Bifonazole
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| Stereoisomers of Bifonazole: ( R ) -form (top) and ( S ) -form (bottom) | |||||||||||||||||||
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| Non-proprietary name | Bifonazole | ||||||||||||||||||
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| Molecular formula | C 22 H 18 N 2 | ||||||||||||||||||
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| Mechanism of action |
Inhibition of the biosynthesis of ergosterol in mushrooms |
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| Physical state |
firmly |
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| Melting point |
142 ° C |
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| solubility |
soluble in ethanol and methanol , practically insoluble in water, easily soluble in acetone and dimethylformamide |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Bifonazole is a synthetic mixture of two isomeric chemical compounds from the group of imidazoles , which is used as a medicinal substance for the treatment of fungal diseases of the skin and nails ( dermatophytoses ) due to its antifungal effect . In addition to its broad spectrum of activity, bifonazole is characterized by a long persistence on the skin , which means that effective concentrations are achieved after six hours. The mode of action of bifonazole is based on the inhibition of the enzyme lanosterol demethylase , which plays an important role in the synthesis of ergosterol , an important component of the cell membranes of fungi. Because of the resulting inhibition of the multiplication of the fungi, the effect of bifonazole is also called fungistatic.
Bifonazole is a locally applicable broad-spectrum antimycotic from the class of azoles, which is used cutaneously in the form of ointments, creams, gels, sprays and solutions. Due to its good skin penetration and antifungal effect, it is used to treat fungal diseases of the skin and nails (mycoses). The active ingredient is also active against certain bacteria such as Corynebacterium minutissimum and thus covers all relevant pathogens in this area.
history
Bifonazole is a further development of clotrimazole and was registered for a patent in Germany in 1974, which was granted in 1984. The active ingredient was patented by Bayer in 1976 and 1978 and is now also commercially available as a generic. The hydrochloride and sulfate are used .
Stereoisomerism
Bifonazole is chiral , there are two enantiomers : ( R ) -1- (4-phenylbenzhydryl) imidazole [= ( R ) form] and ( S ) -1- (4-phenylbenzhydryl) imidazole [= ( S ) form] . The drug used is racemic bifonazole, i.e. a 1: 1 mixture of ( R ) -1- (4-phenylbenzhydryl) imidazole and ( S ) -1- (4-phenylbenzhydryl) imidazole.
properties
Pharmacodynamics
The mechanism of action of all azoles (e.g. clotrimazole as a prototype) is the inhibition of lanosterol-14α-demethylase, which is a key enzyme in the synthesis of ergosterol. In contrast to mammals, which carry out the synthesis of cholesterol, ergosterol is formed in fungi. This difference is important for a targeted therapy against fungal diseases without affecting human cholesterol synthesis. The key enzyme shared by both synthesis routes is HMG-CoA reductase, which converts 3-hydroxy-3-methylglutaryl-coenzyme-A into mevalonic acid (therapeutic target for statins). This enzyme is additionally (dual mechanism of action) inhibited by bifonazole, which, however, also has side effects. This dual approach differentiates bifonazole from other antifungal agents. Bifonazole shows a dose-dependent fungistatic, i.e. H. growth inhibiting property and fungicidal (i.e. fungicidal) effects on dermatophytes and yeasts, the most common fungal pathogens. In addition, the active ingredient has anti-inflammatory properties, so that inflammatory processes can be effectively counteracted.
Pharmacokinetics
Bifonazole penetrates well into the layers of the skin affected by the infection. Six hours after application, concentrations are measured which reach the MIC values (minimum inhibitory concentration) for the fungi that are important in dermatomycoses or exceed them many times over: between 1000 μg / cm 3 in the top layer of the epidermis (stratum corneum) and 5 μg / cm 3 in the stratum papillare. Bifonazole has a long skin retention time in antifungal concentrations. Taking into account the type of fungicidal action, this forms the basis for single application in local therapy. In the case of absorption studies after topical application to intact human skin, the concentrations in the serum were always below the detection limit (<1 ng / ml), and slight absorption could only be detected in inflamed skin. These extremely low concentrations of the active substance (generally less than 5 ng / ml) do not suggest a systemic effect.
