WO2005025582A1 - Compositions antibacteriennes a base de n-acetyl-d-aminoglycosamine et d'antibiotiques - Google Patents
Compositions antibacteriennes a base de n-acetyl-d-aminoglycosamine et d'antibiotiques Download PDFInfo
- Publication number
- WO2005025582A1 WO2005025582A1 PCT/CN2003/000793 CN0300793W WO2005025582A1 WO 2005025582 A1 WO2005025582 A1 WO 2005025582A1 CN 0300793 W CN0300793 W CN 0300793W WO 2005025582 A1 WO2005025582 A1 WO 2005025582A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibiotics
- acetyl
- cgc
- glucosamine
- acetylglucosamine
- Prior art date
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- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims abstract description 146
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the antibacterial use of N-acetylglucosamine and its pharmaceutically acceptable salts, in particular to a compound antibacterial drug containing N-acetyl-D-glucosamine and various antibiotics, and N-acetyl-D- Application of glucosamine in the preparation of compound antibacterial drugs. Background technique
- bacteria have been considered as single-celled organisms. Each bacterium independently carries out life activities, and there is not much connection between them. However, recent studies have shown that, in fact, the individual cells of bacteria and the population of bacteria are different. Especially for the interaction between bacteria and other organisms, the effect produced by bacteria is actually expressed by the bacterial colony as a whole. And its performance is similar to that of multicellular organisms (Shapiro, JA 'B acteria as multicellular organism. "Scientific ⁇ lww cflw 1988, 256: 82-89). The inventors further studied and found that under the appropriate culture conditions, bacteria will Generate a colony pattern similar to a wave, showing a regular phenomenon of life activity.
- the present inventors found that the undulated colonies formed a state of vigorous growth and inhibition of bacterial growth. In the part where bacterial growth was inhibited, the bacteria did not divide, had a slender shape, and had a low degree of metabolism. It has strong mobility, and the inventors have called it CGC [Deng Guohong, et al.]. Observation of aperiodic changes in P. aeruginosa survival in water. Journal of the Third Military Medical University, 1997; 19 (3): 197-201]. In the further study of human pathophysiology, it was found that bacteria were largely transformed into Cryptozoites (CGCs) in an environment with antibacterial substances.
- CGCs Cryptozoites
- the bacterial CGC involved in the present invention can cause damage to the human body regardless of the type of bacteria formed. It has been found that the morphological and slender changes of bacteria in different ecological environments, the physiological metabolism is low, and the toxicity is changed. The damage to the body is very different from that when the same bacteria are in the breeding body (Guo Gang, Huang Chunji, etc.). Comparative study of fibrobacteria and latent organisms induced by antibiotics Sub-MICs. Journal, 1996; 17 (3-C)). However, this difference has not attracted people's attention in the past.
- CGC chronic diarrhea, chronic gastrointestinal dysfunction, especially the irritable bowel syndrome (IBS), which has a greater impact on humans, are caused directly or indirectly by CGC (Xu Qiwang. Bacterial potentials of irritable bowel syndrome Pathogenesis. Science, 1998; 10: 59-61).
- IBS irritable bowel syndrome
- N-acetylaminoglucose is a known substance (2-acetyIamino-2-deoxy-D-glucose; N-acetyl-D-(+)-glucosamine; GlcNAc; CAS No. 7512- 17-6).
- the structure is as follows:
- N-acetyl-D-glucosamine has been publicly used for diseases such as periodontitis (WO91 / 02539A1), inflammatory bowel disease (W099 / 53929A1), corneal disease (JP10-287570A2), and prostate hypertrophy (US5, 116,615).
- treatment Preparation of a vaccine to prevent microbial infections (W097 / 18790A3), as well as cosmetic (JP59-13708A2), shampoo preparations (JP2-11505A2), etc.
- the present inventors have also proposed Chinese patent applications (New Publication No.
- N-acetylglucosamine can effectively prevent bacteria from being transformed into a sub-ecological environment under the action of antibiotics, thereby significantly improving various antibiotics.
- the effect of this invention has completed the present invention.
- the present invention relates to the antibacterial use of N-acetyl-D-glucosamine and its pharmaceutically acceptable salts, and in particular to a compound antibacterial drug containing N-acetyl-D-glucosamine and antibiotics and N- Application of acetyl-D-glucosamine in the preparation of compound antibacterial drugs.
- the invention relates to the application of a composition containing N-acetyl-D-glucosamine and an antibiotic in the preparation of a medicament for preventing or treating diseases such as irritable bowel syndrome, imbalance of flora in the body, and intestinal dysfunction.
- the present invention also relates to a method for enhancing the therapeutic effect of antibiotics by administering a therapeutically effective amount of N-acetylglucosamine and a therapeutically effective amount of antibiotics, and by administering a therapeutically effective amount of N-acetyl-D-glucosamine and treatment to patients.
- An effective amount of antibiotics a method for treating bacterial infections or diseases caused by pathogenic proliferation that antibiotics can treat.
- the invention also relates to the prevention or treatment of irritable bowel syndrome, the body by administering to the patient a therapeutically effective amount of N-acetylglucosamine and a therapeutically effective amount of antibiotics. Endometrial disorders, intestinal dysfunction and other diseases. Detailed description of the invention
- N-acetyl-D-glucosamine In the drug / composition containing N-acetyl-D-glucosamine and antibiotics of the present invention, the structure of N-acetyl-D-glucosamine is as follows:
- N-acetyl-D-glucosamine The physical and chemical data of N-acetyl-D-glucosamine are as follows:
- N-acetyl-D-glucosamine can be from various sources. Regarding its preparation, chemical synthesis or semi-synthetic methods are mostly used at home and abroad, or they are prepared directly from known methods. For example, N-acetylglucosamine is prepared from a chitin polysaccharide enzymatic method disclosed in W097 / 31121. A method disclosed in Japanese Patent Application Publication No. JP 6327327349 is to partially hydrolyze chitin polysaccharides to obtain N-acetyl-chitooligosaccharides. Method for processing N-acetylglucosamine.
- N-acetyl-D-glucosamine can be used as a free base or a pharmaceutically acceptable salt thereof.
- a pharmaceutically acceptable salt of N-acetyl-D-glucosamine for example, hydrochloride, hydrobromide, borate, phosphate, sulfate, hydrogen sulfate formed by N-acetylglucosamine and an inorganic acid can be used.
- Salts and hydrogen phosphates N-acetylamino Citrate, benzoate, ascorbate, methyl sulfate, naphthyl sulfonate, picrate, fumarate, maleate, malonate, oxalic acid Salt, succinate, acetate, tartrate, mesylate, tosylate, isethionate, ⁇ -ketoglutarate, ⁇ -glyceryl phosphate, and glucose-1-phosphate, etc. .
- monomers or pharmaceutically acceptable salts those prepared according to known methods or commercially available products can be used.
- the present invention relates to a composition or a medicine containing N-acetyl-D-glucosamine and an antibiotic.
- the antibiotic refers to a substance that is applied to humans or other mammals and has a chemical therapeutic effect against microorganisms such as bacteria, mycoplasma, and chlamydia.
- the antibiotics described in the present invention may be fermented, semi-synthetic, or fully synthetic, and there is no limitation on this.
- it can be an antibiotic obtained by fermentation of antibiotic-producing microorganisms (molds, actinomycetes, etc.), or a semi-synthetic antibiotic with the same structure or similar mother core as the antibiotic obtained through fermentation, or a structure similar to a conventional antibiotic
- Totally synthetic antibiotics also include various fully synthetic conventional chemotherapeutic drugs with antibacterial effects, such as quinolone compounds.
- the composition / medicine of the present invention can be applied.
- antibiotics that can be used include, but are not limited to:
- Aminoglycoside antibiotics penicillin antibiotics, cephalosporin antibiotics, penicillin, lactam antibiotics other than cephalosporins, chloramphenicol antibiotics, lincomycin antibiotics, macrolide antibiotics, Quinolone, tetracycline antibiotics, etc. are not limited thereto.
- the aminoglycoside antibiotics in the present invention are antibiotics having an aminoglycoside structure in the molecule, such as streptomycin (II), kanamycin, and amikacin produced by or based on streptomyces.
- Antibiotics such as chloramphenicol, gentamicin, sagasin, etc. produced by Micromonas, but are not limited thereto.
- the penicillin antibiotic in the present invention refers to a natural or semi-synthetic antibiotic monomer having a penicillin acid core structure (III) in the molecule or various pharmaceutically acceptable salts thereof, for example: natural penicillin such as penicillin G, Penicillin V, etc .; semi-synthetic penicillin such as ampicillin, carbenicillin, amoxicillin, etc., but not limited thereto.
