Neo-Penotran Forte Mechanism of Action

Pharmacotherapeutic Group: Antibacterial, antiprotozoal, antifungal. ATC Code: G01AF20.
Pharmacology: Pharmacodynamics: NEO-PENOTRAN FORTE PESSARY contains miconazole nitrate for antifungal and metronidazole for antibacterial and antitrichomonal effects. Miconazole nitrate which is a synthetic imidazole derivative antifungal has a wide spectrum of activity and is particularly effective against pathogen fungi including Candida albicans. In addition, miconazole nitrate is effective against Gram positive bacteria. Miconazole shows its effect by ergosterol synthesis in the cytoplasmic membrane. Miconazole nitrate changes permeability of the mycotic cell of Candida species and inhibits glucose utilization in vitro.
Metronidazole, a 5-nitroimidazole derivative is an antiprotozoal and an antibacterial agent and is effective against several infections caused by anaerobic bacteria and protozoa, such as Trichomonas vaginalis, Gardnerella vaginalis and anaerobic bacteria including anaerobic streptococci.
Miconazole nitrate and metronidazole do not have synergic or antagonistic effects.
The clinical cure rates achieved in an open, multicentre, uncontrolled clinical study to assess the efficacy and safety of NEO-PENOTRAN FORTE PESSARY for 7 days in 104 patients with clinical/microbiological diagnosis of vaginitis are 96.6% candidal vulvovaginitis, 98.1% for bacterial vaginosis, 97.3% for trichomonal vaginitis and 98% for mixed vaginal infections. Microbiological cure rates are 89.8%, 96.2%, 100%, 91.7% for each infection respectively.
In a randomized, open, comparative study with NEO-PENOTRAN FORTE PESSARY to assess the efficacy, safety and tolerability, clinical and microbiological cure rates are found to be 84% and 76%, respectively.
Pharmacokinetics: General Properties: Absorption: Miconazole nitrate: Absorption of miconazole nitrate by the intravaginal route is very low (approximately 1.4% of dose). Following intravaginal application of NEO-PENOTRAN FORTE PESSARY, miconazole nitrate was not detected in plasma.
Metronidazole: Bioavailability of metronidazole by this route is 20% compared to the oral route. Steady state levels of metronidazole in plasma ranged from 1.1 to 5.0 μg/ml after daily intravaginal application of NEO-PENOTRAN FORTE PESSARY.
Distribution: Miconazole nitrate: The protein binding is 90%-93%. Its distribution to cerebrospinal fluid is poor, however it is widely distributed to other tissues. Distribution volume is 1400 L.
Metronidazole: It is widely distributed in body tissues and fluids including bile, bone, breast, milk, cerebral abscesses, cerebrospinal fluid, liver and liver abscesses, saliva, seminal fluids and vaginal secretion, and achieves concentrations similar to those in plasma. It crosses the placenta and rapidly enters to fetal circulation. No more than 20% is bound to plasma proteins. Distribution volume is 0.25-0.85 L/kg.
Biotransformation: Miconazole nitrate: It is metabolized in liver. Two non-active metabolites are found (2,4-dichlorophenyl-1 H imidazole ethanol and 2,4-dichloromandelic acid).
Metronidazole: It is metabolized in the liver by oxidation, hydroxy metabolite is active. Major metabolites of metronidazole, hydroxy and acetic acid metabolites, are excreted in urine. The hydroxy metabolite has a 30% of biological activity of metronidazole.
Elimination: Miconazole nitrate: Half-life is 24 hours. Less than 1% is excreted in the urine. Approximately 50%, usually unchanged, excreted by feces.
Metronidazole: Half-life is 6-11 hours. About 6%-15% of metronidazole dose is excreted with feces, 60%-80% is unchanged and excreted in urine as its metabolites. Approximately 20% of metronidazole is excreted in the urine as unchanged drug.
Toxicology: Preclinical safety data: Preclinical data pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproduction toxicity studies reveal no special hazard for humans.
In microbiological in vitro study, there is no synergic or antagonistic interactions against Candida albicans, Streptococcus (Gram B of Lancefield), Gardnerella vaginalis and Trichomonas vaginalis between active substances of the combination.
A preclinical study carried out with the combination of 750 mg metronidazole and 200 mg miconazole nitrate indicated no potentiation or synergism with regards to lethal or toxic effects of the ingredients in female rats.
In a vaginal mucous irritation study in female Beagle dogs with the same combination, it was concluded that it does not cause vaginal mucous irritation as well as nor clinical, biochemical and haematological alterations. In the same study, local and systemic toxic effects are not detected.