Resistance situation
Bifonazole has a favorable resistance level, i. H. Fungi that do not respond to bifonazole from the start are rare. So far there is no evidence that bifonazole develops resistance to an originally sensitive fungal strain.
Mechanism of action
Bifonazole intervenes in two places in the cascade-like ergosterol synthesis of the fungal pathogens and therefore has a pronounced fungicidal effect. This dual approach differentiates bifonazole from other azole derivatives and other antimycotics. The inhibition of the ergosterol biosynthesis leads to disorders in the structure and function of the cytoplasmic membrane. Ergosterol is an essential part of the cell membrane of fungi.
Therapeutic use
application areas
The antimycotic bifonazole is characterized by a broad spectrum of activity, which covers dermatophytes, yeasts, molds and other fungi such as Malassezia furfur and bacteria such as Corynebacterium minutissimum. It is used to treat skin, foot and nail fungus.
Side effects
When used locally, the side effects are limited to reversible effects such as B. dry skin, skin irritation, skin softening, skin peeling, redness, burning, itching, rash, eczema, blisters, hives, contact dermatitis, allergic dermatitis. These side effects were observed after approval during use.
Contraindications
Due to the local effect, damage to the liver due to hepatotoxicity is excluded. Bifonazole should not be used in known hypersensitivities.
There are insufficient data from the use of bifonazole in pregnant women. However, since bifonazole is an exclusively topically applied active ingredient that is only absorbed to a very small extent, a systemic effect and an associated risk are not to be expected. Nevertheless, as a precautionary measure, bifonazole should only be used during pregnancy after a careful risk-benefit assessment.
Interactions
Limited data indicate that an interaction between topically applied bifonazole and warfarin is possible, with an increase in the INR value. If bifonazole and warfarin are used at the same time, patients should be monitored accordingly.
Substance class
Bifonazole is an aromatase inhibitor .
Trade names
Bifomyk (D), Bifon (D), Canesten Bifonazol - Creme (A), Canesten Extra Bifonazol (D), Mycospor (D)
Canesten Extra Nagelset (D), Canesten Bifonazol comp. - ointment + nail set (A)
Individual evidence
- ^ The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 199, ISBN 978-0-911910-00-1 .
- ↑ a b c d Entry on bifonazole. In: Römpp Online . Georg Thieme Verlag, accessed on June 27, 2019.
- ↑ a b Bifonazole data sheet from Sigma-Aldrich , accessed on March 21, 2011 ( PDF ).
- ↑ Entry on bifonazole in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ a b c d e f g h i BCC Clinical Overview - Bifonazole 1%, dated November 2011.
- ^ H. Tronnier, M. Herling, M. Wiebusch, U. Heinrich, N. Becker: Investigations on the anti-inflammatory effect of bifonazole. In: Current Dermatology. 31, 2005, pp. 21-26, doi : 10.1055 / s-2004-826006 .
- ↑ Mechanism of action of bifonazole. Retrieved April 1, 2020 .
- ↑ Eva R. Trösken, Kathrin Fischer, Wolfgang Völkel, Werner K. Lutz: inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS / MS method for the analysis of estradiol product formation . In: Toxicology . tape 219 , no. 1-3 , February 2006, pp. 33-40 , doi : 10.1016 / j.tox.2005.10.020 ( elsevier.com [accessed March 9, 2019]).
- ↑ Chinaza Egbuta, Jessica Lo, Debashis Ghosh: Mechanism of Inhibition of Estrogen Biosynthesis by Azole Fungicides . In: Endocrinology . tape 155 , no. December 12 , 2014, p. 4622-4628 , doi : 10.1210 / en.2014-1561 , PMID 25243857 , PMC 4239419 (free full text).