- cephalosporin antibiotic in the present invention refers to cephalosporanic acid in the molecule
- lactam antibiotics other than penicillin and cephalosporins refer to synthetic, semi-synthetic, or antibiotics having a P-lactam ring structure (VI) but not penicillin or cephalosporin structures,
- P-lactam ring structure VI
- chloramphenicol antibiotics in the present invention refer to synthetic, semi-synthetic or natural antibiotics or derivatives thereof having a structure similar to that of chloramphenicol (X), such as chloramphenicol, succinylchloramphenicol, and sulfomycin Etc., but not limited to this.
- the lincomycin antibiotic according to the present invention refers to, for example, an antibiotic having a structure such as lincomycin (XI) or an analog, a derivative thereof, for example, lincomycin, clindamycin, etc., but Not limited to this.
- the macrolide antibiotics in the present invention refer to macrolide antibiotics such as erythromycin, spiramycin (XII), roxithromycin, azithromycin, and derivatives thereof such as salts and esters. , But not limited to this.
- quinolones described in the present invention belong to synthetic chemotherapeutic drugs The scope of biotin, but for the sake of brevity in this article, it is also considered to be an antibiotic from the perspective of its efficacy, and this is not distinguished in the description of this specification.
- Quinolones include norfloxacin, ofloxacin, ofloxacin, ciprofloxacin, enoxacin, oxolinecarboxylic acid mother core (XIV), pyridopyrimidinecarboxylic acid Mother core (XV) -like piperidine and the like, but are not limited thereto.
- the tetracyclines in the present invention refer to natural, semi-synthetic or synthetic antibiotics having a phenanthrene group skeleton produced by actinomycetes, such as tetracycline (XVI), chlortetracycline, oxytetracycline, etc., but not Limited to this.
- actinomycetes such as tetracycline (XVI), chlortetracycline, oxytetracycline, etc., but not Limited to this.
- Potential bacteria that can be induced by antibiotics include, but are not limited to, intestinal gram-negative pestles, including pathogenic bacteria and resident flora, anaerobic and facultative bacteria.
- Antibiotics work through the reaction of bacteria. When bacteria are transformed into latent organisms, they do not respond to antibiotics, making antibiotics ineffective; N-acetyl-D-glucosamine can restore the latent organisms to the form of bacterial reproduction, thus It is susceptible to antibiotics to enhance antibiotic efficacy.
- N-acetyl-D-glucosamine When N-acetyl-D-glucosamine is used together with antibiotics in the compound preparation of the present invention, the amount and ratio of N-acetyl-D-glucosamine and antibiotics are different due to different antibiotics, specifically, because N- Acetyl-D-glucosamine has The synergistic effect of antibiotics, so the amount of antibiotics can be used or less than the conventional amount, for example, reduced to the conventional 50% or less.
- N-acetyl-D-glucosamine itself is non-toxic, so its amount is not particularly limited.
- the daily amount can be in the range of 100 mg to 10 g. Specifically:
- streptomycin injection
- the dosage for adults is lg / day.
- Compound kanamycin, injection, for intramuscular injection dosage is 300mg / day, 8 hours / time.
- Compound gentamicin injection, for muscle Injection or intravenous infusion the dosage is 90-300mg / day, 8 hours / time.
- the above dosage is antibiotic, the same below.
- compound spiramycin is mixed into powder to make capsules, and the dosage is 2-3g / day for 8 hours / time.
- compound norfloxacin, capsules, orally, used at 1200mg / day, 8 hours / time; compound ciprofloxacin, capsules, orally, used at 1200mg / day, 8 hours / time can also be prepared Injectable, intravenously, 200 mg / time, 1-2 times / day.
- the mixed powder is made into a capsule, 0.6-1.8g per day; it can also be made into an intravenous injection.
- N-acetylglucosamine is mixed with cefuroxime to make injections for intravenous or intramuscular injection, 1.5-6 g / day, 2 times / day; mixed with cefotaxime to make injections for intravenous or intramuscular injection. , 2g / day, 2 times / day.
- penicillins 1: 1 to 1: 30.
- ampicillin for example, mixed with ampicillin to make capsules, orally, 50-100mg / kg / day, as injections, intramuscular or intravenous injection, 100-200 mg / kg / day; and carbenicillin as injection, intramuscular or intravenous drip. , 4-8g / day, 4 times / day.
- N-acetyl-D-glucosamine when used in combination with antibiotics, as long as the purpose of the present invention can be achieved, the two can be made into a compound preparation and used simultaneously, or they can be made into separate preparations at the same time or sequentially, for example You can give antibiotics first and then take N-acetyl-D-glucosamine over a period of time; or you can take N-acetyl-D-glucosamine first and then antibiotics, and there is no restriction on this.
- E. coli (No. 33310, purchased by Chengdu Institute of Biological Products, Ministry of Health) was used for this test; antibiotics were taken at various concentrations, and the amount of N-acetylglucosamine was used from 10 mg to 300 mg for the lattice method design. Flat coating was performed separately, and the drug was applied by K-B method. The colonies were picked at the edges of the drug inhibition zone and observed under a microscope. In each visual field, the length of the bacterial cells is more than 50 ⁇ m, and the number of 5 or more is CGC positive, which is indicated by "+”. In each visual field, the length of the bacterial cells is less than 50 ⁇ m, and the number of 0-4 is CGC negative. "-" Means. At this time, the ratio of the two substances is 3 ⁇ 4 "effective ratio", and the experimental results are shown in the following Table 1-1-Table 1-9.
- the dosage is 50mg to 500mg;
- Macrolide antibiotics use spiramycin, the dosage is 300mg to 1500mg
- the quinolones are ciprofloxacin and norfloxacin, and the dosage is 150mg to
- N-acetyl in a compound antibacterial agent that prevents the formation of E. coli CGC The effective ratio of glucosamine to quinolone drugs is 1: 2 ⁇ 1: 15.
- Lincomycin antibiotics use Lincomycin, the dosage is 100mg to 700mg
- CONCLUSION The effective ratio of N-acetylglucosamine to lincomycin in a compound antibacterial agent that prevents the formation of E. coli CGC is 1: 2.5 to 1: 10.
- Chloramphenicol is 100mg to 700mg Chloramphenicol (mg)
- Tetracyclines use tetracycline, the dosage is 10mg to 300mg
- CONCLUSION The effective ratio of N-acetylglucosamine to tetracyclines in the compound antibacterial agent that prevents the formation of E. coli CGC is 1: 1 to 1:30.
- Cephalosporins use cefuroxime and cefotaxime, the dosage is 50mg to
- Penicillin is selected from ampicillin and carbenicillin, the dosage is 10mg to 300mg
- cefoxitin and ampicillin-sulbactam are used.
- N-acetyl-D-glucosamine and macrolide antibacterial compound preparation (N-acetylglucosamine 100 mg, spiramycin 900 mg, powder mixed) in Experimental Example 1 was spiramycin 900 mg Spiramycin E. coli-+
- N-acetyl-D-glucosamine and quinolone antibacterial compound preparation (mixed with N-acetylglucosamine 100 mg and norfloxacin 400 mg) in Experimental Example 1 are the same dose of norfloxacin
- N-acetylglucosamine (100 mg) and Lincomycin (400 mg) were used as a compound in Experimental Example 1. Lincomycin (400 mg) was used as a control drug.
- N-acetylglucosamine (100 mg) and chloramphenicol (400 mg) were used as a compound in Experimental Example 1, and the control drug was chloramphenicol (400 mg).
- N-acetyl-D-glucosamine and cephalosporin antibacterial compound in Experimental Example 1 100 mg of N-acetylglucosamine and 300 mg of cefuroxime
- the control drug is cefuroxime 300 mg
- Wistar rats were selected, and the effective ratio of N-acetylglucosamine to antibiotics was experimentally observed.
- the compound preparation was tested in vivo against rats infected with typhus and uninfected rats (the ratio of the drug composition is given in the following example.
- the dosage form is the same as before Take the same amount of antibiotics without N-acetyl-D-glucosamine as a control.
- the dosage of rats is 6.5 times per kilogram of human dosage (as described above). The experiment is randomly divided into groups, each Group of 15 animals.
- the effective dose is intramuscular injection or oral for 1 week.
- Fecal CGC examinations were performed twice a day, and the intestinal mucosal CGC colonization test was performed on the seventh day to determine the corresponding relationship with fecal CGC.
- the feces were positive for CGC and intestinal mucosal CGC colonization, otherwise they were negative.
