Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: COSTAKIS TSISIOS & CO. LTD, 22, Filopoimenos street, 4002 Mesa Geitonia, Limassol, Cyprus
Pharmacotherapeutic group: Imidazole derivative, Broad-spectrum antimycotic for topical use
ATC-Code: G01AF02
Clotrimazole is a chlorine substituted triphenylmethyl-imidazole belonging to the class of “imidazole antimycotics” and is primary fungistatic but in higher concentrations also fungicidal. Clotrimazole only has an effect on proliferating fungi. Additional to the antimycotic effect, clotrimazole has in vitro also an antibacterial effect (e. g. on gram-positive staphylo- and streptococci) as well as a trichomonacide (on Trichomonas vaginalis) and an amoebacide effect (on Naegleria fowleri).
Clotrimazole is a broad-spectrum antimycotic which has an effect on the biggest part of human-pathogenic fungi. The efficacy is high and resistances against clotrimazole have only been observed under special experimental conditions.
A cross-resistance with amphotericin, flucytosine, griseofluvin and nystatin does not exist. The antimycotic effect of clotrimazole, basing on current knowledge, can be traced back to an inhibition of the ergosterol biosynthesis of lanosterol. In this process enzymes are blocked which convert 24-methylenedihydrolanosterol into 14-desmethylsterol (they are both intermediates between lanosterol and ergosterol). As ergosterol is an essential element of the fungi cell membrane, clotrimazole influences the composition and characteristics of the membrane in a very strong way. Nevertheless, this process does not happen immediately but delayed because cytoplasmatic ergosterol is used up first. Normal membrane permeability and structure is disturbed which finally leads to cell lysis. Furthermore, clotrimazole interferes in fungistatic concentrations with mitochondrial and peroxisomal enzymes. As a result, the toxic concentration of hydrogen peroxides increases which probably contributes to cell necrosis (“hydrogen peroxide autodigestion”). In vitro studies showed that clotrimazole in very high doses can inhibit the synthesis of cholesterol. The clinical significance of these experimental findings is not clear.
Applying it topically a namable systemic availability can be excluded even under unfavorable conditions (skin lesions, occlusive bandage). The concentration of clotrimazole when it is applied on the skin (mixed with a special ointment basis) decreases strongly when it passes the different skin layers from the epidermis (especially horny layer, tissue concentrations of about 1 mg/ml were measured) to corium (dermis, tissue concentrations of 2 to 30 mg/ml) to subcutis (tissue concentrations less than 0.1 mg/ml). Still 6 hours after application of this special mixed preparation, sufficient microbiological efficient concentrations were achieved or exceeded.
After vaginal application the systemic availability of clotrimazole is about 3–10%. Fungicide concentrations can there be maintained for more than 3 days after application. The plasma-protein-compound of the small amount that will be resorbed is about 98%. That means that the substance will be almost fully metabolized and eliminated renally as well as faecally in a microbiologically ineffective form.
The tests regarding tolerance of clotrimazole were carried out on albino rabbits using a cream (1% clotrimazole in standard oil-in-water emulsion) and a solution (1% clotrimazole in polyethylene glycol). The primary stimulation effect was observed as well as the tolerance in case of long-term treatment. The intact rabbit skin showed no stimulation effect and also the sacrified skin did not show any edemas.
Intra vaginal application forms: Tests were carried out on dogs and monkeys using vaginal tablets (100 mg clotrimazole). 1, 4 and 24 hours after the application of the tablet the vaginal mucous membrane did not show any local intolerance. The application was repeated using dogs and monkeys again: The vaginal mucous membrane was observed during application period and after the 14th day of treatment. Concomitantly serum tests were conducted. The local tolerance was good. Histological examinations did not show any pathologic findings. Notable serum concentrations were not detected.
The acute toxicity, indicated as LD50, is 700 to 900 mg/kg bodyweight (oral) for mice and rats, 1000 to 2000 mg/kg bodyweight (oral) for rabbits, 1000 and 2000 mg/kg bodyweight (oral) respectively for cats and dogs; in this case LD50 could only roughly be determined because of strong emesis.
The long-term oral treatment of high doses given to rats, dogs and monkeys caused changes of liver and adrenal gland. A dose-dependent liver hypertrophy did occur (cell hypertrophy and increase of total weight) due to a microsomal enzyme induction in hepatocytes (Indications of an intrahepatic cholestasis or pathological changes were not observed in dogs or monkeys; only rats showed degenerative changes in hepatocytes when they were given less than 200 mg/kg bodyweight due to high sensibility to clotrimazole.). This functional hypertrophy is quickly reversible after ending of therapy.
Thickening of the adrenal cortex did occur due to increased accumulation of fat in the zona reticularis and fasciculata; parenchymal tissue damage was not observed. These changes are also reversible after discontinuing the therapy but last longer than liver changes.
Testing chronic toxicity, no indication of cancerogenity was found.
The existing mutagenity test is negative but is insufficient for a final evaluation.
Teratogenic studies were carried out using mice, rats and rabbits; all of them were given up to 200 mg clotrimazole per kg bodyweight orally and rats were also given 100 mg clotrimazole per kg bodyweight, which was applied into the vagina. In these studies, clotrimazole did not have any influence on the fertility; the substance is neither embryotoxic nor teratogenic. Present experiences with pregnant women using clotrimazole topically did not gave any evidence of an embryotoxic and fetotoxic effect respectively.
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