CN101019864A - Nifuratel for treating oral cavity infection - Google Patents
Nifuratel for treating oral cavity infection Download PDFInfo
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- CN101019864A CN101019864A CNA2006101440057A CN200610144005A CN101019864A CN 101019864 A CN101019864 A CN 101019864A CN A2006101440057 A CNA2006101440057 A CN A2006101440057A CN 200610144005 A CN200610144005 A CN 200610144005A CN 101019864 A CN101019864 A CN 101019864A
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- nifuratel
- metronidazole
- oral cavity
- cavity infection
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Abstract
The present invention relates to medicine technology, and is especially the application of nifuratel for treating oral cavity infection. Nifuratel has high safety, few untoward reactions and drug resistance. Experiments show that nifuratel is superior to metronidazole and other oral cavity infection treating medicines, and has broad antibacterial spectrum and high antibacterial activity. Therefore, it is hopeful to replace metronidazole with nifuratel for treating oral cavity infection.
Description
One. technical field:
The invention belongs to field of medicaments. be intended to develop the new indication of anti-infectives nifuratel aspect the treatment oral cavity infection that has been widely used in gynecological and urinary system.
Two. background technology:
1. name of product: nifuratel (has another name called the: magmilor, nifuratel) chemical name: the methyl 5-[(methyl mercapto)]-3-[(5-nitro-2-furyl) methylene amino]-the 2-oxazolidone. be the derivant of furans, belong to anti-infective, very wide in range anti-bacterium Spectrum arranged.
2. product structure and molecular formula:
Magmilor Xiaofu ' etong
Nifuratelum
C
10H
11N
3O
5S＝285.27
CAS-4936-47-4
The 5-[(methyl mercapto) methyl]-3-[(5-nitro 2-furyl) methylene amino] the 2-oxazolidone
5-[(Methylthio)methyl]-3-[(5-nitro-2-furanyl)methylene?amino]-2-oxazolidinone.
Anti-infective
Nifuratel (nifuratel)
Tydantil，Macmiror，Polmiror?Inimur，Magmilor，Omnes，Nifuratel.
INN，BAN，DCF，DCIT，NFN，USAN，MI.
3. product introduction:
Nifuratel is a wide spectrum infection medicine of researching and developing in Italian POLI INDUSTRIA CHIMICA S.p.A. company's sixties.More than 20 country goes on the market in the world, so far the clinical use experience of existing three more than ten years.This product is mainly used in the infection of treatment gynaecologic vaginal, urinary system infection and intestinal amebiasis at present.Main competing product on clinical the use (is commonly called as: metronidazole) as metronidazole.
The effect that this product suppresses infusorian merely is identical with metronidazole, but because its antimicrobial spectrum is much more wide in range than metronidazole, so effect is more remarkable when the more common clinically mixed cell of treatment infects.And because this Product Safety height, side effect is little, and youngster does not have toxicity and untoward reaction; So by State Food and Drug Administration's approval is the product that can be used in the anemia of pregnant woman.And there is not metronidazole because the long bacterial drug resistance that has produced of clinical use age.
4. the mechanism of action of nifuratel and pharmacological characteristics:
The mechanism of action:
Nifuratel causes microorganism self dysbolismus, to reach antibacterial, the effect of sterilization by the generation of the tricarboxylic acid cycle coenzyme A of various microorganisms of blocking-up and protozoon self.Therefore no matter nifuratel is to antibacterial, fungus, and trichomonas vaginitis, mycoplasma, Ureaplasma urealyticum is according to substance; Still gram aerobe and gram anaerobe all have very strong inhibitory action.