- the expression method is that the total animal experiment number is only the denominator, and the number of positive animals is the numerator. The results are as follows:
- N-acetylglucosamine 100 mg + spiramycin (900 mg)
- spiramycin 900 mg
- Results Infected and uninfected rats were given an effective dose of a compound antibacterial preparation of N-acetylglucosamine and macrolides
- the positive rates of CGC and intestinal mucosal CGC in the feces were 0 (0/15), and the positive rates of CGC in the infected and uninfected rats given only to spiramycin were 100% (15/15).
- CGC in stool Both the positive result and the positive CGC colonization result were in good agreement. It shows that the compound antibacterial preparation of N-acetylglucosamine and macrolides can effectively prevent the formation of CGC in animals.
- N-acetyl-D-glucosamine 100mg
- ciprofloxacin 500mg
- the positive rate of CGC in feces and intestinal mucosa CGC was 0 (0/15), while the positive rate of CGC in both infected and uninfected rats given ciprofloxacin was 100% (15/15).
- CGC positivity in feces coincided with positive colonic CGC colonization. It shows that N-acetylglucosamine and quinolone compound antibacterial preparations can effectively prevent the formation of CGC in animals.
- N-acetylglucosamine 100mg + Lincomycin (400 mg)
- N-acetylglucosamine 100mg + Lincomycin (400 mg)
- an effective dose of N-acetylglucosamine and lincomycin compound antibacterial preparations are given.
- the positive rate of CGC in the feces and intestinal mucosa CGC was 0 (0/15), while the positive rate of CGC in infected and uninfected rats given only lincomycin was 100% (15/15).
- CGC positivity in feces coincided with positive colonic CGC colonization. It shows that the compound antibacterial preparation of N-acetylglucosamine and lincomycin can effectively prevent the formation of CGC in animals.
- N-acetyl-D-glucosamine 100 mg
- chloramphenicol 400 mg
- An effective dose of N-acetylglucosamine and chloramphenicol was given to the rats infected with typhoid fever and uninfected rats. After preparation, the positive rate of CGC in the feces and intestinal mucosa CGC was 0 (0/15), while the positive rate of CGC in the infected and uninfected rats given only chloramphenicol was 100% (15/15).
- CGC positive in stool The results were in good agreement with the positive colonic mucosa CGC colonization. It shows that the compound antibacterial preparations of N-acetyl-D-glucosamine and chloramphenicol can effectively prevent the formation of CGC in animals.
- Rats infected with typhoid fever and uninfected rats were given effective doses of N-acetylglucosamine and tetracycline compound antibacterial preparations in the stool and intestinal mucosa.
- the positive rate of CGC was 0 (0/15), while the positive rate of CGC in both infected and uninfected rats given tetracycline was 100% (15/15).
- N-acetyl-D-glucosamine 100 mg + cefuroxime (300 mg).
- N-acetylglucosamine and macrolides are effective Prevent bacterial CGC from irritable bowel syndrome.
- N-acetylglucosamine and quinolones can effectively prevent the occurrence of irritable bowel syndrome caused by bacterial CGC.
- N-acetyl-D-glucosamine and lincomycin can effectively prevent the occurrence of irritable bowel syndrome caused by bacterial CGC.
- N-acetyl-D-glucosamine and cephalosporin compounds can effectively prevent the occurrence of irritable bowel syndrome caused by bacterial CGC.
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Description
含有 N-乙酰 -D-氨基葡萄糖的复方抗菌药物 技术领域
本发明涉及 N-乙酰 氨基葡萄糖及其药物可接受的盐的抗 菌用途， 具体的说是涉及含有 N - 乙酰- D -氨基葡萄糖和各种 抗生素制成的复方抗菌药物以及 N - 乙酰- D -氨基葡萄糖在制 备复方抗菌药物中的应用。 背景技术
抗生素发明以来， 使人类对付病原微生物的感染有了一个有力的武 器， 千百万人远离感染的威胁。 但是， 随着时间的推移， 为对付广泛的 细菌耐药， 抗生素种类不断增多， 用量不断加大， 其结果是在对治细菌 耐药问题和医院内感染问题中收效甚微， 而由此引起细菌多种方式的变 异， 包括本发明提出的细菌潜生体这种细菌在不利环境中出现的新的适 应形式。 细菌的变异导致正常菌群转变为条件致病菌， 引起菌群紊乱及 医院内感染。 其中细菌潜生体的产生和定植与肠易激综合症以及肠道功 能紊乱的发生密切相关， 这在临床调查中得到证明。
长期以来， 细菌被认为是单细胞的生物， 各个细菌独立地进 行生命活动， 彼此之间并不发生太多的联系。 但是， 近年来的研 究表明， 实际上细菌的单个细胞与细菌的群体表现是不同的， 特 别是对于细菌与其他生物的相互作用来说， 细菌所产生的效果实 际上是细菌菌落作为整体而表现的， 其表现类似于多细胞生物 ( Shapiro, J. A. 'B acteria as multicellular organism. " Scientific ^lww cflw 1988, 256: 82 - 89 ) 。 本发明人进一步研究发现， 在合 适的培养条件下， 细菌会生成类似于波的菌落图形， 表现出有规 律的生命活动现象。 这一现象对于认识细菌的生命规律是令人感 兴趣的， 本发明人等将此现象命名为 "生物波" （徐启旺等， 微
