Source: Health Products and Food Branch (CA) Revision Year: 2018
Metronidazole is bactericidal against anaerobic bacteria; it exerts trichomonacidal activity and is also active against Giardia lamblia and Entamoeba histolytica. Its exact mechanism of action has not been entirely determined as yet. It has been proposed that an intermediate in the reduction of metronidazole, produced only in anaerobic bacteria and protozoa is bound to deoxyribonucleic acid and electron-transport proteins, inhibits subsequent nucleic acid synthesis.
At present, the mechanism by which topical metronidazole reduces the lesions and erythema associated with acne rosacea is not precisely known. Despite the established antimicrobial effects of metronidazole, there is no evidence that the suppression of bacteria or parasitic mites harbored in the skin is directly responsible for its beneficial effects in rosacea. In vitro and in vivo studies indicate that metronidazole has direct antiinflammatory activity and affects neutrophil chemotaxis and cell-mediated immunity. An antioxidant action via inhibition of neutrophil-generated reactive oxygen species has also been demonstrated; this action is believed to underlie its antiinflammatory effect. It has been proposed that the reduction in rosacea lesions and erythema is the result of antiinflammatory or immunosuppressive actions of metronidazole.
Nystatin is an antifungal antibiotic, produced by a strain of Streptomyces noursei, active against yeasts and yeast like fungi, including Candida albicans. The antifungal activity is probably due to the binding of sterols in the cell membrane of the fungus with a resultant change in membrane permeability allowing leakage of intracellular components. Nystatin has no appreciable activity against bacteria.
Metronidazole shows little or no effect on the cardiovascular, respiratory or autonomic nervous systems of dogs, rats and mice.
In vitro, activity was studied using decreasing concentrations of metronidazole which were added to a series of Trichomonas vaginalis cultures maintained at 37ºC. A 1:400,000 dilution of metronidazole kills up to 99% of the trichomonads in 24 hours.
In vivo, 0.5 mL of a 48-hour culture of Trichomonas vaginalis injected under the dorsal skin in a control and a test group of mice revealed, seven days later, extensive abscess-like lesions swarming with trichomonads in the control group and normal subcutaneous tissue free of trichomonads in the animals which had received oral metronidazole in a daily dosage of 12.5 mg/kg of body weight.
Nystatin is not absorbed from mucous membranes; therefore, no systemic manifestations are observed after local application of the product.
In vitro, nystatin is fungistatic against Candida albicans at a concentration of 3.12 μg/mL (4.4-6.2 U/mL) in liquid medium. A fungicidal activity is observed after a 5-hour contact with 1000 μg/mL (1400-2000 U/mL) or after 24 hours with 100 μg/mL (140-200 U/mL).
In vivo, rabbits were infested by the oral route with 2.5 × 108 cells of C. albicans. The administration of 50 mg/kg (100,000 U/kg) per os for 3 days reduced the number of organisms found in the feces from a few millions to less than 20 yeast cells per g.
Mortality in rabbits infested with C. albicans by the I.V. route is usually 100%. It is reduced to 62.5% when 20 mg (40,000 I.U.) is administered twice daily by the S.C. route for 4 days.
Metronidazole and nystatin do not show antagonism in vitro. It was demonstrated that, when used in combination, (in the proportion of 5μg of metronidazole to 1 unit of nystatin as in FLAGYSTATIN vaginal inserts) nystatin does not alter the antitrichomonal activity of metronidazole and that metronidazole does not affect the anticandidal activity of nystatin. Furthermore, the presence of excessive amounts of either product failed to alter the specific effectiveness of the other.
It was also shown that both FLAGYSTATIN vaginal inserts and ovules and metronidazole/nystatin cream exert antitrichomonal and anticandidal activities comparable to those of the individual components.
FLAGYSTATIN vaginal inserts were administered daily to six female Rhesus monkeys for thirty days. As compared with a control group given a placebo insert, no significant compound-related effects were observed with respect to appearance, behavior, signs of toxicity, hematological or biochemical values. No distinctive consistent gross or microscopic alterations in the vagina or cervix of treated animals were seen.
The acute toxicity of metronidazole by the oral route is 4.35 g/kg of body weight in the mouse and 5 g/kg in the rat.
Orally, doses of 7.68 million units/kg of nystatin in rats and of 8.1 to 12.5 million units/kg in mice were still non-toxic. By the I.P. route, the LD50's were in the range of 29,430 to 50,040 units/kg in mice and 85,068 to 93,440 units/kg in rats.
In rats, doses of up to 1,000 mg/kg per os of metronidazole for thirty days were well tolerated. Dogs given up to 50 mg/kg for a period of one month showed no sign of toxicity while others given up to 225 mg/kg for a period of 6 months developed signs of ataxia, muscular rigidity and tremor. This might be due to species difference in addition to high dosage over a prolonged time.
In the rat given daily oral doses of 121,000 to 810,000 units/kg of nystatin for a period of three months, no effects on red or white blood cells were noted. With the lower dosages, diarrhea, depression of growth and nasal discharge could be observed. In the animals given 810,000 units/kg per day, gastro-intestinal irritation, diarrhea, emaciation, dehydration and death occurred. In dogs, daily oral doses of up to 450,000 units/kg for periods of 185 to 217 days produced no histological changes in the organs.
Metronidazole has been shown to be carcinogenic in the mouse and in the rat. However similar studies in the hamster have given negative results. Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole.
Therefore, the use of FLAGYSTATIN for prolonged treatment duration should be carefully weighed (see WARNINGS section).
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