CN105687271A - Application of phenolic acid compounds in preparation of drugs for resisting diabetic foot drug-resistant bacterium infection - Google Patents
Application of phenolic acid compounds in preparation of drugs for resisting diabetic foot drug-resistant bacterium infection Download PDFInfo
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- CN105687271A CN105687271A CN201610188958.7A CN201610188958A CN105687271A CN 105687271 A CN105687271 A CN 105687271A CN 201610188958 A CN201610188958 A CN 201610188958A CN 105687271 A CN105687271 A CN 105687271A
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- diabetic foot
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/232—Angelica
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The invention relates to application of phenolic acid compounds for resisting drug-resistant bacterium infection, and especially diabetic foot drug-resistant bacterium infection. Experimental results show that the phenolic acid compounds have a similar and even better inhibition effect on biological membranes of pseudomonas aeruginosa and drug-resistant pseudomonas aeruginosa like positive drugs, so that the effect on inhibiting pseudomonas aeruginosa and drug-resistant pseudomonas aeruginosa is exerted, and the healing time of an ulcer wound induced by diabetic foot drug-resistant bacterium infection can be obviously shortened. The phenolic acid compounds can be used for treating drug-resistant bacterium infection, and especially diabetic foot drug-resistant bacterium infection, and are favorable for avoiding the problem of antibiotic resistance.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to phenolic acid compound and preparing drug-resistance bacteria medicine, particularly the application in anti-diabetic foot drug-resistant bacteria infection medicine。
Background technology
Along with antibiotic extensive use, the drug resistance intensity of microorganism is more and more higher, Antibiotic Resistance is increasingly wider, the speed rising proportional to antibiotics sterilization capability that drug resistance is formed。Drug resistance is once produce, it will keep。Antibiotic it is continuing with, only can continue to provide selection pressure for high Resistant strain, promote it to replicate, fabric and jointly enjoy drug resistant gene, cause that the quickening of multiple antibiotic resistant strain is formed。At present, antibiotic resistance has become as the public health problem that the whole world is serious。
Because of abuse of antibiotics, China causes that 80,000,000,000 yuan of medical expenses increase every year, cause 80,000 patients dead because of its untoward reaction simultaneously。Because no matter illness weight, operation size, all using antibiotic and tending to high-titer antibiotic and frequent a large amount of blindly long-time drug combinations, cause that new Resistant strain constantly occurs even at the antibiotic using more than 4 kinds in a short time individually。Some experts even predict that, China is likely to rate and is introduced into " rear antibiotic epoch ", namely returns to the epoch before antibiotic finds。
Dysautonomia in diabetic foot's complication can cause that skin soft tissue destroys, outer derived bacterium is caused to invade, and hyperglycemia, decrease in oxygen partial pressure and malnutrition etc. can cause tissue edema jointly, acid is gathered, height blends poor efficiency anaerobic metabolism, this type of environment is suitable for bacterial growth, and hinder the function of leukocyte, it is limited that angiopathy will also result in antibiotic transport, further result in antibacterial elimination efficiency to reduce, improve diabetic foot antibacterial to infect, especially the treatment difficulty that diabetic foot drug-resistant bacteria infects, the serious local soft tissue that may result in infects, even myelitic formation。
China has extremely abundant Chinese medicine and natural pharmaceutical resources, medicinal plants nearly ten thousand kinds, provides abundant material base and source for new drug discovery。And, carry out antibacterial, antiinflammatory with Chinese patent medicine substitute antibiotics, there is untoward reaction and side effect is relatively small, do not produce the advantages such as drug resistance。On the other hand, world medical circle does not have new antibiotic to be truly born in the time of existing 40 years。Therefore, many researchers are focused on crude drug " antibiotic " in spite of oneself。From Chinese medicine resource, find the substituting product of the antibiotic having anti-inflammation curative effect equally, this world-famous puzzle of antibiotic resistance can be solved well。
In recent years, bacterial community sensing (Quorumsensing, QS) system becomes the important target studying novel drug-resistance bacteria medicine。QS is in bacterial cell or a kind of mode of intercellular signal transmission, by monitoring some signaling molecule (also known as autoinducer) such as homoserine lactone (acyl-homoserinelactone, AHL) concentration, control and coordinate whole bacterial community behavior, common surrounding is stimulated is made a response, and greatly enhances the survival ability of whole bacterial community。