生物生长的群体、 周期和波， 自然杂志， 1992年， 15 ( 3 ) , 195 - 197 ) , 并对此进行了研究（刘俊康等， 生物波理论的研究， 中 国微生态学杂志， 1994, 6 ( 6 ) , 40 - 46; 徐启旺等， 生物波的 非平衡机制研究， 西北大学学报（ 自然科学版） ， 1997, 27 (增 刊） ， 320 - 325 ) 。
本发明人等在对生物波理论的研究中， 发现形成为波状的菌 落， 成细菌生长旺盛和抑制交替存在的状态， 在细菌生长抑制的 部分， 细菌不分裂、 形状纤细、 代谢程度低、 但活动能力强， 本 发明人等将其称为潜生体（CGC ) 〔邓国宏， 等。 绿脓杆菌水中 生存的非周期性变化观察。 第三军医大学学报， 1997; 19 ( 3 ) : 197-201〕。 在进一步研究人体病理生理时， 发现细菌在有抗菌物 质的环境中大量转变为潜生体（CGC )， 在潜生体（CGC ) 的状 态下， 细菌对抗生素极不敏感， 即使应用了大量的抗生素也难以 将其杀死〔邓国宏。 抗菌药物对细菌潜生体的作用。 大自然探索， 1999； 18 ( 69 ) : 67-68〕。 而一旦抗生素消失或浓度降低到 MIC 以下水平， 细茵适应环境的变化， 发生相应的改变即迅速断裂而 成个体细胞堆积在一起， 形成菌落。 实验研究表明抗生素对大肠 埃希氏菌、 变形杆菌、 沙门氏菌、 痢疾杆菌等革兰氏阳性或阴性 细菌均可诱导成 CGC,体内试验包括动物及人体均证明这一作用 与体外一致（王振维等， 潜生体自旋性实验观察， 中国公共卫生， 2000, 16 ( 5 ) , 1 - 3; Liu, Junkang, et al， Turbulene under the microscope, Journal of Biological Physics, 2000， 00 ( 1 ) , 1-7 ) 。
本发明所涉及到的细菌 CGC, 不分哪类细菌所形成的均可对 人体产生损伤。 已经发现， 细菌在不同生态环境下发生的形态纤 细状改变， 生理上代谢低下、 毒性上发生改变， 对机体的损伤与 同一种细菌正处于繁殖体时有很大差别 （郭刚， 黄春基等。 抗生 素 Sub-MICs诱导的纤细菌与潜生体的比较研究。 中华流行病学
杂志， 1996; 17 ( 3-C ) )。 但是以往这种差别并未引起人们的注 意， 细菌向潜生体的转变导致抗生素的用量不断增加， 而效果却 逐渐降低， 从而增加了误诊、 乱投药的可能性， 导致病情加重甚 至延误治疗时机， 引起大量的药物不良反应。
本发明人等经过长期研究，已经证明细菌 CGC是人类接触化 学物质所致， 特别是抗生素的普遍使用使肠道细菌发生 CGC 变 化。 已经发现， 慢性腹泻、 慢性胃肠功能紊乱， 特别是对人类影 响较大的肠易激综合征（IBS ) , 都是由于 CGC直接或间接引起 的 （徐启旺.肠易激综合征的细菌潜生体发病机制. 科学， 1998; 10:59-61 ) 。
本发明人等在进行生物波理论研究过程中， 发现这种波动有 其内在的调控机制，可以利用化学物质对生物波动过程进行调节， 经分离纯化和鉴定， 确定有一种物质为 N-乙酰 -D-氨基葡萄糖。 确认有促进波动的生物波作用 （黄辉等， 细菌生物波调控因子实 验分析， 第三军医大学学报， 1999, 21 ( 3 ) , 178 - 180 ) 。
N- 乙 酰 氨 基 葡 萄 糖 是 一 种 已 知 物 质 (2-acetyIamino-2-deoxy- D-glucose; N-acetyl-D-(+)-glucosamine; GlcNAc; CAS No. 7512- 17-6)。 结构如下：
N - 乙 酰 -D-氨基 葡 萄 糖 已 被 公 开 用 于 牙 周 炎 ( WO91/02539A1 ) 、 炎性肠疾（ W099/53929A1 ) 、 角膜疾病 ( JP10-287570A2 )、 前列腺肥大（ US5， 116,615 )等疾病的治疗，
制备防治微生物感染的疫苗 （ W097/ 18790A3 ) ， 以及美容 ( JP59-13708A2 ) 、 洗发制剂 ( JP2-11505A2 ) 等。 近年来本发 明人等对其促波作用进行深入研究的基础上， 也提出了作为治疗 IBS的新药应用的中国专利申请（CN1156027号公报） ， 以及用 于抗细菌定植的治疗剂 （专利申请号 01104884.0 ) , 但是对于治 疗抗生素所致细菌 CGC以及由此引发的疾病的作用还没有报道， 也没有以其作用于细菌从而增强抗生素效果的报道。 发明内容
本发明人等在进行 N-乙酰 氨基葡萄糖的促波作用研究的 时候， 意外地发现 N-乙酰 氨基葡萄糖可以有效地防止细菌在 抗生素的作用下转变为潜生态， 从而可以显箸增进各种抗生素的 作用效果， 由此而完成了本发明。
就是说，本发明涉及 N-乙酰 -D-氨基葡萄糖及其药物可接受的 盐的抗菌用途， 具体地说是涉及含有 N - 乙酰- D -氨基葡萄糖 和抗生素制成的复方抗菌药物以及 N - 乙酰- D -氨基葡萄糖在 制备复方抗菌药物中的应用。
本发明涉及含有 N - 乙酰- D -氨基葡萄糖和抗生素的组合 物在制备预防或治疗肠易激综合症、 体内菌群失调、 肠道功能紊 乱等疾病的药物中的应用。
另外本发明还涉及通过给予患者治疗有效量的 N-乙酰 氨 基葡萄糖和治疗有效量的抗生素， 从而增强抗生素治疗作用的方 法， 以及通过给予患者治疗有效量的 N-乙酰 -D-氨基葡萄糖和治 疗有效量的抗生素， 治疗抗生素可以治疗的细菌感染或者致病性 增殖所导致疾病的方法。
本发明还涉及通过给予患者治疗有效量的 N-乙酰 氨基葡 萄糖和治疗有效量的抗生素， 从而预防或治疗肠易激综合症、 体
内菌群失调、 肠道功能紊乱等疾病的方法。 发明具体实施方式
以下详细叙述本发明。
本发明的含有 N - 乙酰- D -氨基葡萄糖和抗生素的药物 / 組合物中， N-乙酰 -D-氨基葡萄糖结构如下：
N -乙酰- D -氨基葡萄糖的各项理化数据如下：
分子式： C8H15N06
分子量： 221.21 (精确分子量 221.2096 )
熔点： 201 - 204 °C
N一乙酰 _D_氨基葡萄糖可以是各种来源的， 关于其制备， 国内 外多采用化学合成或半合成方法， 也有直接从已知的方法制得。 例如 W097/ 31121公开的从甲壳素多糖酶法制备 N-乙酰 氨基 葡萄糖， 日本专利申请公开 JP6一 3273493公开的一种将甲壳素多 糖部分酸水解获得 N-乙酰-壳寡糖， 然后再经酶处理得 N-乙酰 氨基葡萄糖的方法。
本发明的含有 N - 乙酰- D -氨基葡萄糖和抗生素的药物 / 組合物中， N-乙酰 -D-氨基葡萄糖可以使用其游离碱或者药物可接 受的盐。 作为 N-乙酰 -D-氨基葡萄糖的药物可接受的盐， 例如可 以使用 N-乙酰 氨基葡萄糖与无机酸形成的盐酸盐、 氢溴酸盐、 硼酸盐、 磷酸盐、 硫酸盐、 硫酸氢盐和磷酸氢盐， N-乙酰 氨基
葡萄糖与有机酸形成的柠檬酸盐、 苯甲酸盐、 抗坏血酸盐、 甲基 硫酸盐、 萘乙磺酸盐、 苦味酸盐、 富马酸盐、 马来酸盐、 丙二酸 盐、 草酸盐、 琥珀酸盐、 乙酸盐、 酒石酸盐、 甲磺酸盐、 甲苯磺 酸盐、 羟乙磺酸盐、 α -酮戊二酸盐、 α -甘油磷酸盐和葡萄糖 -1- 磷酸盐等。 上述单体或者可药用盐均可以使用按照已知方法所制 备者或者市售产品。
本发明涉及含有 Ν -乙酰- D -氨基葡萄糖和抗生素的组合 物、 药物中， 抗生素是指应用于人或其他哺乳动物， 可以对抗细 菌、 支原体、 衣原体等微生物具有化学治疗作用的物质。 本发明 中所述的抗生素， 可以是发酵、 半合成或者全合成的， 对此没有 限定。 例如可以是由产抗生素的微生物 （霉菌、 放线菌等）发酵 获得的抗生素， 或者是采用发酵所得的抗生素经过结构改造、 母 核相同或者类似的半合成抗生素， 或者是与常规抗生素结构类似 的全合成抗生素， 也包括各种全合成的具有抗菌作用的常规也视 为抗生素的化疗药物如喹诺酮类化合物等。
本发明中所述的抗生素， 只要是作用于细菌等， 可以诱导其 产生潜生态， 就可以应用本发明的组合物 /药物。
本发明中， 可以使用的抗生素包括但不限于：
氨基糖甙类抗生素、 青霉素类抗生素、 头孢菌素类抗生素、 青霉素、 头孢菌素类以外的其它 内酰胺类抗生素、 氯霉素类抗 生素、 林可霉素类抗生素、 大环内酯类抗生素、 喹诺酮类、 四环 素类抗生素等， 但不限于此。
本发明所述的氨基糖甙类抗生素是分子中具有氨基糖苷结构 的抗生素， 例如由链霉菌产生的或以其为基础半合成的链霉素 ( II ) 、 卡那霉素、 丁胺卡那霉素等抗生素， 小单孢菌产生的庆 大霉素、 沙加霉素等， 但不限于此。
本发明所述的青霉素类抗生素是指分子中具有青霉烷酸母核 结构 （III ) 的天然或者半合成的抗生素单体或者其各种可药用盐 等， 例如： 天然青霉素如青霉素 G、 青霉素 V等； 半合成青霉素 如氨苄西林、 羧苄西林、 阿莫西林等， 但不限于此。
本发明所述的头孢菌素类抗生素是指分子中具有头孢烷酸
( IV ) 或者氧头孢烯（V ) 母核结构的合成、 半合成或者天然抗 生素， 例如： 头孢立新、 头孢拉定、 头孢克洛、 头孢呋新、 头孢 噻肟、 拉氧头孢等， 但不限于此。
， （χ=Η， 0CH3) :
本发明所述的青霉素、 头孢菌素类以外的其它 内酰胺类抗 生素， 是指具有 P -内酰胺环结构（VI )、 但不具有青霉素、 头孢 菌素类结构的合成、 半合成或者抗生素， 例如： 诺卡霉素、 具有 碳青霉烯结构 (VII)的硫霉素、亚胺培南；具有硫青霉烷结构 (VIII) 的舒巴坦、 它唑巴坦、 舒它西林（氨苄西林 -舒巴坦）； 氧青霉烷 结构 (IX)的克拉维酸等， 但不限于此。
本发明所述的氯霉素类抗生素， 是指具有与氯霉素 (X)类似结 构的合成、 半合成或者天然抗生素或其衍生物， 例如氯霉素、 琥 珀氯霉素、 甲砜霉素等， 但不限于此。
本发明所述的林可霉素类抗生素， 是指例如具有林可霉素 (XI) 或其类似物、 衍生物等结构的抗生素， 例如、 林可霉素、 氯林可 霉素等， 但不限于此。
