Originator
Fungirox Esmalte, UCI-Farma
Definition
ChEBI: A cyclic hydroxamic acid that is 1-hydroxypyridin-2(1H)-one in which the hydrogens at positions 4 and 6 are substituted by methyl and cyclohexyl groups, repectively. A broad spectrum antigfungal agent, it also exhibits antibacterial acti
ity against many Gram-positive and Gram-negative bacteria, and has anti-inflammatory properties. It is used a a topical treatment of fungal skin and nail infections.
Indications
Ciclopirox penetrates rapidly into and through the skin and nail keratin. After dermal application ofa1% cream formulation, about 1.3 % of the dose is absorbed. Serum levels range around 10 μg/L after application of a dose of 37 mg of ciclopirox. After vaginal administration, 15 – 20 % of the dose is absorbed. Ciclopirox penetrates well into the skin and nail matrix. Absorbed ciclopirox is mainly eliminated by the kidneys; 1.1 – 1.7 % of the topical dose is eliminated in the urine within four days. Only a fraction thereof is unaltered ciclopirox. Approximately 96% of the absorbed drug is bound to human serum proteins.
Manufacturing Process
A mixture of 5-oxo-3-methyl-5-cyclohexylpentene-2 acid 1-methyl ester and
5-oxo-3-methyl-5-cyclohexylpentene-3 acid 1-methyl ester was obtained by
condensation of hexahydrobenzoyl chloride with β,β-dimethylacrylic acid
methyl ester. 11.2 g of this mixture and a solution of 4.6 g of sodium acetate
and 4 g of hydroxylamine hydrochloride were shaken for 20 hours at 25°C
with a mixture of 8 ml of water and 15 ml methanol. Subsequently, a solution
of 4 g of sodium hydroxide in 8 ml of water was then added, while cooling,
shaken for 1 hour at room temperature. The mixture was extracted by means
of benzene and the aqueous phase was acidified to reach a pH of 6. 3.5 g of
1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone were obtained; melting point
144°C.
For preparation of cyclopirox from 1-hydroxy-4-methyl-6-cyclohexyl-2-
pyridone was added 2-aminoethanol (1:1).Merck Index, Monograph number: 2325, Twelfth edition, 1996, Editor: S.
Budavari; Merck and Co., Inc.
Greene L.A.; US Patent No. 5,846,984; Dec. 8, 1998; Assigned to The
Trustees of Columbia University in the City of New York (New York, NY)
Lohaus G. et al.; US Patent No. 3,883,545; May 13, 1975; Assigned to
Hoechst Aktiengesellschaft, Frankfurt am Main, Germany
Brand name
Loprox(Medicis); Penlac (Sanofi Aventis).
Therapeutic Function
Antifungal
Antimicrobial activity
Ciclopirox has a broad in vitro antifungal activity spectrum, including dermatophytes, yeasts, and moulds. The most important fungi within the activity spectrum of ciclopirox. Ciclopirox is primarily fungistatic, but if the contact time is long enough and the concentration exceeds 20 μg/mL, it exerts a fungicidal effect on yeasts and dermatophytes. In vitro, the effect is limited to proliferating fungi and is greatly dependent on the nutrient medium.
Biological Activity
Ciclopirox is a chemical compound belonging to the class of hydroxypyridones. It is found active against dermatophytesyeastsmoldssome bacterias and also azole-resistant Candida species. Unlike other antifungal agents th at act for ergosterol inhibitionciclopirox has a different action. It targets metal-dependent enzymeswhich degrades fungal cell peroxides. This unique action of ciclopirox provides less chance for resistance in pathogenic fungi. This compound is used in topical formulations specifically for nails and skin.''Ciclopirox is an antifungal and cell-permeable iron-chelating agent. It has been found to inhibit multiple enzymes and signaling pathways including prolyl hydroxylase 2 (PHD2)eukaryotic translation initiation factor 5A (eIF5A)Wnt/β-cateninhypoxia-inducible factor-1α (HIF-1 α)/vascular endothelial growth factor (VEGF)vascular endothelial growth factor receptor 3 (VEGFR-3)mammalian target of rapamycin (mTOR)and cyclin depen
Mechanism of action
Ciclopirox has a unique mechanism of action through chelation of polyvalent cations, such as Fe3+, which causes inhibition of a number of metal-dependent enzymes within the fungal cell.
Clinical Use
Ciclopirox is a hydroxylated pyridinone that is employed for superficial dermatophytic infections, principally onychomycosis.
Side effects
Topically applied, ciclopirox is well tolerated. The incidence of local irritations such as itching and burning sensations range between 1 and 4 % and are often due to the galenic formulation.