Pseudomonas aeruginosa (P.aeruginosa) has and very strong forms biomembranous ability at tissue surface, and its QS systematic study obtains also thorough, and therefore Pseudomonas aeruginosa is chosen as the pattern bacterium of this project research。Pseudomonas aeruginosa is a kind of important conditioned pathogen, usually cause the nosocomial infections such as respiratory tract infection, pneumonia, urinary tract infection, infection in diabetic foot, be considered as patient occur during hospital infect the third-largest pathogenic bacterium, health and the life of the mankind in serious harm。The inherent Drug resistance that Pseudomonas aeruginosa is high is inseparable with its intervention school-based, and this QS system controls to include the expression of nearly all virulence factors such as biomembrane, extracellular toxin, elastoser, hemolysin, pyo。These virulence factors determine the Pseudomonas aeruginosa pathogenecity to host。Wherein, biomembranous formation and diffusion are to cause the multidrug resistant important mechanisms of P.aeruginosa。A authority's investigation report that NIH (NIH) issues is pointed out, it is mediated by bacterial biofilm (Biofilm, BF) that human microbial's infection has more than 80%。BF is as a kind of bacterial community behavior, and its differentiation is closely related with bacterial community sensing with growth。The antibacterial that bacterial community induction system is complete can form the biomembrane growing and breaking up normally, typically can resist antibacterial, bacterial community induction system incomplete antibacterial then can not form typical biomembrane, antibiotic resistance is remarkably decreased, easily it is rinsed, antibacterial is sensitive。Control bacterial biof iotalm by quencher and form the QS system with pathogen virulence factor expression, because of not direct bacteria growing inhibiting, antibacterial will not be produced selection pressure, act on novel targets by getting a good chance of obtaining, the group that antibacterial produces drug resistance will not be made to feel inhibitor (QSinhibitors, QSI)。
When the dry rhizome being classified as Umbelliferae Rhizoma Ligustici plant Radix Angelicae Sinensis Angelicasinensis (Oliv) Diels, sweet in the mouth, property is pungent, warm, returns liver, the heart, spleen channel, has effect of benefiting blood and regulating blood circulation, menstruction regulating and pain relieving。Begin to be loaded in Shennong's Herbal, it is classified as middle product, its drug effect is unique, it it is always doctor's treasure, have the title of " ten side's rules for doing division with a one-digit divisor on the abacus ", Radix Angelicae Sinensis extract comprises multiple chemical composition, such as phenolic acid compound ferulic acid etc., phenolic acid compound in Radix Angelicae Sinensis extract has antitumor, antioxidation, anti-platelet aggregation, antithrombotic and cytoprotection, the document of system reviews Radix Angelicae Sinensis finds, modern pharmacology and clinical research also indicate that Radix Angelicae Sinensis has good antimicrobial antiphlogistic effect, but do not find the phenolic acid compound antimicrobial agent in Radix Angelicae Sinensis extract and suppress bacterial community induction system, the bibliographical information that particularly anti-diabetic foot antibacterial infects。
Summary of the invention
The primary and foremost purpose of the present invention is in that to provide phenolic acid compound application in preparing drug-resistance bacteria medicine, specifically the present invention relates to phenolic acid compound application in preparing anti-diabetic foot bacterium infection medicine, more particularly the present invention relates to phenolic acid compound application in preparing anti-diabetic foot drug-fast bacteria infection medicine, preferred described fastbacteria is tolerant Pseudomonas aeruginosa, and described phenolic acid compound plays the effect of resisting pseudomonas aeruginosa and tolerant Pseudomonas aeruginosa by suppressing tolerant Pseudomonas aeruginosa biomembrane。
Described phenolic acid compound has a structure that
Another object of the present invention is to provide a kind of drug-resistance bacteria medicine compositions, particularly a kind of anti-diabetic foot antibacterial infection medicine compositions, more particularly a kind of diabetic foot drug-resistant bacteria infection medicine compositions, the pharmaceutically acceptable adjuvant of it phenolic acid compound of the present invention including 10%-90% and 10%-90%, described pharmaceutical composition is oral drugs or topical formulations, further described combination of oral medication is tablet, capsule, granule etc., and described topical formulations is ointment, ointment, gel or subcutaneous injection agent etc.。
