CN103520157B - Application of combination of tacrolimus and fluconazole in preparing antifungal drugs - Google Patents
Application of combination of tacrolimus and fluconazole in preparing antifungal drugs Download PDFInfo
- Publication number
- CN103520157B CN103520157B CN201310499539.1A CN201310499539A CN103520157B CN 103520157 B CN103520157 B CN 103520157B CN 201310499539 A CN201310499539 A CN 201310499539A CN 103520157 B CN103520157 B CN 103520157B
- Authority
- CN
- China
- Prior art keywords
- fluconazole
- tacrolimus
- flc
- drug
- combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention discloses application of combination of tacrolimus and fluconazole in preparing antifungal drugs. According to the invention, static and dynamic combined antifungal effects of combination of tacrolimus and fluconazole to common non-albicans candida species are researched by various methods. The researches show that combination of tacrolimus and fluconazole has a remarkable synergic antifungal effect to common non-albicans candida species (candida glabrata and candida krusei). Predictably, combination of tacrolimus and fluconazole can be used for preparing antifungal drugs. According to the invention, tacrolimus and fluconazole are applied in a combined way to enhance the antimicrobial activity of fluconazole to non-albicans candida species so as to generate the synergic antifungal effect. Combination of tacrolimus and fluconazole can reverse the drug resistance of non-albicans candida species to fluconazole, thereby providing a research direction for development of new drugs and new use of old drugs.
Description
Technical field
The present invention relates to tacrolimus associating fluconazol and prepare the application in antifungal drug.
Background technology
Along with the continuous increase of tumor and HIV sufferers, organ transplantation, generally the carrying out of intubation catheter and endoscopic technique, the extensive use of high-efficiency broad spectrum antibiotic, FK506 and hormone, the sickness rate of mankind's deep fungal infection increases year by year, and fungus has become the important pathogenic bacteria of nosocomial infection.Candida albicans is isolate common in fungus Infection, and fluconazol (fluconazole, FLC) is effective to it.But along with FLC is in clinical extensive use, to its insensitive non-white candidiasis (non-Candida albicansspecies), as Candida glabrata (Candida glabrata, CG), Oidium tropicale, Candida krusei (Candida krusei, CK), Candida parapsilosis etc., separation rate rises gradually, and in the patient of organ transplantation, increasing non-white candidiasis is separated, even at the separation rate of certain areas non-white candidiasis higher than Candida albicans.According to the literature, non-white candidiasis reaches 57.5% to FLC resistant rate, and wherein Oidium tropicale, Candida glabrata reach 19.4% to FLC drug resistance, and Candida krusei reaches 100% to FLC resistant rate.In addition, there is crossing drug resistant in various degree to the medicine such as FLC, itraconazole in non-white candidiasis, cross resistance is higher than Candida albicans.Therefore, non-white candidiasis is in recent years because separation rate constantly raises, and low to the sensitivity of conventional antifungal drug, brings challenge, attract attention and pay attention to clinical anti-infective therapy.
Non-white candidiasis is all different from Candida albicans in structure, pathogenic, drug resistance etc.; Although virulence is weak, it is very strong to the adhesion of biological surface, and the patient of easy infection immunocompromised, mortality rate is high.Existing antifungal drug kind is limited, although new triazole antifungal agent voriconazole, echinocandin class medicine Caspofungin and amphotericin B for clinical are effective to non-white candidiasis, but they are expensive, and side effect is large, and develop the medicine that new antimicrobial spectrum can cover non-white candidiasis, consuming time costly.FLC is clinical the most frequently used antifungal drug, has that low price, side effect are little, bioavailability advantages of higher.Therefore, if find to increase the composition of FLC to non-white candidiasis sensitivity from the medicine applied clinically, combine and overcome the drug resistance of non-white candidiasis to FLC, will important clinical meaning be had.
Study about FLC and other drug coupling antifungal and can be divided into two large classes: one is the coupling be all between antifungal drug; Two is the couplings between FLC and non-antifungal drug.In recent years, the second coupling mode provides new thinking to antifungal research, and becomes the focus of everybody research.When these non-antifungal drugs are applied separately to the action effect of fungus very weak or nothing, but its antifungic action can be strengthened with during FLC coupling, present synergistic action effect.
Tacrolimus (tacrolimus, FK506) is widely used in the patient of organ transplantation, autoimmune disease clinically, and these patients subject to fungal infection.FK506 has the chance with FLC use in conjunction clinically; In addition, now there are some researches show that FK506 combines with azole drug, there is the effect of anti-candida albicans, particularly to fastbacteria.But the drug resistance of non-white candidiasis to FLC can be reversed for FK506 and FLC coupling, there is no large-scale quantitative study report at present.
