CN106619621B - Licofelone combines antifungal products and its application of Fluconazole - Google Patents
Licofelone combines antifungal products and its application of Fluconazole Download PDFInfo
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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
- A61K31/33—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
- A61K31/4196—1,2,4-Triazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
The invention discloses a kind of antifungal products of Licofelone joint Fluconazole and its applications, and the minimum inhibitory concentration of Licofelone and Fluconazole is respectively as follows: 16 μ g/ml, 1 μ g/ml when use in conjunction.Quantitative assessment of the present invention Licofelone combines antifungic action with Fluconazole, analyze its effect of enhanced sensitivity to Fluconazole, and static and dynamic system evaluation is carried out, as a result, it has been found that, antifungal action of fluconazole can be remarkably reinforced in Licofelone, and the minimum effective concentration for reducing FLC, reduces the dosage of antifungal drug, to reduce the generation of the adverse reaction of drug.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of antifungal products of Licofelone joint Fluconazole and its
Using.
Background technique
In recent years, increasing with hypoimmunity crowd (patients such as malignant tumour, AIDS, autoimmunity disease), leads
The development of the technologies such as cannula and organ transplant, broad-spectrum antibiotic, cortin and immunosuppressor are widely used, fungi sense
The disease incidence of dye steeply rise (AJ.Antifungal agents:mode of action in yeast
cells.Rev Esp Quimioter.2006,19:130-9).Candida albicans is separation common in fungus Infection
Bacterium, it can cause superficial infection can also be to cause system infections in intrusive body.
Fluconazole (fluconazole, FLC) is as antifungal drug safely, effectively, cheap, to Candida albicans
Bacterium has good curative effect.But with the extensive use of FLC clinically so that Candida albicans to the drug resistance of azole drug not
It is disconnected to increase, therefore it is extremely urgent to find new antimycotic means.
It is the important channel for solving antifungal agent resistance that new drug research and drug combination, which are studied,.But the new drug research period is long, at
This height, and drug combination early investment is few, significant effect, by concern both domestic and external.Drug combination research includes two kinds anti-true
Bacterium medicine joint and non-antifungal are combined with antifungal.There is antimycotic work since antifungal drug kind is limited, and newly
Drug price is expensive and side effect is obvious, so that the use in conjunction research of non-antifungal drug and antifungal drug is by pass
Note.
Licofelone (licofelone) is the double inhibition of a kind of cyclooxygenase (COX), 5- lipoxygenase (5-LOX)
Agent is the non-steroidal anti-inflammatory drugs with dual anti-inflammatory effect, can be combined with the active site of COX and LOX, is generated efficient anti-
Inflammation effect, and can alleviate, improve and overcome NSAIDs to toxicity such as gastrointestinal tract, cardiovascular system and kidneys.Currently, benefit gram
Drug of the flying dragon as treatment osteoarthritis enters three phases clinical trial (Payandemehr B.A COX/5-LOX
Inhibitor Licofelone Revealed Anticonvulsant PropertiesThrough iNOS
Diminution in Mice.Neurochemical research.2015,40:1819-28).But Licofelone and fluorine health
Azoles is combined the growth that whether can inhibit Candida albicans, there is no correlative study to report at present.
Summary of the invention
For the above-mentioned prior art, it is an object of the invention to provide a kind of antifungal products of Licofelone joint Fluconazole and
It is treating the application in drug resistant candida albicans infection.
To achieve the above object, the present invention adopts the following technical scheme:
The first aspect of the present invention provides Licofelone joint Fluconazole and is preparing the purposes in antifungal products.
Preferably, when use in conjunction, the minimum inhibitory concentration of Licofelone and Fluconazole is respectively as follows: 16 μ g/ml, 1 μ g/
ml。
The result shows that effective greater than 16 μ g/ml Licofelones and the fluconazole application greater than 1 μ g/ml.
It is further preferred that the concentration of Licofelone and Fluconazole is respectively as follows: 16-128 μ g/ml, 1-64 when use in conjunction
μg/ml。
The fungi is drug resistance Candida albicans.