本发明所述的大环内酯类抗生素， 是指例如红霉素、 螺旋霉 素 (XII)、 罗红霉素、 阿齐霉素等大环内酯类抗生素及其盐、 酯等 衍生物， 但不限于此。
本发明中所述的喹诺酮类属于合成化学治疗药物
生素的范畴， 但是本文中为了简明起见， 从其药效出发也认为它 属于抗生素， 在本说明书的叙述中对此不加区别。 喹诺酮类化合 物包括萘啶酸类母核 (XIII)的诺氟沙星、 氧氟沙星、 环丙沙星， 噌 啉羧酸类母核 (XIV)的依诺沙星，吡啶并嘧啶羧酸类母核 (XV)的吡 哌酸等， 但不限于此。
本发明中所述的四环素类， 是指由放线菌类等产生的具有菲 烷基本骨架的天然、 半合成或合成抗生素， 例如四环素 (XVI)、 金 霉素、 土霉素等， 但不限于此。
可以被抗生素诱导产生潜生态的细菌， 包括但不限于肠道革 兰氏阴性杵菌， 包括病原菌和常居菌群， 厌氧的和兼性的细菌等。
虽不拟拘泥于任何已有理论， 但是本发明中 N-乙酰- D-氨基 葡萄糖与抗生素并用可以增强药效的机理考虑如下：
抗生素是通过细菌的反应而发挥作用，当细菌转变为潜生体 时，对抗生素不发生反应， 而使抗生素无效； N-乙酰- D-氨基葡萄 糖能够使潜生体回复为细菌繁殖体形态,从而使之对抗生素敏感， 以此增强抗生素药效。
本发明复方制剂中 N-乙酰- D-氨基葡萄糖与抗生素共同使用 时， N-乙酰 - D-氨基葡萄糖与抗生素的用量和比例因抗生素的不 同而不尽相同， 具体来说， 因为由于 N-乙酰- D-氨基葡萄糖具有
抗生素增效作用， 故抗生素的用量可以采用常规用量或者少于常 规用量， 例如减少到常规的 50 %甚至更少。 N-乙酰- D-氨基葡萄 糖本身无毒， 因此其用量没有特别限制， 例如每日用量可以为 lOOmg ~ 10g的范围。 具体来说：
当 N-乙酰" D-氨基葡萄糖和氨基糖甙类抗生素组合时，两者比 例可以为 N-乙酰 氨基葡萄糖：氨基糖甙类抗生素 =1: 1.6 - 1： 5。 如复方链霉素， 注射剂， 用于静滴或肌注， 成人用量为 lg/天。 复方卡那霉素， 注射剂， 用于肌注， 用量为 300mg/天， 8 小时 / 次。 复方庆大霉素注射剂， 用于肌注或静滴， 用量为 90-300mg/ 天， 8小时 /次。 以上所述的剂量是抗生素的， 以下同。
N-乙酰 氨基葡萄糖与大环内酯类抗生素组合时， 比例为 N-乙酰 氨基葡萄糖： 大环内酯类抗生素 =1: 5 ~ 1： 30。 如 复 方螺旋霉素， 按比例混合粉末制成胶嚢， 口服， 用量为 2-3g/天， 8小时 /次。
N-乙酰 -D-氨基葡萄糖与喹诺酮类组合时， 比例为 N-乙酰 -D - 氨基葡萄糖：喹诺酮类 =1: 2 ~ 1： 15。 如， 制成复方诺氟沙星， 胶囊， 口服， 用量为 1200mg/天， 8 小时 /次； 复方环丙沙星， 胶 嚢， 口服， 用量为 1200mg/天， 8 小时 /次， 也可制成注射剂， 静 滴， 200mg/次， 1-2次 /天。
N -乙酰 氨基葡萄糖与林可霉素类抗生素組合时， 比例为 N-乙酰 氨基葡萄糖：林可霉素类抗生素 =1: 2.5 - 1： 10。 例如， 混合粉末制成胶嚢， 每天 0.6-1.8g;也可制成针剂静滴。
N-乙酰 -D-氨基葡萄糖与氯霉素类抗生素组合时， 比例为 N- 乙酰 氨基葡萄糖：氯霉素类抗生素 =1: 2.5 - 1： 10。 混合药粉， 作成糖衣片或糖浆， 口 JI艮， 25-50mg/kg; 或为注射剂， 肌注或静 滴， l-2g/天， 2-4次 /天。
N-乙酰 氨基葡萄糖与四环素类抗生素组合时， 比例为 N-
乙酰 -D-氨基葡萄糖：四环素类抗生素 =1: 1 - 1： 30。 作成胶嚢或 糖衣片， 口服， l-2g/天； 也可作成针剂静滴， l-1.5g/天
N-乙酰 氨基葡萄糖与头孢菌素类抗生素组合时， 比例为 N-乙酰 -D-氨基葡萄糖： 头孢菌素类抗生素 =1: 2.6 - 1： 5。 如， N- 乙酰 氨基葡萄糖与头孢呋新混合作成注射剂，用于静滴或肌 注， 1.5-6 g/天， 2次 /天； 与头孢噻肟混合作成注射剂，用于静滴或肌 注， 2g/天， 2次 /天。
N-乙酰 氨基葡萄糖与青霉素类组合时， 比例为 N-乙酰 氨基葡萄糖：青霉素类 =1: 1 ~ 1： 30。 如， 与氨苄青霉素混合作 成胶嚢， 口服， 50-100mg/kg/天， 作成针剂， 肌注或静注， 100-200 mg/kg/天； 与羧苄青霉素作成注射剂， 肌注或静滴， 4-8g/天， 4 次 /天。
N-乙酰 -D-氨基葡萄糖与其它 P -内酰胺类抗生素组合时， 比 例为 N-乙酰 氨基葡萄糖：其它 内酰胺类抗生素 =1: 8 ~ 1： 50。 如， 与头孢西丁作成注射剂， 静注或肌注， 8-10g/天； 制成复 方氨苄西林-舒巴坦注射剂， 1.5-6g/天， 2-3次 /天，肌注或静注.
应予说明， 当 N - 乙酰- D -氨基葡萄糖与抗生素组合使用 时， 只要能够实现本发明的目的， 二者可以制成复方制剂同时使 用， 也可以分别制成制剂， 同时或者相继应用， 例如可以先给予 抗生素， 过一段时间再服用 N - 乙酰- D -氨基葡萄糖； 或者反 过来先服用 N -乙酰- D -氨基葡萄糖， 再给予抗生素， 对此不 加限制。
以下实验实施例证明本发明 N-乙酰 氨基葡萄糖和抗生素 的组合对抗 CGC 的作用和预防治疗肠道菌群紊乱、 肠易激综合 症等作用。
以下所用的抗生素均为市售品,购自第三军医大学西南医院 药房.
实验例 1
复方抗菌剂中氨基糖甙类和 N-乙酰 -D-氨基葡萄糖的不同比 例对大肠杆菌 CGC诱导实验
本试验选用大肠杆菌 （ 33310 号， 卫生部成都生物制品研究 所购买）；抗生素取各种浓度， N-乙酰 氨基葡萄糖用量从 10mg 到 300mg进行格子法设计。分别进行平 涂布，药物采用 K-B法。 在药物抑菌圈边缘挑取菌落， 显微镜下观察。 每个视野中， 菌体 长度在 50μπι以上， 数量在 5个以上为 CGC阳性， 用 "+"表示； 每个视野中， 菌体长度在 50μιη以内， 数量在 0-4个为 CGC阴 性， 用 "-"表示。 此时两种物质的比例为 ¾ "效比例 "， 实验结 果统计于下表 1-1 -表 1-9。
表 1 - 1
氨基糖甙类抗生素选用卡那霉素和庆大霉素，用量均是 50mg 到 500mg;
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 氨基葡萄糖与氨基糖甙类药物的有效比例为 1： 1.6 1： 5。
表 1-2
大环内酯类抗生素选用螺旋霉素， 用量 300mg到 1500mg
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 Ν-乙酰 氨基葡萄糖与大环内酯类药物的有效比例为 1： 5~ 1： 30。
表 1-3
喹诺酮类选用环丙沙星和诺氟沙星， 用量均是 150mg 到
600mg;
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰
氨基葡萄糖与喹诺酮类药物的有效比例为 1： 2~ 1： 15。
表 1-4
林可霉素类抗生素选用林可霉素， 用量均是 lOOmg到 700mg
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 氨基葡萄糖与林可霉素药物的有效比例为 1： 2.5~ 1： 10。
表 1-5
氯霉素类用量是 lOOmg到 700mg 氯霉素类 (mg)
100 200 300 400 500 600 700 式（ I )化合物 (mg)
10 + + + + + +
50 一 + + + + +
100 ― ― 一 + + + +
150 ― ― ― ― + + +
200 ― ― ― 一 + +
250 一 _ ― 誦 +
300 _ _ 一
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 氨基葡萄糖与氯霉素类药物的有效比例为 1： 2.5 1
表 1 - 6
四环素类选用四环素， 用量是 10mg到 300mg
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 氨基葡萄糖与四环素类药物的有效比例为 1： 1 ~ 1： 30。
头孢菌素类选用头孢呋新和头孢噻肟， 用量均是 50mg 到
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 氨基葡萄糖与头孢菌素类药物的有效比例为 1： 2.6 1： 5
表 1 - 8
青霉素类选用氨苄西林和羧苄西林，用量均是 10mg到 300mg
P -内酰胺类 (mg)
10 50 100 150 200 250 300 式（ I )化合物 (mg)
10 + + + + + +
50 + + + + +
100 ― ― + + + +
150 ― ― + + +
200 ― + +
250 ― +
300 _ _ ―
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 N-乙酰 -D - 氨基葡萄糖与 内酰胺类药物的有效比例为 1： 1~1： 30。
表 1-9
其它 P-内酰胺类选用头孢西丁和氨苄西林-舒巴坦，用量均是
500m 到 2500mg
结论:在阻止大肠杆菌 CGC形成的复方抗菌剂中 Ν-乙酰 氨基葡萄糖与其它 内酰胺类药物的有效比例为 1： 8~1： 50。
实验例 2
Ν-乙酰 氨基葡萄糖抗生素复方制剂在体外阻止细菌 CGC 形成的功效实验
本试验在体外分别对革兰氏阴性兼性菌、革兰氏阴性厌氧菌、 革兰氏阳性需氧菌分别进行平 涂布， 实验药物和对照药物分别 以相同体积的无菌注射用水溶解， 取 10微升制备药敏纸片， 药物 实验采用 K-B法， 观察 CGC形成被抑制情况， 实验结果见表 2 一 1~2一 9。
.