The main antimicrobial spectrum and the antibacterial activity of nifuratel
Antibacterial activity (CMI, mcg/ml)
| Metronidazole | Acinitrazole | Nifuratel | |
| The pyococcus T04 of Ao Li department | ＞200 | ?50 | ?5 |
| The pyococcus T07 of Ao Li department | ＞200 | ?25 | ?10 |
| The pyococcus C40 of Ao Li department | ＞200 | ?50 | ?10 |
| The pyococcus C12 of Ao Li department | ＞200 | ?50 | ?10 |
| The pyococcus G74 of Ao Li department | ＞200 | ?25 | ?2.5 |
| Sarcina ATCC934 | ＞200 | ?25 | ?20 |
| Bacillus subtilis | ＞200 | ?10 | ?5 |
| The false single bacterium of verdigris color | ＞200 | ?＞200 | ?＞200 |
| Typhus fever C901 Salmonella | ＞200 | ?25 | ?5 |
| Secondary typhus fever B Salmonella | ＞200 | ?25 | ?10 |
| Ordinary bacillus variabilis | ＞200 | ?50 | ?50 |
| Proteus mirabilis | ＞200 | ?＞200 | ?＞200 |
| Klebsiella pneumoniae | ＞200 | ?100 | ?50 |
| The Sonnei shigella | ＞200 | ?25 | ?5 |
Antibacterial activity (CMI, mcg/ml)
| Metronidazole | Acinitrazole | The nitre furan draws dai | |
| Candida albicans col its | ＞500 | ＞500 | 500 |
| The isolating Candida albicans of vagina | ＞500 | ＞500 | ＞500 |
| The isolating Candida albicans of vagina | ＞500 | ＞500 | 500 |
| Candida guillermondi?var. Membranaefacens | 500 | ＞500 | 250 |
| Canadida guillermondi?b4?II | 250 | ＞500 | 250 |
| Candida parapsilopsis dutch?brood | 250 | ＞500 | 250 |
| Debaryomyces heoformans | ＞500 | ＞500 | 125 |
| Torulopsis | ＞500 | ＞500 | 500 |
| Trichophyton | ＞500 | ＞500 | 31.25 |
| Neogenesis cryptococcus | ＞500 | ＞500 | 62.50 |
| Escherichia coli To 110 | ＞200 | 25 | 5 |
| Escherichia coli coll lst. 1 | ＞200 | 25 | 10 |
| Escherichia coli col lst.2 | ＞200 | 50 | 5 |
| Escherichia coli col lst.3 | ＞200 | 50 | 5 |
| Vagina adds the Nader bacterium | 7.8 | 1.9 |
As can be seen, the Mlc of nifuratel all is lower than the above two from the comparison of last table and metronidazole and Homogyn, and the antibacterial activity that nifuratel is described is higher than other both far away.And report is arranged in addition: the activity of nifuratel anaerobe resistant and Fusobacterium also is better than nitrofurantoin, the MIC minimal inhibitory concentration of nifuratel is 0.28 μ g/ml, meanwhile the minimal inhibitory concentration of nitrofurantoin is 7.70 μ g/ml (auspicious see Arzneibucs: itrofurans, nitre furan draw peptide Nifuratel one joint).
The toxicological experiment of nifuratel
Acute toxicological experiment: nifuratel does not demonstrate toxicity in acute toxicological experiment: because do not find median lethal dose(LD 50) LD50.The dosage of experimental rabbit is increased to 5 gram/pers kilogram of body weight (being equivalent to 1250 times therapeutic dose) took continuously 5 days, still do not have dead the generation.
Subacute and chronic toxicological experiment: laboratory animal oral every day of dosage is increased to 450 milligrams/kg body weight (being equivalent to the 10-30 effective dose) by 50 milligrams/kg body weight, and medication did not occur the weight of animals in 47 days and descends or other signs of toxicity.Drug withdrawal kidney only after 48 hours, lung finds to have minimal residue.
The pharmacokinetics of nifuratel
Reach whole body behind the rabbit intravenously administrable rapidly, the total body clearance height can be got rid of in body very soon.Nifuratel absorbs fully at intra-arterial, and absolute bioavailability is 1%.The rabbit liver section shows that 40% nifuratel decomposed fully in 90 minutes.In 21-25 year, reached the highest blood concentration Cmax9.48 microgram/every milliliter behind the oral 200 milligrams of nifuratels of the female volunteers that average weight is 55 kilograms in 2 hours; Half-life is 2.75 hours (1.89-4.39 hour).Go out externally with the prototype metabolism very soon thereupon, do not absorb substantially.