The second aspect of the present invention provides a kind of antimycotic pharmaceutical composition.The pharmaceutical composition includes Licofelone
And Fluconazole.
In aforementioned pharmaceutical compositions, the concentration of Licofelone is greater than or equal to 16 μ g/ml, and the concentration of Fluconazole is greater than or waits
In 1 μ g/ml.
Preferably, in aforementioned pharmaceutical compositions, the concentration of Licofelone is 16-128 μ g/ml, and the concentration of Fluconazole is 1-
64μg/ml。
It is further preferred that the concentration of Licofelone is 16 μ g/ml in aforementioned pharmaceutical compositions, the concentration of Fluconazole is 1
μg/ml。
The fungi is drug resistance Candida albicans.
Combined antimicrobial agents can behave as four kinds of " unrelated ", " addition ", " collaboration " and " antagonism " in vitro or in animal body
Effect, for inhomogeneous drug combination, due to mechanism of action and the mode of action difference of drug, it is more likely that will increase toxicity
Or there is antagonism because of the same target position of the generation or competition that induce inactivator；Moreover, different establish a capital of same class drug has
Identical effect, such as cephalosporins, the main resisting gram-positive bacteria of generation cephalo, mainly anti-leather is blue for three, four generation cephalosporins
Family name's negative bacterium, and the third generation cephalosporin kind of only part and four generation cephalos just have the function of resisting pseudomonas aeruginosa, therefore,
For the combination of antibacterials, the antibacterial effect after being used in combination has great unpredictability.
To overcome Candida albicans to the drug resistance of Fluconazole drug, by widely furtheing investigate, invention of the invention
People is found surprisingly that, as non-antimycotic drug, when concentration is applied alone less than 128 μ g/ml in Licofelone, to Candida albicans
Act on it is very weak or even without, only be higher than 128 μ g/ml concentration under just can to Candida albicans generate bacteriostasis；And incite somebody to action
When Licofelone and Fluconazole are combined, powerful collaboration antifungic action is showed.
Quantitative assessment of the present invention Licofelone combines antifungic action with Fluconazole, analyzes its increasing to Fluconazole
Quick effect, and carried out static and dynamic system evaluation.
The interaction that the concentration of two kinds of drug combinations both will affect, the present invention using drug resistance albicans cell into
Row research, using liquid quantitative method, minimum effective concentration when measuring Fluconazole and Licofelone drug combination, and with the choosing of FICI method
It selects optimal drug combined concentration and evaluates the effect of combination therapies；The present invention also uses time-kill curve method to evaluate medicine
Internet of Things dynamic antifungic action.
Beneficial effects of the present invention:
The present invention provides therapeutic scheme of the drug combination as treatment drug resistance fungal infection for clinic.In addition, epoxy closes
Enzyme/synergistic effect of the lipoxygenase economic benefits and social benefits inhibitor to Fluconazole, disclosing its synergistic effect mechanism may be with intracellular prostate
Plain E is related, and the novel targets for research antifungal drug effect provide thinking.
Present invention demonstrates that can produce collaboration antifungic action when Fluconazole and Licofelone are combined.It is resistance to fight Fluconazole
Albicans strain (the MIC of medicineFLC> 512 μ g/ml) when, the Licofelone of 16 μ g/ml can make the minimum antibacterial of Fluconazole
Concentration drops to 1 μ g/ml from 512, and concentration increases again, and effect is stronger.
It is new drug present invention demonstrates that destroying the mechanism that intracellular prostaglandin E synthesis may be joint antifungic action
Exploitation and old medicine are newly with the possible research direction of offer.
Present invention demonstrates that antifungal action of fluconazole can be remarkably reinforced in Licofelone, and reduce the minimum effectively dense of FLC
Degree, reduces the dosage of antifungal drug, to reduce the generation of the adverse reaction of drug.