表 2 - 1
实验例 1的 N-乙酰 氨基葡萄糖 lOOmg与氨基糖甙类抗菌
以上菌种， 鉴定至属。
结论： N-乙酰 氨基葡萄糖与氨基糖甙类药物组合的复方抗 菌制剂与单独使用氨基糖甙类药物相比， 在体外可有效地阻止消 化道常见的细菌转变为 CGC。
表 2 - 2
实验例 1 的 N-乙酰 -D-氨基葡萄糖与大环内酯类抗菌复方制 剂（N-乙酰 氨基葡萄糖 lOOmg, 螺旋霉素 900 mg，粉末混合)对 照药物为螺旋霉素 900 mg
菌 名 复方制剂 螺旋霉素 大肠杆菌 ― +
革
沙门氏菌 +
阴 志贺氏菌 +
性
兼 克雷伯氏菌 +
性
囷 变形杆菌 ― +
枸橼酸杆菌 +
革 脆弱类杆菌 +
it
氧 氏 产黑色素类杆菌 +
菌 阴
性 艰难梭菌 一 +
厌
核酸杆菌 +
性 革 类白喉杆菌 +
二
氧 氏 李斯特氏菌 +
菌 阳
蜡样芽胞杆菌 一 + 结论： N-乙酰 氨基葡萄糖与大环内酯类药物組合的复方抗 菌制剂与单独使用大环内酯类药物相比， 在体外可有效地阻止消 化道常见的细菌转变为 CGC。
表 2 - 3
实验例 1 的 N-乙酰 -D-氨基葡萄糖与喹诺酮类抗菌复方制剂 (N-乙酰 氨基葡萄糖 100 mg， 诺氟沙星 400mg混合而成）对照 药物为相同剂量诺氟沙星
实验例 1 的 N-乙酰 氨基葡萄糖 (100 mg)与林可霉素 (400 mg)组成复方制剂， 对照药物为林可霉素 (400 mg)
结论： N-乙酰 -D-氨基葡萄糖与林可霉素药物组合的复方抗菌 制剂与单独使用林可霉素药物相比， 在体外可有效地阻止消化道 常见的细菌转变为 CGC。
表 2 - 5
实验例 1的 N-乙酰 氨基葡萄糖 (lOOmg)与氯霉素 (400 mg) 作成复方制剂, 对照药物为氯霉素 (400 mg)
结论： N-乙酰 氨基葡萄糖与氯霉素类药物组合的复方抗菌 制剂与单独使用氯霉素类药物相比， 在体外可有效地阻止消化道 常见的细菌转变为 CGC：。
表 2 - 6
实验例 1的 N-乙酰 氨基葡萄糖 (50 mg)与四环素 (150 mg) 组成复方剁剂， 对照药物为四环素 (150 mg)
表 2 - 7
实验例 1 的 N-乙酰 -D-氨基葡萄糖与头孢菌素类抗菌复方制 剂， （N-乙酰 氨基葡萄糖 lOOmg与头孢呋新 300mg混合)，对照 药物为头孢呋新 300mg
实验例 1的 N-乙酰 氨基葡萄糖与青霉素类抗菌复方制剂， (N-乙酰 -D-氨基葡萄糖 150mg， 氨苄西林 150 m 混合組成)对照 药物为氨苄西林
结论： Ν-乙酰 氨基葡萄糖与 Ρ -内酰胺类药物组合的复方 抗菌制剂与单独使用 Ρ -内酰胺类药物相比， 在体外可有效地阻止 消化道常见的细菌转变为 CG
表 2 - 9
实验例 1的 N-乙酰 氨基葡萄糖与其它 内酰胺类抗菌复 方制剂（N-乙酰 氨基葡萄糖 100mg， 氨苄西林-舒巴坦 1500 mg 混合组成)， 对照药物为氨苄西林-舒巴坦
N -乙酰 氨基葡萄糖与抗生素复方抗菌制剂体内阻止 CGC
形成的效力试验。
选用 Wistar大鼠， 实验观察 N-乙酰 氨基葡萄糖与抗生素 有效比例組成复方制剂对感染鼠伤寒杆菌的大鼠和未感染大鼠体 内试验（以下示例中给出的是药物组成比例。 其剂型同前所述。 取等量的不含 N -乙酰- D-氨基葡萄糖的抗生素作为对照。 大鼠 用药量为人用量（如前所述） 的每千克药量乘以 6.5倍。 实验采 取随机分组， 每组 15只。
给药剂量采用有效剂量的肌肉注射或口服， 持续 1周。 每天 进行 2次粪便 CGC检查， 第七天进行了肠粘膜 CGC定植检测确 定与粪便中 CGC的对应关系， 粪便有 CGC及肠粘膜 CGC定植 为阳性， 反之为阴性。 表示方法为总的动物实验只数为分母， 阳 性的动物数为分子。 结果如下：
实验例 3 - 1氨基糖甙类抗生素
药物： N _乙酰- D-氨基葡萄椒 lOOmg ) +卡那霉素（ 200 mg ) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与氨基糖甙类复方抗菌制剂后粪便中 CGC及 肠粘膜 CGC的阳性率为 0 ( 0/15 ) , 而仅给卡那霉素的感染大鼠 和未感染大鼠 CGC阳性率均为 100% ( 15/15 ) 。 粪便中的 CGC 阳性与肠粘膜 CGC定植阳性两者结果吻合。 表明 N-乙酰 氨基 葡萄糖与氨基糖甙类复方抗菌制剂在动物体内能有效地阻止 CGC的形成。
实验例 3 - 2大环内酯类抗生素
药物： N-乙酰 氨基葡萄糖（lOO mg ) +螺旋霉素（ 900 mg ) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与大环内酯类复方抗菌制剂后粪便中 CGC及 肠粘膜 CGC的阳性率为 0 ( 0/15 ) , 而仅给螺旋霉素的感染大鼠 和未感染大鼠 CGC阳性率均为 100% ( 15/15 ) 。 粪便中的 CGC
阳性与肠粘膜 CGC定植阳性两者结果吻合。表明 N-乙酰 氨基 葡萄糖与大环内酯类复方抗菌制剂在动物体内能有效地阻止 CGC的形成。
实验例 3-3喹诺酮类药物
药物： N-乙酰 -D-氨基葡萄糖（ lOOmg) +环丙沙星（ 500mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与喹诺酮类复方抗菌制剂后粪便中 CGC及肠 粘膜 CGC的阳性率为 0 (0/15) ， 而仅给环丙沙星的感染大鼠和 未感染大鼠 CGC阳性率均为 100% ( 15/15)。 粪便中的 CGC阳 性与肠粘膜 CGC定植阳性两者结果吻合。表明 N-乙酰 氨基葡 萄糖与喹诺酮类复方抗菌制剂在动物体内能有效地阻止 CGC 的 形成。
实验例 3-4林可霉素类抗生素
药物： N-乙酰 氨基葡萄糖（ lOOmg) +林可霉素（400 mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N - 乙酰 氨基葡萄糖与林可霉素复方抗菌制剂后粪便中 CGC及肠 粘膜 CGC的阳性率为 0 (0/15) , 而仅给林可霉素的感染大鼠和 未感染大鼠 CGC阳性率均为 100% ( 15/15)。 粪便中的 CGC阳 性与肠粘膜 CGC定植阳性两者结果吻合。表明 N-乙酰 氨基葡 萄糖与林可霉素复方抗菌制剂在动物体内能有效地阻止 CGC 的 形成。
实验例 3-5氯霉素类抗生素
药物： N-乙酰 -D-氨基葡萄糖（ lOOmg) +氯霉素（ 400 mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与氯霉素类复方抗菌制剂后粪便中 CGC及肠 粘膜 CGC的阳性率为 0 (0/15) , 而仅给氯霉素的感染大鼠和未 感染大鼠 CGC阳性率均为 100% ( 15/15 )。 粪便中的 CGC阳性
与肠粘膜 CGC定植阳性两者结果吻合。 表明 N-乙酰 -D-氨碁葡萄 糖与氯霉素类复方抗菌制剂在动物体内能有效地阻止 CGC 的形 成。
实验例 3-6四环素类抗生素
药物： N-乙酰 氨基葡萄糖（150mg) +四环素（150mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与四环素类复方抗菌制剂后粪便中 CGC及肠 粘膜 CGC的阳性率为 0 (0/15) ， 而仅给四环素的感染大鼠和未 感染大鼠 CGC阳性率均为 100% ( 15/15 )。 粪便中的 CGC阳性 与肠粘膜 CGC定植阳性两者结果吻合。表明 N-乙酰 -D-氨基葡萄 糖与四环素类复方抗菌制剂在动物体内能有效地阻止 CGC 的形 成。
实验例 3- 7 头孢菌素类抗生素
药物： N-乙酰 -D-氨基葡萄糖（ lOOmg) +头孢呋新（ 300 mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 氨基葡萄糖与头孢菌素类复方抗菌制剂后粪便中 CGC及 肠粘膜 CGC的阳性率为 0 (0/15) , 而仅给头孢呋新的感染大鼠 和未感染大鼠 CGC阳性率均为 100% ( 15/15) 。 粪便中的 CGC 阳性与肠粘膜 CGC定植阳性两者结果吻合。表明 N-乙酰 氨基 葡萄糖与头孢菌素类复方抗菌制剂在动物体内能有效地阻止 CGC的形成。
实验例 3-8青霉素类抗生素
药物： N-乙酰 氨基葡萄糖（ lOOmg) +氨苄西林（ 200 mg) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 -D-氨基葡萄糖与 P -内酰胺类复方抗菌制剂后粪便中 CGC及 肠粘膜 CGC的阳性率为 0 (0/15) , 而仅给氨苄西林的感染大鼠 和未感染大鼠 CGC阳性率均为 100% ( 15/15) 。 粪便中的 CGC
阳性与肠粘膜 CGC定植阳性两者结果吻合。 表明 N-乙酰 氨基 葡萄糖与 P -内酰胺类复方抗菌制剂在动物体内能有效地阻止
CGC的形成。
实验例 3 - 9其它 内酰胺类