The extremely abnormal property and the pregnancy period of nifuratel use
The toxicity of nifuratel is extremely low, and the median lethal dose(LD 50) LD50 of rat is 1500 times of therapeutic dose.Do not find death or histology's pathological change ((Scuri) to human treatment's dosage 6 wheat harvesting periods for oral 10 times for Canis familiaris L..Human experimentation (Candela and Romano) is not all found the extremely abnormal property of nifuratel yet.Therefore, the pregnancy period is used the not absolute taboo of this medicine.
The extremely abnormal property and the pregnancy period of metronidazole use
The active main interaction by metabolite that forms behind its nitroreduction and DNA of the antibiont of metronidazole is determined (Roe).And the metabolite acetamide of metronidazole is found to have to the cancer effect in the Cavia porcellus test.Experiment in vitro shows: metronidazole has to mutation effect, therefore has to abnormal effect.
The safety of nifuratel and toleration
Use result's investigation to show according to clinical trial and listing back: the toleration of nifuratel is very good, untoward reaction of mentioning only are slight gastrointestinal symptom (take medicine crowd 3.9%) in all reports, and the incidence rate of these symptoms is in fact similar to normal population.There are not serious adverse effects and serious sense of discomfort to take place.Because of some patient has ignored the warning that can not drink when taking medicine,, feel sick symptoms such as vomiting and flush so headache has taken place.This is the interaction of at present known unique relevant nifuratel.
The safety of metronidazole and toleration
There is 30% patient that untoward reaction takes place after taking metronidazole, as headache, the smooth road of stomach discomfort, erythra, metallic taste, urine blackout, oral ulcer, numbness, dysaudia.Serious adverse effects also has neural ataxia, faints from fear; The atrioventricular block of blood circulation, sinus bradycardia; The renal colic of urinary system, renal damage; Anaphylactic shock etc.Metronidazole has the effect of tangible abstinyl sample: drink therebetween if take medicine, just might suffer from abdominal pain, vomiting, headache etc.From the blood aspect, instantaneous leukopenia or neutropenia can take place in only a few patient.Because of metronidazole is a nitro-derivative, should make regular check on blood phase, hepatic and renal function, electrocardiogram etc. during long-term treatment.(see appendix: the serious adverse reaction of Chinese medicine Tribune/metronidazole)
Three. summary of the invention:
In sum: nifuratel is similar to the treatment field of metronidazole, considers the safety that nifuratel is outstanding, applicable to the anemia of pregnant woman, and does not produce drug resistance; Progressively substitute the gesture of metronidazole at present at the big useful nifuratel of gynecological.
Because metronidazole mainly has stronger inhibitory action to pathogenic bacteria-anaerobe etc. to what cause oral disease, still be widely used in the department of stomatology now; Does this make us associate nifuratel and whether also can substitute metronidazole and playing a role aspect the treatment of oral disease? thereby overcome because of taking the injury that metronidazole causes to the patient for a long time, and the pregnancy period oral cavity infection does not have the available situation of medicine.
In order to estimate the effect of nifuratel anaerobe resistant, we urge clinical laboratory of Beijing Hospital that it has been carried out guiding external control experiment with metronidazole.Checked to come from the clinical 50 strain anaerobe of separating, the result shows that nifuratel all has better antibacterial activity to the common anaerobe of clinical major part, and the nifuratel minimal inhibitory concentration all is lower than metronidazole; Especially the antibacterial activity nifuratel to some facultative anaerobes significantly is better than metronidazole especially.Particular content sees the following form.