Detailed description of the invention
Fig. 1 is that fluconazole Licofelone fights CA10 effect 3 d effect graph (X-axis: FLC concentration；Y-axis: benefit gram flies
Imperial concentration；Z axis: the Δ E value under each concentration combination)；
Fig. 2 is that fluconazole Licofelone fights CA16 effect 3 d effect graph (X-axis: FLC concentration；Y-axis: benefit gram flies
Imperial concentration；Z axis: the Δ E value under each concentration combination)；
Fig. 3 is the time-kill curve that fluconazole Licofelone fights CA10；
Fig. 4 is the time-kill curve that fluconazole Licofelone fights CA16.
Specific embodiment
The present invention is further illustrated in conjunction with the embodiments, it should explanation, following embodiments explanation merely to
It explains the present invention, its content is not defined.
Embodiment 1: Fluconazole combines antifungic action measurement with Licofelone
1. material
1.1 drugs and reagent
Fluconazole (fluconazole, FLC), Shandong Cheng Chuan medical sci-tech Development Co., Ltd；
Licofelone (licofelone), Shanghai Bo Famu Pharmaceutical Technology Co., Ltd；
Kerma (unit of kinetic energy) praises Candida chromogenic medium, Zhengzhou Bo Sai bioengineering Co., Ltd；
TTC- sand Borrow's agar, Hangzhou day and microorganism reagent Co., Ltd；
Sodium hydroxide, state-run Shandong Dan County Organic Chemical Plant, lot number 940420；
Potassium dihydrogen phosphate, the new precious Fine Chemical Works in Shanghai, lot number 200602132；
Dimethyl sulfoxide (DMSO), Tianjin is extensively at chemical reagent Co., Ltd；
1640 raw material medicinal powder of RPMI, GIBCO company, the U.S.；
3- (N- morpholino) propane sulfonic acid (MOPS), Jinan Peng Yuan Bioisystech Co., Ltd；
Menadione (Menadione), Sigma Co., USA；
XTT (dimethoxy azoles is yellow), Nanjing optically-active Science and Technology Ltd.；
Lactated Ringer'S Solution (ringer's solution), Shandong Lukang Cisen Pharmaceutical Co., Ltd；
Acetone, one factory of Shanghai development chemical industry, lot number 200209510；
XTT (- two (4- methoxyl group -6- nitro) benzene sulfonic acid sodium salt of 3,3'- [1- (phenylamino acyl group) -3,4- tetrazole])-first naphthalene
The preparation of quinone solution: taking XTT powder 0.0500g, is dissolved in the solution that the sterilized ringer's solution of 100ml is made into 0.5mg/ml,
With 0.22 μm of filter membrane filtration sterilizing；The menadione acetone soln that the 10mmol/L of 10 μ l is added (takes menadione 0.0860g to be dissolved in
5ml acetone), make its final concentration of 1 μm of ol/L, shake up, 2 DEG C~8 DEG C are kept in dark place.
Drug solution: Fluconazole is dissolved with sterile distilled water, and other drugs dmso solution is made into 2560 respectively
The stock solution of μ g/ml filters (0.22 μm) packing.All medical fluids are saved in -20 DEG C of refrigerators, spare.
PBS (phosphate buffer): with the PBS phosphate buffer (powder of Beijing prosperity Bioisystech Co., Ltd, ancient cooking vessel state
Agent), one bag of inner wrapping is dissolved in 1L distilled water, that is, is made into 0.01M, the PBS phosphate buffer of PH7.4,121 DEG C of high temperature and pressure
Moist heat sterilization 20min, cooling are spare.
RPMI (Roswell Park Memorial Institute) 1640 liquid mediums: take RPMI 1640 (containing L-
Glutamine is free of sodium bicarbonate) powder 2.08g, 10% glucose solution 40ml (containing sugared final concentration 2%) and MOPS is added
(3- (N- morpholinyl) propane sulfonic acid) powder 6.906g, adds distilled water to 200ml, molten with the NaOH of 1mol/L at 22 DEG C after mixing
Liquid tune pH is 7.0 ± 0.1, before use with 0.22 μm of composite fibre film filtration sterilization.