Summary of the invention
For above-mentioned prior art, the present invention intends in a variety of ways, research FLC and FK506 coupling is to the static and dynamic Status associating antifungic action of common non-white candidiasis, research finds, tacrolimus associating fluconazol has obvious inhibitory action to non-white candidiasis (Candida glabrata and Candida krusei), these non-white candidiasises can be reversed to the drug resistance of FLC, can predict, tacrolimus associating fluconazol may be used for preparing antifungal drug, and these funguses comprise Candida glabrata and Candida krusei.
Further, for the Candida glabrata to fluconazol being dose dependent sensitivity, during use in conjunction, the minimum inhibitory concentration of tacrolimus is 0.5 μ g/ml, and the minimum inhibitory concentration of fluconazol is 8 μ g/ml.For the Candida glabrata to fluconazole resistant, the minimum inhibitory concentration of tacrolimus is 8 μ g/ml, and the minimum inhibitory concentration of fluconazol is 16 μ g/ml.For the Candida krusei to fluconazol being low drug resistance, the minimum inhibitory concentration of tacrolimus is 0.25 μ g/ml, and the minimum inhibitory concentration of fluconazol is 8 μ g/ml; For the Candida krusei to fluconazol high drug resistance, the minimum inhibitory concentration of tacrolimus is 8 μ g/ml, and the minimum inhibitory concentration of fluconazol is 16 μ g/ml.
Further, the concentration of described tacrolimus and fluconazol is best with tacrolimus 0.5 μ g/ml, fluconazol 8 μ g/ml.
Through retrieval, although the report of existing tacrolimus and fluconazole anti-candida albicans, combine the antifungic action research report to non-white candidiasis both there is no at present, so application of the present invention possesses unobviousness.Tacrolimus and fluconazole are applied by the present invention, the antibacterial activity of fluconazol to non-white candidiasis can be strengthened, produce collaborative antifungic action, and the drug resistance of non-white candidiasis to fluconazol can be reversed, for the exploitation of new drug and old medicine are newly with providing research direction.Accompanying drawing explanation
Fig. 1: FLC and the anti-CK9 action effect of FK506 coupling (with XTT show two medicines associating time in the action effect of 96 hole flat boards).
Fig. 2: FLC and FK506 coupling anti-CK9 effect 3 d effect graph (X-axis: FLC concentration; Y-axis: FK506 concentration; Z axis: the Δ E value under each concentration combination).
Fig. 3: FLC and FK506 coupling to the time-kill curve of non-white candidiasis, wherein, (A): FLC and FK506 coupling to the curve chart of Candida glabrata CG4, FLC concentration 10 μ g/mL, FK506 concentration 0.5 μ g/mL; (B): FLC and FK506 coupling to the curve chart of Candida krusei CK4, FLC concentration 10 μ g/mL, FK506 concentration 0.25 μ g/mL.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1FLC and FK506 combines antifungal static action and measures
1. material
1.1 experimental strain
Quality-control strains: reference culture CPATCC10231(Candida parapsilosis).
Experimental strain: the non-white candidiasis of clinical separation, differentiates to confirm through Kerma (unit of kinetic energy) good colour developing differential medium, Secondary Culture on solid medium.Candida glabrata is numbered CG1, CG2, CG3, CG4, CG5, CG8, and Candida krusei is numbered CK2, CK3, CK4, CK6, CK7, CK8, CK9, CK10.
1.2 medicines and reagent
FLC, Shandong Chengchuang Medicine Technology Development Co., Ltd.
FK506, Nat'l Pharmaceutical & Biological Products Control Institute.
PBS(phosphate buffer) powder, Beijing Suo Laibao Science and Technology Ltd., lot number 101012.
PBS solution: take PBS powder (Beijing Suo Laibao Science and Technology Ltd.) 24g, be dissolved in the PBS buffer solution namely obtaining pH7.2 in 2L distilled water.121 DEG C of High Temperature High Pressure moist heat sterilization 20min, cooling subpackage is for subsequent use.
Dimethyl sulfoxide (DMSO), Merck company.
MOPS (MOPS), Beijing DingGuo ChangSheng Biology Technology Co., Ltd.
Yeast extract, Beijing extensive and profound in meaning star biotechnology Co., Ltd, lot number 100402.
Peptone, Beijing extensive and profound in meaning star biotechnology Co., Ltd, lot number 100526.
Glucose, Chemical Reagent Co., Ltd., Sinopharm Group, lot number 20101102.
Agar powder, Beijing DingGuo ChangSheng Biology Technology Co., Ltd.
RPMI1640 liquid medium: get RPMI1640(containing L-glutaminate, not containing sodium bicarbonate) powder (GIBCO company of the U.S.) 4.16g, add 10% glucose solution 80ml and MOPS powder 13.812g, adding distil water is to being about 400ml, adjust pH to be 7.0 22 DEG C of NaOH solution with 1mol/L after mix homogeneously, use the sterilizing of 0.22 μm of composite fibre membrane filtration before use.