Table 1 nifuratel and metronidazole are to 50 strain anaerobe in-vitro antibacterial result of the tests (μ g/ml)
Table 2 nifuratel and metronidazole compare mg/L to the antibacterial activity of clinical separation 50 strain anaerobe
| Bacteria name | The strain number | The antibiotic title | The MIC scope | MIC 50 | MIC 90 |
| Peptostreptococcus | 7 | The nifuratel metronidazole | 0.5～1 1 | 0.5 1 | 1 1 |
| The middle type streptococcus | 3 | The nifuratel metronidazole | 0.5～32 0.5～≥256 | 32 ≥256 | 32 ≥256 |
| Propionibacterium acnes | 4 | The nifuratel metronidazole | 8.0 ≥256 | 8.0 ≥256 | 8.0 ≥256 |
| Actinomyces pseudonecrophorus | 2 | The nifuratel metronidazole | 0.125-0.5 0.125～0.5 | 0.125 0.125 | 0.5 0.5 |
| The bacillus acidophilus | 2 | The nifuratel metronidazole | 8 ≥256 | 8 ≥256 | 8 ≥256 |
| Bacillus perfringens | 4 | The nifuratel metronidazole | 1-2 0.25～1 | 1 0.5 | 2 1 |
| Bacteroides | 16 | The nifuratel metronidazole | 0.125～1 0.25～2 | 0.5 0.5 | 1 1 |
| The fertile Pseudomonas of mouth Prey | 2 | The nifuratel metronidazole | 0.06 0.125 | 0.06 0.125 | 0.06 0.125 |
| Produce the fertile Pseudomonas of melanin Prey | 6 | The nifuratel metronidazole | 0.5 0.5～1 | 0.5 0.5 | 0.5 1 |
| Separate the fertile Pseudomonas of sugared peptone Prey | 2 | The nifuratel metronidazole | 1 1 | 1 1 | 1 1 |
| The aerogenesis Eubacterium | 1 | The nifuratel metronidazole | 1 0.25 | ||
| Clostridium hastiforme | 1 | The nifuratel metronidazole | 0.125 0.25 |
In order further to confirm nifuratel to the definite effect of oral cavity to pathogenic bacteria, we again please the Capital University of Medical Sciences's attached Beijing School of Stomatology stomatology institute have carried out control experiment with metronidazole at 5 with the closest bacterial strain of periodontal relation once more on this basis.Three anaerobe particularly: cause 1 of pulpitis.Dental pulp porphyrin Zymomonas mobilis; Cause 2 of gingivitis.Porphyromonas gingivalis; With 3.Tool nuclear fusiform bacilarmature.Two microaerobies: easily cause 4 of young woman's oral cavity infection.Bacterium actinomycetem comitans; Cause 5 of dental caries teeth inflammation.Actinomyces viscosus.And according in the past clinical experience, metronidazole is insensitive to the 4th, the 5 kind of bacterial strain.Auspicious seeing the following form:
Two. result: unit: millimeter
| Concentration (mg/ml) | P·g | P·e | F·n | A·a | A·v | ||||||
| ① | ② | ① | ② | ① | ② | ① | ② | ① | ② | ||
| 1 | 200 | 28 | 15 | 30 | 28 | 13 | 22 | 13 | 15 | 50 | 13 |
| 2 | 100 | 20 | 13 | 31 | 25 | 13 | 18 | 13 | 14 | 50 | 12 |
| 3 | 50 | 15 | 12 | 30 | 24 | 13 | 15 | 12 | 12 | 50 | 13 |
| 4 | 25 | 15 | 12 | 29 | 22 | 12 | 15 | 13 | 12 | 50 | 14 |
| 5 | 12.5 | 15 | 10 | 29 | 24 | 13 | 15 | 14 | / | 45 | 13 |
| 6 | 7.25 | 14 | 13 | 27 | 24 | 14 | 13 | 15 | / | 40 | 12 |
| 7 | 3.64 | 13 | / | 27 | 23 | 13 | 13 | 12 | / | 40 | 12 |
| 8 | 1.82 | 13 | / | 28 | 18 | 12 | 13 | 13 | / | 40 | 12 |
| 9 | 0.91 | 13 | / | 25 | 15 | 12 | 16 | 12 | / | 40 | 13 |
| 10 | 0.45 | 13 | / | 25 | / | 13 | 15 | 11 | / | 38 | 16 |
| 11 | 0.23 | 12 | / | 24 | / | 12 | / | / | / | 35 | 15 |
| 12 | 0.11 | 13 | / | 23 | / | 11 | / | / | / | 35 | 15 |
| 13 | 0.057 | 12 | / | 24 | / | / | / | / | / | 40 | 13 |
| 14 | 0.?029 | 12 | / | 25 | / | / | / | / | / | 37 | 12 |
| 15 | 0.015 | 13 | / | 23 | / | / | / | / | / | 39 | 12 |
| MIC | ＜ 0.015 | 7.25 | ＜ 0.015 | 0.91 | 0.11 | 0.4 | 0.45 | 25.00 | ＜ 0.015 | 0.015 | |
Annotate: 1. 1. wheat rice promise, 2. metronidazole in showing.