1.2 instrument
1.3 experimental strain
Quality-control strains: candida albicans ATCC10231, pharmacology teaching and research room, Shandong University give；
Experimental strain: the Candida albicans that provincial hospital, Qianfo Mount hospital clinical separate；
Bacterial strain identification: experimental strain is cultivated 48 hours in the case where Kerma (unit of kinetic energy) praises 35 DEG C of Candida chromogenic medium, and bacterium colony is in green
Or emerald green all bacterial strains, then through Shandong Center for Disease Control & Prevention's microbe research room with the identification of standard microbiology method
For Candida albicans.Obtained albicans strain is numbered respectively are as follows: CA4, CA8, CA10 and CA16, according to drug susceptibility test
As a result, CA10 and CA16 is the bacterial strain to fluconazole resistant, CA4, CA8 are the bacterial strain to fluconazole-sensitive.
Bacterium solution preparation: the Candida albicans saved at -20 DEG C thaws at room temperature, is inoculated into TTC- sand Borrow's agar medium
On, 35 DEG C of 24~48h of culture take well-developed single bacterium colony to be inoculated with again, and 35 DEG C of cultures for 24 hours, are given birth to guaranteeing that bacterial strain is in
For a long time.Choose it is several individually compared with macrocolony, PBS is configured to bacteria suspension, with Chinese bacterial turbidity mark after vortice shaken well
Quasi- pipe is than turbid, and adjustment sample cell is consistent with standard pipe turbidity, and the bacteria concentration of Candida albicans is about 4.5 × 10 at this time6CFU/ml,
It is serially diluted and obtains work bacterium solution, and concentration verifying is carried out with count plate.
2. content and method
2.1 Fluconazoles combine antifungic action measurement with Licofelone
2.1.1 micro-dilution method
According to the chessboard method of CLSI M27-A3 scheme, 4 times are become with RPMI-1640 fluid nutrient medium dilute liquid medicine
Working concentration, screens Licofelone and Fluconazole concentration application range, the i.e. final concentration of Licofelone are respectively 128~2 μ g/
Ml, Fluconazole are 64~0.125 μ g/ml.50 μ l of azole medical fluid is drawn by the sequence of concentration from low to high, it is flat to be separately added into 96 holes
2nd~12 column of plate draw 50 μ l of Licofelone medical fluid by the sequence of concentration from low to high, are separately added into the G of 96 hole plates
~A row, each hole adds 100 μ l bacterium solutions respectively again in addition to A12, remaining is supplied less than the hole of 200 μ l with RPMI-1640 culture solution.Its
Middle H1 is growth control, and containing only bacterium solution, drug containing, A12 are not blank control, is free of bacterium solution containing only medical fluid.96 hole plates are set 35
After being cultivated for 24 hours in DEG C constant incubator, is measured after being loaded with XTT with microplate reader and record result.All experiments are in triplicate.
2.1.2 time-kill curve method
By concentration be 2560 μ g/ml Fluconazole and Licofelone medicine storage liquid with 1640 fluid nutrient medium 10 of RPMI
It is diluted to working concentration again.
Take the experimental strain (CA10) passed on TTC- sand Borrow's agar medium twice, picking individually compared with macrocolony, with
Bacteria suspension is made in PBS, is carried out using Chinese bacterial turbidity standard than turbid, when standard pipe is consistent with sample cell concentration, at the beginning of bacterium solution
Beginning concentration is about 4.5 × 106CFU/ml, with RPMI-1640 dilution bacterium solution be 10 times of working concentrations, and by viable bacteria counting method into
The verifying of row concentration.