药物： N-乙酰 -D-氨基葡萄糖（ 100 mg ) +头孢西丁（ 150 mg ) 结论： 感染鼠伤寒杆菌大鼠及未感染大鼠给予有效剂量的 N- 乙酰 -D-氨基葡萄糖与其它 P -内酰胺类复方抗菌制剂后粪便中 CGC及肠粘膜 CGC的阳性率为 0 ( 0/15 ) , 而仅给头孢西丁的 感染大鼠和未感染大鼠 CGC 阳性率均为 100% ( 15/15 ) 。 粪便 中的 CGC阳性与肠粘膜 CGC定植阳性两者结果吻合。 表明 N- 乙酰 -D-氨基葡萄糖与其它 P -内酰胺类复方抗菌制剂在动物体内 能有效地阻止 CGC的形成。 实验例 4 N-乙酰 -D-氨基葡萄糖与抗生素复方制剂对细菌 CGC导致菌群紊乱预防作用实验观察
对照各组大鼠 15只， 分别单一给予卡那霉素、 庆大霉素、 螺 旋霉素、 环丙沙星、 诺氟沙星、 林可霉素、 氯霉素、 四环素、 头 孢呋新、 头孢噻肟、 氨苄西林、 羧苄西林、 头孢西丁或氨苄西林- 舒巴坦， 均采用有效剂量， 2次 /天， 连续 15天， 检测肠道菌群结 果； 实验各组分别给予如实验例 1 的 N-乙酰 氨基葡萄糖与卡 那霉素、 庆大霉素、 螺旋霉素、 环丙沙星、 诺氟沙星、 林可霉素、 氯霉素、 四环素、 头孢呋新、 头孢噻肟、 氨苄西林、 羧苄西林、 头孢西丁或氨苄西林 -舒巴坦的有效复方制剂， 也连续给药 15天， 检测肠道菌群。 结果： 对照各组肠道常居菌种类由开始的 12种減 少为 5种， 革兰氏阳性杆菌与阴性菌的比例发生了改变， 出现大 便含水量由平均 45%上升到 60% (腹泻症状）， 实验各组未出现 上述表现。 结论： 复方制剂不出现菌群失调， 避免菌群失调症发
生。 实验例 5 N-乙酰 氨基葡萄糖与抗生素复方抗菌制剂有效 预防细菌 CGC致肠易激综合征（IBS )发生的功效实验。
选大鼠 60只， 随机分为实验组和对照组， 每组各 30只。 实 验组给予有效量的. N-乙酰 氨基葡萄糖与抗生素复方制剂， 对 照组单纯给予有效剂量的抗生素。 肌肉注射， 连续 10天， 试验組 给予 N-乙酰 -D-氨基葡萄糖-氨基糖甙类复方抗菌制剂， 采取有效 剂量连续给药 10天， 观察给药期间和停药 1周内的大鼠粪便， 确 认 CGC的存在与否。 停药一周后大鼠粪便中仍未检出 CGC；。 在 此基础上给予电刺激、 川椒水灌胃、 寒冷与束縛等诱导 IBS的刺 激试验， 观察到两組 IBS的发生率。
实验例 5 - 1氨基糖甙类
药物： N-乙酰 氨基葡萄糖 +卡那霉素， 对照： 卡那霉素 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CG (。 电刺 激、 川椒水灌胃、 寒冷与束縛等诱导 IBS发生率， 给药组均为 0 ( 0/30 )，对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与氨基糖甙类复方制剂能有效地 预防细菌 CGC致肠易激综合征发生。
实验例 5-2大环内酯类
药物： N-乙酰 氨基葡萄糖 +螺旋霉素， 对照： 螺旋霉素 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验組大鼠粪便中未检出 CGC：。 电刺 激、 川椒水灌胃、 寒冷与束缚等诱导 IBS发生率， 给药組均为 0 ( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与大环内酯类复方制剂能有效地
预防细菌 CGC致肠易激综合征发生。
实验例 5 - 3喹诺酮类
药物： N-乙酰 氨基葡萄糖 +环丙沙星， 对照： 环丙沙星 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 给药组大鼠粪便中未检出 CGC；。 电刺 激、 川椒水灌胃、 寒冷与束縛等诱导 IBS发生率， 给药組均为 0 ( 0/30 ),对照組分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与喹诺酮类复方制剂能有效地预 防细菌 CGC致肠易激综合征发生。
实验例 5 - 4林可霉素类
药物: N-乙酰 -D-氨基葡萄糖 +林可霉素， 对照： 林可霉素 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC：。 电刺 激、 川椒水灌胃、 寒冷与束缚等诱导 IBS发生率， 给药组均为 0 ( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 -D-氨基葡萄糖与林可霉素复方制剂能有效地预 防细菌 CGC致肠易激综合征发生。
实验例 5 - 5氯霉素类
药物： N-乙酰 氨基葡萄糖 +氯霉素， 对照： 氯霉素 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC。 电刺 激、 川椒水灌胃、 寒冷与束縛等诱导 IBS发生率， 给药组均为 0 ( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与氯霉素类复方制剂能有效地预 防细菌 CGC致肠易激综合征发生。
实验例 5 - 6四环素类
药物： N-乙酰 氨基葡萄糖 +四环素
结果： 对照組大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC。 电刺 激、 川椒水灌胃、 寒冷与束缚等诱导 IBS发生率， 给药组均为 0 ( 0/30 )，对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与四环素类复方制剂能有效地预 防细菌 CGC致肠易激综合征发生。
实验例 5 - 7头孢菌素类
药物： N-乙酰 氨基葡萄糖 +头孢呋新， 对照： 头孢呋新 结果： 对照組大鼠粪便中出现大量的 CGC， 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC：。 电刺 激、 川椒水灌胃、 寒冷与束縛等诱导 IBS发生率， 给药组均为 0 ( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 -D-氨基葡萄糖与头孢菌素类复方制剂能有效地 预防细菌 CGC致肠易激综合征发生。
实验例 5 - 8青霉素类
药物： N-乙酰 氨基葡萄糖 +氨苄西林， 对照： 氨苄西林 结果： 对照組大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC„ 电刺 激、 川椒水灌胃、 寒冷与束缚等诱导 IBS发生率， 给药组均为 0 ( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。
结论： N-乙酰 氨基葡萄糖与青霉素类复方制剂能有效地预 防细菌 CGC致肠易激综合征发生。
实验例 5 - 9其它 P -内酰胺类
药物： N-乙酰 氨基葡萄糖 +头抱西丁， 对照： 头孢西丁 结果： 对照组大鼠粪便中出现大量的 CGC, 停药一周后， 大 鼠粪便中仍有 CGC存在， 试验组大鼠粪便中未检出 CGC。 电刺 激、 川椒水灌胃、 寒冷与束缚等诱导 IBS发生率， 给药组均为 0
( 0/30 ),对照组分别为 33 % ( 10/30 )、 33 % ( 10/30 )、 33 % ( 10/30 )。 结论： N-乙酰 氨基葡萄糖与其它 内酰胺类复方制剂能 有效地预防细菌 CGC致肠易激综合征发生。
Claims
1. 含有 N - 乙酰 氨基葡萄糖和抗生素制成的复方抗菌 药物。
2. 根据权利要求 1 的药物， 其中 N-乙酰 -D -氨基葡萄糖是 其游离碱或者可药用盐， 抗生素选自氨基糖甙类、 大环内酯类、 四环素类、 喹诺酮类、 林可霉素类、 氯霉素类、 头孢菌素类、 青 霉素类、 其它 P -内酰胺类抗生素。
3. 根据权利要求 1 的应用， 其中所述药物为注射剂、 片剂、 胶嚢及其它混合形式的制剂。
4. N - 乙酰- D -氨基葡萄糖在制备复方抗菌药物中的应用。
5. 根据权利要求 4的应用， 其中 N-乙酰 -D -氨基葡萄糖是 其游离碱或者可药用盐， 抗生素选自氨基糖甙类、 大环内酯类、 四环素类、 喹诺酮类、 林可霉素类、 氯霉素类、 头孢菌素类、 青 霉素类、 其它 P -内酰胺类抗生素。
6. N - 乙酰- D 氨基葡萄糖和抗生素的组合物在制备预防 或治疗肠易激综合症、 体内菌群失调、 肠道功能紊乱等疾病的药 物中的应用。
7. 根据权利要求 6的应用， 其中 N-乙酰 -D -氨基葡萄糖是 其游离碱或者可药用盐， 抗生素选自氨基糖甙类、 大环内酯类、 四环素类、 喹诺酮类、 林可霉素类、 氯霉素类、 头孢菌素类、 青 霉素类、 其它 P -内酰胺类抗生素。
8. 通过给予患者治疗有效量的 N-乙酰 -D-氨基葡萄糖和治疗 有效量的抗生素， 从而增强抗生素治疗作用的方法。
9. 根据权利要求 8的方法， 其中 N-乙酰 -D -氨基葡萄糖是 其游离碱或者可药用盐， 抗生素选自氨基糖甙类、 大环内酯类、 四环素类、 喹诺酮类、 林可霉素类、 氯霉素类、 头孢菌素类、 青
霉素类、 其它 内酰胺类抗生素。
10. 通过给予患者治疗有效量的 N-乙酰 氨基葡萄糖和治疗 有效量的抗生素， 治疗抗生素可以治疗的细菌感染或者致病性增 殖所导致疾病的方法。