Beneficial effects of the present invention:
The invention provides a kind of new purposes of phenolic acid compound, the phenolic acid compound of the experimental result display present invention all can suppress Pseudomonas aeruginosa 9027, the biomembrane of Pseudomonas aeruginosa 27853 and tolerant Pseudomonas aeruginosa, show that phenolic acid compound of the present invention is for Pseudomonas aeruginosa, the inhibition of tolerant Pseudomonas aeruginosa, diabetic foot drug-fast bacteria infection be also show obvious inhibitory action by the phenolic acid compound of the present invention that more prominent is, significantly shorten the healing time of ulcer after diabetic foot drug-fast bacteria infection, thus providing the drug-resistance bacteria medicine of a kind of non-antibiotic class, particularly a kind of non-antibiotic class anti-diabetic foot drug-fast bacteria infection medicine, help avoid antibiotics resistance problem。
Detailed description of the invention
Further below illustrate the present invention。It is pointed out that following description is only the illustration to claimed technical scheme, the not any restriction to these technical schemes。The content that protection scope of the present invention is recorded with appended claims is as the criterion。
Embodiment 1: the biomembrane Inhibition test of phenolic acid compound
Test compound: with furan ketone compound (Z)-4-bromo-5-(bromine methylene)-2 (5H)-furanone for positive control, with DMSO for negative control, the phenolic acid compound of positive drug and the Formulas I-Formula II of the present invention is configured to 32,64,128 μ g/mL respectively。
Experimental technique: be separately added into the 100 μ L compound to be tested prepared in orifice plate, inoculates 100 μ L bacterium solution。Blank group (LB culture medium 200 μ L) and negative control group (LB culture medium and each 100 μ L of bacterium solution) are set。It is placed in 37 degrees Celsius of incubators and hatches。After 20h, draw endosexine, hole bacterium solution, distilled water wash three times, wash away planktonic bacteria。Drying or after oven for drying, adding 220 μ L concentration is the crystal violet of 1%, room temperature places 30min, and then distilled water carefully washs 3 times；Adding 230 μ L95% ethanol and dissolve biomembrane-crystal violet complex, microplate reader 630nm wavelength place measures orifice plate absorbance, parallel assay three times。
Table 1 phenolic acid compound is for the inhibitory action of three kinds of aeruginosa biofilms
The Inhibition test result of three kinds of aeruginosa biofilms shows that the phenolic acid compound of the present invention is respectively provided with inhibition for the biomembrane of three kinds of Pseudomonas aeruginosas, wherein Formulas I, Formula II compound are respectively provided with prominent inhibition for three kinds of Pseudomonas aeruginosas, Formula II compound is respectively provided with and positive drug furan ketone compound quite or better inhibition for the biomembrane of tolerant Pseudomonas aeruginosa, it was shown that the phenolic acid compound of the present invention inhibition for the green pseudomonas of green pseudomonas and drug resistance。
The therapeutic effect experiment of the diabetic foot drug-fast bacteria infection ulcer of embodiment 2 phenolic acid compound
Test compound: with furan ketone compound (Z)-4-bromo-5-(bromine methylene)-2 (5H)-furanone for positive control, with normal saline for negative control, the phenolic acid compound of positive drug and the Formulas I-Formula II of the present invention is configured to 32,64,128 μ g/mL respectively。
Experimental technique: 75 SD rats are randomly divided into normal drug-fast bacteria infection ulcer group (15), diabetes drug-fast bacteria infection matched group (15), positive controls (15), compound of formula I group (15), Formula II compound group (15)。
Normal drug-fast bacteria infection ulcer group adopts normal diet to feed, and other groups adopt high lipid food to feed 8 weeks, on an empty stomach after 24 hours, and lumbar injection 1.5% streptozotocin (the citric acid-sodium citrate buffer of pH value 4.5) 35mg Kg-1, after 3 days, tail venous blood sampling measures blood glucose > 16.7mmol L-1, make diabetes model, blood glucose > 16.7mmol L-1。After one week, all rats adopt 3% pentobarbital sodium 2ml Kg-1Under dosage intraperitoneal injection of anesthesia, scald apparatus scalds (1000kg, 90 DEG C, 10S), reaches degree of depth II and scalds。After three days, at all rat ulcer positions subcutaneous injection PBS liquid, 1 × 108ufc ml-1The each 0.1ml of P. aeruginosa fastbacteria。Normal drug-fast bacteria infection ulcer group processes with diabetes drug-fast bacteria infection matched group normal saline every day, positive controls adopts (Z)-4-bromo-5-(bromine methylene)-2 (5H)-furanone to process every day, compound of formula I group and Formula II compound group are respectively adopted Formulas I, Formula II compound treatment every day, measuring each group of healing time, concrete outcome is referring to table 2。
