mild to moderate severity. Other studies report the effectiveness of ciclopirox nail lacquer in onychomycosis caused by Candida sp and nondermatophyte molds. Ciclopirox nail lacquer may also be valuable in the treatment of early cases of reinfection/relapse. Ciclopirox nail lacquer solution 8% may be an important adjunct to oral antifungal therapy in certain presentations that might be poorly responsive to oral antifungal therapy alone (eg, lateral onychomycosis, longitudinal spike, dermatophytoma, and extensive onycholysis). In some cases, surgical therapies may need to be considered in addition to, or in preference to, topical nail lacquer treatment. The use of ciclopirox nail lacquer solution 8% as an adjunct to oral antifungal therapy may widen the spectrum of activity of the combination because of the broad spectrum of coverage provided by the lacquer. The use of combination therapy may be synergistic in terms of efficacy, enabling a reduction in the duration and cumulative dosage of oral therapy. This could result in a decrease in the frequency and severity of systemic adverse effects associated with the oral antimycotics and the need to be vigilant about drug interactions. Studies need to be conducted to determine the place of combination oral and topical lacquer therapy in the management of onychomycosis. (J Am Acad Dermatol 2000;43:S96-102.).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11002200&dopt=Abstract ciclopirox Penlac



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Inhibition of Candida albicans adhesiveness to human buccal and vaginal cells by sub-inhibitory concentrations of rilopirox.

Braga PC, Dal Sasso M, Maci S, Piatti G, Dannhorn DR, Bohn M.

Department of Pharmacology, School of Medicine, University of Milan, Italy.

Candida albicans is an opportunistic dimorphic pathogenic yeast which is present on the human mucosal epithelial cell surface. Its adhesion is considered to be an important first step in colonization and in the subsequent symptomatic or asymptomatic infection of buccal or vaginal mucosa. Because the ability to adhere is an important element of the pathogenicity of Candida we investigated in this study the compared effects of sub-inhibitory concentrations (sub-MICs) of rilopirox (CAS 104153-37-9) with those of ciclopirox olamine (CAS 41621-49-2) in inhibiting Candida adhesion to human buccal (BEC) and vaginal cells (VEC). Rilopirox is a new hydroxypyridone antimycotic agent with strong activity, especially against Candida albicans. There was a significant reduction in the mean number of Candida adhering to both buccal and vaginal cells with up to 1/8 MIC rilopirox for buccal and 1/16 MIC for vaginal cells, while for ciclopirox olamine reduction was significant up to 1/16 MIC for buccal and 1/8 MIC for vaginal cells. There were no significant differences in the dose-effect curves for BEC and VEC with either rilopirox and ciclopirox olamine, but on a molar basis, rilopirox was more active than ciclopirox olamine. The present in-vitro results support the developmental concept of an oropharyngeal and vaginal preparation of rilopirox. It can be expected that even sub-inhibitory concentrations of rilopirox exert an important additional effect in the treatment of oral and vaginal candidosis by impairing the pathogenic adhesion process of the fungus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7893277&dopt=Abstract ciclopirox Penlac