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03750251A EP1669077A4 (en) | 2003-09-18 | 2003-09-18 | ANTIBACTERIAL COMPOSITIONS BASED ON N-ACETYL-D-AMINOGLYCOSAMINE AND ANTIBIOTICS |
| AU2003271022A AU2003271022A1 (en) | 2003-09-18 | 2003-09-18 | Antibacterial compositions of n-acetyl-d-aminoglycosamine and antibiotics |
| BRPI0318497-8A BR0318497A (pt) | 2003-09-18 | 2003-09-18 | composto de droga antibacteriana compreendendo n-acetil-d-glucosamina |
| US10/572,226 US20070191291A1 (en) | 2003-09-18 | 2003-09-18 | Compound antibacterial drugs comprising n-acetyl-d-glucosamine |
| PCT/CN2003/000793 WO2005025582A1 (fr) | 2003-09-18 | 2003-09-18 | Compositions antibacteriennes a base de n-acetyl-d-aminoglycosamine et d'antibiotiques |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2003/000793 WO2005025582A1 (fr) | 2003-09-18 | 2003-09-18 | Compositions antibacteriennes a base de n-acetyl-d-aminoglycosamine et d'antibiotiques |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005025582A1 true WO2005025582A1 (fr) | 2005-03-24 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2003/000793 WO2005025582A1 (fr) | 2003-09-18 | 2003-09-18 | Compositions antibacteriennes a base de n-acetyl-d-aminoglycosamine et d'antibiotiques |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20070191291A1 (zh) |
| EP (1) | EP1669077A4 (zh) |
| AU (1) | AU2003271022A1 (zh) |
| BR (1) | BR0318497A (zh) |
| WO (1) | WO2005025582A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105682638A (zh) * | 2013-11-05 | 2016-06-15 | 雀巢产品技术援助有限公司 | 富含葡糖胺的植物组合物的用途 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108913768B (zh) * | 2018-07-23 | 2021-10-22 | 广东省实验动物监测所 | 一种同时检测七个氨基糖胺类耐药基因的多重液相基因芯片引物、试剂盒及其分析方法 |
| CN111557946A (zh) * | 2020-07-01 | 2020-08-21 | 上海玉曜生物医药科技有限公司 | N-乙酰-d-氨基葡萄糖的新用途及相关产品 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0372730A2 (en) * | 1988-11-18 | 1990-06-13 | University Of British Columbia | N-acetyl glucosamine as a cytoprotective agent |
| US5217962A (en) * | 1992-01-28 | 1993-06-08 | Burton Albert F | Method and composition for treating psoriasis |
| CN1471920A (zh) * | 2002-07-29 | 2004-02-04 | 中国人民解放军第三军医大学 | 含有n-乙酰-d-氨基葡萄糖的复方抗菌药物 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5455240A (en) * | 1994-06-20 | 1995-10-03 | The Rockefeller University | Modulators of pneumococcal adhesion to cellular targets involving the platelet activating factor receptor, and uses thereof |
| US6426099B1 (en) * | 1997-12-03 | 2002-07-30 | Renew Life, Inc. | Herbal formulation for rebuilding intestinal bacteria |
| US6046179A (en) * | 1998-04-17 | 2000-04-04 | Murch; Simon | Composition for and treatment of inflammatory bowel disease by colon administration of N-acetylglucosamine |
| US6037333A (en) * | 1998-05-07 | 2000-03-14 | Trustees Of Tufts College | Microbe-inhibiting compositions |
| CN1173706C (zh) * | 2001-02-28 | 2004-11-03 | 中国人民解放军第三军医大学 | N-乙酰-d-氨基葡萄糖在制备治疗宫颈糜烂药物中的应用 |
-
2003
- 2003-09-18 BR BRPI0318497-8A patent/BR0318497A/pt not_active IP Right Cessation
- 2003-09-18 US US10/572,226 patent/US20070191291A1/en not_active Abandoned
- 2003-09-18 AU AU2003271022A patent/AU2003271022A1/en not_active Abandoned
- 2003-09-18 WO PCT/CN2003/000793 patent/WO2005025582A1/zh active Application Filing
- 2003-09-18 EP EP03750251A patent/EP1669077A4/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0372730A2 (en) * | 1988-11-18 | 1990-06-13 | University Of British Columbia | N-acetyl glucosamine as a cytoprotective agent |
| US5217962A (en) * | 1992-01-28 | 1993-06-08 | Burton Albert F | Method and composition for treating psoriasis |
| CN1471920A (zh) * | 2002-07-29 | 2004-02-04 | 中国人民解放军第三军医大学 | 含有n-乙酰-d-氨基葡萄糖的复方抗菌药物 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105682638A (zh) * | 2013-11-05 | 2016-06-15 | 雀巢产品技术援助有限公司 | 富含葡糖胺的植物组合物的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003271022A1 (en) | 2005-04-06 |
| EP1669077A4 (en) | 2007-10-03 |
| US20070191291A1 (en) | 2007-08-16 |
| BR0318497A (pt) | 2006-09-12 |
| EP1669077A1 (en) | 2006-06-14 |
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