2.MIC be minimum inhibitory concentration.
Method: steel pipe method
Take turns doing 1: 1 continuous doubling dilution (1ml+200mg first) with sterilized water for injection, original content is calculated in interior 15 concentration altogether.
Right as can be seen from minimal inhibitory concentration MIC:
1. dental pulp porphyrin Zymomonas mobilis; MIC nifuratel=0.015/MIC metronidazole=7.25;
2. porphyromonas gingivalis MIC nifuratel=0.015/MIC metronidazole=0.91;
3. tool is examined fusiform bacilarmature MIC nifuratel=0.11/MIC metronidazole=0.40;
4. bacterium actinomycetem comitans; MIC nifuratel=0.45/MIC metronidazole=25.00
5. actinomyces viscosus MIC nifuratel=0.015/MIC metronidazole=0.015
Nifuratel Mlc (MIC) is all low than metronidazole, wherein to the 1st, the 2 and the 5th kind of bacterial strain bacteriostasis is still arranged when being diluted to the 15th concentration.Nifuratel antibacterial stronger to the relevant pathogenic bacterium of five kinds of periodontal diseases is described, and obviously is better than metronidazole.Especially nifuratel obviously is better than metronidazole to the activity of facultative anaerobe.At present increasing oral cavity expert thinks: for " during clinical treatment oral cavity infection disease, remove and use the antianaerobic-microbacterial drug beyond the region of objective existence, the medicine that uses anti-facultative anaerobe or aerobe simultaneously of still needing (auspiciously see: the 16th volume second phase of stomatology 1996.6).
As everyone knows, the difficult healing of periodontal disease, long relevant with its treatment phase.And do not have fool proof effective medicine at oral cavity anaerobium at present.Metronidazole is too big as poison of drug commonly used, can not obey for a long time.Other nitre azole medicines are even more serious to the infringement of human body.
Women, particularly anemia of pregnant woman are because endocrine variation very easily causes oral cavity infection; Have investigation to find that 80% anemia of pregnant woman suffers from periodontal, the disease of gingiva (is seen appendix: medical information).Even more serious is anemia of pregnant woman's oral cavity infection often causes the infection of amniotic cavity, can cause the fetal growth obstacle, under-weight, premature labor or miscarriage.
To sum up all these to force us to seek a kind of new, safely and effectively, the medicine of control oral cavity infection.Because the safety that nifuratel is outstanding, and at the relevant pathogenic bacterium of five kinds of periodontal diseases, facultative anaerobe all has stronger bacteriostasis than metronidazole, so I think that it is the alternative medicine of very good metronidazole.
Four. concrete using method:
The clinical research of nifuratel is very ripe, reaches the time and the half-life of blood medicine peak value according to it, be designed to clinically oral 200 milligrams/each; Can keep required blood drug level 3 times/every day.
This is the mode of at present general clinical application just.Specific to being applicable to oral cavity partial, whether such blood drug level is suitable, needs great dosage etc., still needs and continue the experiment and the research of a lot of aspects.
Claims (1)
1. the chemical compound nifuratel (NIFURATEL) that the present invention relates to
Chemical name: the methyl 5-[(methyl mercapto)]-3-[5-nitro-2-furyl] methylene amino]-the 2-oxazolidone; Structural formula:
And pharmaceutically acceptable salt, or contain pharmaceutical composition any among them; Be used for the treatment of purposes in the oral cavity infection medicine in preparation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2243482A1 (en) * | 2009-04-20 | 2010-10-27 | Polichem SA | Use of nifuratel to treat infections caused by atopobium species |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2243482A1 (en) * | 2009-04-20 | 2010-10-27 | Polichem SA | Use of nifuratel to treat infections caused by atopobium species |
| WO2010121980A1 (en) * | 2009-04-20 | 2010-10-28 | Polichem S.A. | Use of nifuratel to treat infections caused by atopobium species |
| US8673886B2 (en) | 2009-04-20 | 2014-03-18 | Polichem Sa | Use of nifuratel to treat infections caused by Atopobium species |
| EA021557B1 (en) * | 2009-04-20 | 2015-07-30 | Полихем С.А. | Use of nifuratel to treat infections caused by atopobium vaginae species |
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