It takes the 500 μ l of medical fluid of above-mentioned preparation to be added in corresponding test tube, adds 1640 fluid nutrient medium of RPMI to liquid
Total volume is 4.5ml；500 μ l of the bacterium solution prepared according to the above method is taken to be added to the training that this 4.5ml contains (or being free of) drug at this time
It supports in base, concussion mixes.This experiment is divided into four groups, it may be assumed that group, fluorine health is applied alone in growth control group (not dosing), Licofelone drug
Group, Licofelone and fluconazole medication group is applied alone in azoles, totally 4 systems.Each system total volume is 5ml, fluorine health in system
The final concentration of azoles and Licofelone is respectively 1 μ g/ml and 16 μ g/ml, and bacterium solution final concentration is about 4.5 × 10 in system3CFU/ml。
The system that preparation is finished is in 35 DEG C of stationary cultures, in the point in time sampling survey of the pharmaceutically-active 0th, 6,12,24,36,48h
It is fixed.
2.2 evaluation methods and result judgement
2.2.1 LA is theoretical
The basic thought of Loewe additivity (LA) theory thinks that drug can not interact with itself,
Therefore drug is applied alone or is combined and generated the concentration (equivalent site) of identical drug effect and be compared.Its analysis method score is antibacterial dense
It spends index method (fractional inhibitory concentration index, FICI), is expressed as follows:
Σ FIC=FICA+FICB=CA/MICA+CB/MICB
MICAAnd MICBIt is minimal inhibitory concentration when drug A and B are applied alone, C respectivelyAWith CBTo reach phase when the combination of two medicines
Respective concentration when with drug effect.FICI > 4 is antagonism, and FICI is added between 0.5 and 4 or unrelated effect, FICI≤
0.5 is defined as acting synergistically.
2.2.2 XTT method (dimethoxy azoles Huang colorimetric method)
Each system is mixed on spiral oscillator in sampling time point, the bacteria suspension drawn in 100 μ l systems is added
Into 96 hole flat-bottomed plates, using sterile 1640 fluid nutrient medium of RPMI of 100 μ l as blank control, then distinguish
The prepared XTT- menadione solution of 100 μ l is added into the hole after each sample-adding, it is small that culture plate is protected from light culture 2 at 35 DEG C
When, single hole blank is arranged in microplate reader, and the OD value in each hole is surveyed 492nm at, and each system does three groups, be averaged record as a result,
Test is repeated 3 times.
3. result
3.1 Fluconazoles combine antifungic action result with non-antibacterials
3.1.1 Fluconazole and the medication combined minimum effective bacteria concentration of non-antibacterial
The calculation method of fungi growth percentage in each hole are as follows:
Fungi grows percentage=(each hole OD value-blank control wells OD value)/growth control hole OD value
Percentage is grown by hole fungi each in above-mentioned formula calculate flat board, takes and is able to suppress the minimum of fungi growth 80%
Be interpretation terminal with drug concentration, if fungi growth rate not be exactly equal to 20%, take therewith immediate medication combined hole be
Interpretation terminal.
Fluconazole combines antifungic action with Licofelone, unobvious for sensitive strain, mostly unrelated, and to drug resistance
Strain, then be presented Strong synergy.Growth percentage experimental result wherein in persister CA10 plate is as shown in table 1；Persister
Growth percentage experimental result in CA16 plate is as shown in table 2.
Table .1. indicates that the drug combination overriding resistance Candida albicans CA10 of Fluconazole and Licofelone grows percentage with chessboard
Rate (shares gray scales with drug the best use group that FICI method converts to go out).
Table .2. indicates that the drug combination overriding resistance Candida albicans CA16 of Fluconazole and Licofelone grows percentage with chessboard
Rate (shares gray scales with drug the best use group that FICI method converts to go out).
3.1.2 the synergistic effect of FICI method evaluation FLC/ Licofelone
Repeated experiment acquired results are shown in Table 3 three times.By measurement result as it can be seen that Licofelone and fluconazole application
When, equal to the effect FICI of drug resistance Candida albicans < 0.5, synergistic effect is presented.And then to the FICI value of sensitive Candida albicans
Between 0.5 and 1, unrelated effect is presented.