Table 2 diabetic foot P. aeruginosa drug-fast bacteria infection healing time
Experimental result shows that the ulcer wound healing time of diabetes drug-fast bacteria infection control rats is obviously prolonged relative to normal drug-fast bacteria infection group, show that diabetes drug-fast bacteria infection rat meets the feature of chronic ulcer, Formulas I, Formula II compound group all show the effect being significantly shorter ulcer wound healing time, indicate its effect with treatment diabetic foot drug-fast bacteria infection, can be used for diabetic foot antibacterial to infect, the treatment that particularly diabetic foot drug-resistant bacteria infects。
Embodiment 3 resisting pseudomonas aeruginosa capsule
The preparation process of resisting pseudomonas aeruginosa capsule is:
(1) compound of formula I first with lactose mixing 10-15 minute；
(2) mix 10-15 minute after adding microcrystalline Cellulose；
(3) mix 3-5 minute after adding Pulvis Talci；
(4) mixture loads gelatine capsule shell, obtains resisting pseudomonas aeruginosa capsule of the present invention。
Embodiment 4 overriding resistance Pseudomonas aeruginosa tablet
The preparation process of overriding resistance Pseudomonas aeruginosa tablet is:
(1) Formula II compound first with lactose mixing 10-15 minute；
(2) add 10% starch slurry soft material, cross 14 mesh sieves, dry after granulation, cross 12 mesh sieve granulate；
(3) it is subsequently adding polyvinylpolypyrrolidone and magnesium stearate, mixes 3-5 minute；
(4) tabletting after mix homogeneously, obtains overriding resistance Pseudomonas aeruginosa tablet of the present invention。
Embodiment 5 anti-diabetic foot tolerant Pseudomonas aeruginosa ointment
Formula II compound 1g；
Liquid paraffin is appropriate；
Vaseline adds to 20g；
The preparation process of anti-diabetic foot tolerant Pseudomonas aeruginosa ointment is: modus ponens II compound 1g is placed in mortar, adds appropriate amount of fluid paraffin and is ground into pasty state, and gradation adds vaseline, grinds well and get final product。
The foregoing is only the preferred embodiment of the present invention; it should be pointed out that, for those skilled in the art, under the premise without departing from raw material of the present invention; can also making some improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention。
Claims (9)
1. phenolic acid compound purposes in preparing antimicrobial agent infection medicine。
2. purposes according to claim 1, it is characterised in that: described drug resistant infection is diabetic foot drug-fast bacteria infection。
3. purposes according to claim 1 and 2, it is characterised in that: described fastbacteria is tolerant Pseudomonas aeruginosa。
4. purposes according to claim 3, it is characterised in that preferred: the effect that phenolic acid compound plays overriding resistance Pseudomonas aeruginosa by suppressing tolerant Pseudomonas aeruginosa biomembrane。
5. the purposes according to any one of claim 1-2, it is characterised in that: described phenolic acid compound has a structure that
6. the purposes according to any one of claim 1-2, it is characterised in that: prepare into pharmaceutically acceptable preparation after adding pharmaceutically acceptable adjuvant。
7. purposes according to claim 6, it is characterised in that: described pharmaceutically acceptable preparation is oral formulations or topical formulations。
8. purposes according to claim 7, it is characterised in that: described oral formulations is capsule, tablet or granule。
9. purposes according to claim 7, it is characterised in that: described topical formulations is ointment, ointment, gel or subcutaneous injection agent。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103804185A (en) * | 2012-11-15 | 2014-05-21 | 中国医学科学院药用植物研究所 | Chemical structures of 11 novel phenolic acid compounds with clinical urinary system drug-resistant bacteria resistant activity and application thereof |
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| CN103804185A (en) * | 2012-11-15 | 2014-05-21 | 中国医学科学院药用植物研究所 | Chemical structures of 11 novel phenolic acid compounds with clinical urinary system drug-resistant bacteria resistant activity and application thereof |
Non-Patent Citations (2)
| Title |
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| ANABELA BORGES等: "The activity of ferulic and gallic acids in biofilm prevention and control of pathogenic bacteria", 《THE JOURNAL OF BIOADHESION AND BIOFILM RESEARCH》 * |
| 无: ""香精香料信息17则"", 《国内外香化信息》 * |
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| CN111544433A (en) * | 2020-06-09 | 2020-08-18 | 青岛市中医医院(青岛市海慈医院、青岛市康复医学研究所) | A pharmaceutical composition for treating and preventing diabetic foot |
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