Table 3 comments Fluconazole/Licofelone drug combination antifungic action with FICI method
3.1.3 time-kill curve method evaluates Fluconazole/Licofelone synergistic result
The result of various time points joint antifungic action is connected into curve, the dynamic action after observable drug combination
Effect, as shown in Figure 3,4: 4.5 × 103Bacterium solution in front of 6h the variation of dosing group and control group OD value it is little, and it is right
It is compared according to group, each group containing Fluconazole starts growth delay occur after 6h, wherein Fluconazole/Licofelone combination group processing
Fungi growth delay become apparent from.Compared with the control group, each drug effect group is best to the inhibitory effect of fungi for 24 hours, finally
Effect slowly dies down with the time.
4. conclusion
Antifungal drug is less in clinical application and the status of drug resistance phenomenon occurs, the antifungal drug of development of new
It is to solve the problems, such as one of this approach, while come to increase fungi be also one to the sensibility of drug by way of drug combination
The preferable selection of kind.Licofelone has certain anti-true when being applied alone as cyclooxygenase/lipoxygenase economic benefits and social benefits inhibitor high concentration
Bacterium effect, when being combined with FLC to overriding resistance Candida albicans, Licofelone can significantly reduce the MIC value of FLC, show strong association
Same-action.But Licofelone and Fluconazole are combined to the Candida albicans of non-white candida albicans and sensitivity almost without effect.It is existing
It is applied alone some researches show that cyclooxygenase-2 inhibitors or all there is certain antifungic action, the antifungic action with Fluconazole combination
There is substantial connection with the synthesis of prostaglandin E is inhibited.As cyclooxygenase/lipoxygenase economic benefits and social benefits inhibitor Licofelone with
Whether the synergistic effect mechanism of FLC is also related with prostaglandin E synthesis is affected, and needs further to be studied.Present invention demonstrates that FLC
Clinically there is certain application prospect with the drug resistant candida albicans infection of Licofelone combination therapy.
Above-mentioned, although specific embodiments of the present invention have been described in conjunction with the embodiments, not protects to the present invention
The limitation of range, those skilled in the art should understand that, based on the technical solutions of the present invention, those skilled in the art
The various modifications or changes that can be made are not needed to make the creative labor still within protection scope of the present invention.
Claims (5)
1. Licofelone joint Fluconazole is preparing the purposes in overriding resistance Candida albicans product, which is characterized in that combine and answer
The concentration of used time, Licofelone and Fluconazole is respectively as follows: 16-128 μ g/ml, 1-64 μ g/ml.
2. a kind of pharmaceutical composition of overriding resistance Candida albicans, which is characterized in that described pharmaceutical composition includes Licofelone
And Fluconazole.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that in pharmaceutical composition, the concentration of Licofelone is greater than
Or it is equal to 16 μ g/ml, the concentration of Fluconazole is greater than or equal to 1 μ g/ml.
4. pharmaceutical composition as claimed in claim 2, which is characterized in that in pharmaceutical composition, the concentration of Licofelone is 16-
128 μ g/ml, the concentration of Fluconazole are 1-64 μ g/ml.
5. pharmaceutical composition as claimed in claim 2, which is characterized in that in pharmaceutical composition, the concentration of Licofelone is 16 μ
G/ml, the concentration of Fluconazole are 1 μ g/ml.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103520157A (en) * | 2013-10-22 | 2014-01-22 | 山东省千佛山医院 | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs |
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| CN103520157A (en) * | 2013-10-22 | 2014-01-22 | 山东省千佛山医院 | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs |
Non-Patent Citations (2)
| Title |
|---|
| Licofelone, a Balanced Inhibitor of Cyclooxygenase and 5-Lipoxygenase, Reduces Inflammation in a Rabbit Model of Atherosclerosis;Cristina Vidal等;《THE JOURNAL OF PHARMACOLOGYAND EXPERIMENTAL THERAPEUTICS》;20071231;第320卷(第1期);第108-116页，尤其是第108页摘要 |
| Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review;Xinning Liu等;《Frontiers in Microbiology》;20161206;第7卷;第1925页，尤其是第1页摘要，第3页右栏第2段，第6页右栏第1段 |
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