Yeast extract-peptone-glucose (YPD) agar culture medium: glucose 20g, peptone 20g, yeast extract 10g, agar powder 20g, dissolve with 1000ml distilled water, stir rear 121 DEG C of sterilizing 20min, cool rear 4 DEG C of Refrigerator stores for subsequent use;
XTT-menadione solution: get XTT powder 0.0500g, is dissolved in the solution that the sterilized ringer's solution of 100ml is made into 0.5mg/ml, filters sterilizing with 0.22 μm of filter membrane; Add the menadione acetone soln (get menadione 0.0860g and be dissolved in 5ml acetone) of the 100mmol/L of 10 μ l, make its final concentration be 10 μm of ol/L, shake up, 4 DEG C keep in Dark Place.
96 well culture plates, COSTAR company of the U.S..
1.3 instrument
2. content and method
The determination of 2.1 experimental strains and bacterial strain
Non-white candidiasis is mainly divided into Candida glabrata, Candida parapsilosis, Oidium tropicale and Candida krusei etc.In above-mentioned 4 kinds of bacterium, Candida krusei drug resistance is maximum, and it constantly rises to itraconazole resistant rate to FLC natural drug resistance, and between azole drug, there is crossing drug resistant phenomenon; Candida glabrata has very strong acquisition drug resistance because of it, and its drug resistance is only second to Candida krusei; Oidium tropicale and Candida parapsilosis are to FLC rdativery sensitive.But with regard to separation rate, be the highest in non-white candidiasis at the separation rate of a lot of regional Candida glabrata, be secondly Oidium tropicale and Candida parapsilosis, Candida krusei relative separation rate is low, only has higher separation rate in minority area.Comprehensively to sensitivity and the clinical separation rate of FLC, this test selects Candida glabrata and Candida krusei to carry out follow-up research.
After experimental strain is determined, Candida glabrata and the Candida krusei bacterial strain of different sensitivity are selected in the drug sensitive test that the M27-A3 scheme of recommending according to NCCLS carries out FLC.96 orifice plates add well, and constant temperature 35 DEG C cultivates 24h.Then add XTT-menadione solution lucifuge and cultivate 2h, survey OD value by microplate reader at 492nm place.According to the newest standards at 24h interpretation break, (for CG:MIC≤32 μ g/ml, being dose dependent sensitive strain SDD, MIC > 32 μ g/ml, is Resistant strain R; For CK: be natural drug resistance bacterial strain R), the Candida glabrata chosen is CG4(SDD), CG8(SDD), CG2(R), CG3(R); The low drug resistance of Candida krusei CK2(), the low drug resistance of CK3(), the low drug resistance of CK4(), the low drug resistance of CK6(), the low drug resistance of CK7(), CK8(high drug resistance), CK9(high drug resistance), CK10(high drug resistance).
2.2 experimental bacteria liquid and the preparation of testing medicinal liquid
2.2.1 the preparation of bacterium liquid
Strain subject transferred species 2 times in YPD culture medium, picking single comparatively macrocolony PBS buffer is made into bacteria suspension, and with Chinese antibacterial standard turbidity pipe than turbid, adjustment concentration is about 4.5 × 10
6cFU/mL, is diluted with RPMI1640 fluid medium and makes to work bacterial concentration for 2.25 × 10 in 96 hole flat boards
3cFU/mL.Under the microscope with blood counting chamber checking work bacterial concentration.
2.2.2 the preparation of medicinal liquid
FLC is made into 2560 μ g/ml with sterile purified water, and FK506 is made into 6400 μ g/ml with DMSO, each mother liquid medicine is carried out two-fold dilution with RPMI1640 and reaches series of tasks concentration.
2.3 associating drug sensitive detections
According to the Fungus antifungal susceptibility M27-A3 scheme that NCCLS promulgates, adopt MIC value when 96 orifice plate model determination FLC and FK506 coupling.Premenstruum, experiment condition was groped, and each bacterial strain work bacterial concentration is 2.25 × 10
3the concentration of CFU/mL, FLC is designed to 0.25-128 μ g/ml, the concentration of the CG of dose dependent sensitivity (SDD) and the CK of low drug resistance, FK506 is designed to the drug level 0.008-0.5 μ g/ml that can reach in body; 0.25-16 μ g/ml is designed to the concentration of the CG of drug resistance and the CK of high drug resistance, FK506.12nd row do not add bacterium liquid as blank, and all the other each holes add 100 μ l bacterium liquid, and H1 hole is growth control wells.All the other holes less than 200 μ l are with RPMI-1640 polishing.After 35 DEG C of constant temperature culture 24h, then add XTT-menadione solution lucifuge and cultivate 2h, survey OD value by microplate reader at 492nm place.Conk percent is calculated as follows: conk percent=(each hole OD value one blank control wells OD value)/growth control hole OD value × 100%, to suppress the lowest concentration of drug of more than 80% conk for MIC value after obtaining OD value.All experiments in triplicate.
2.4 evaluation methodologys and result judge
The theoretical basic thought of Loeweadditivity (LA) thinks that medicine can not interact with itself, and the concentration (equivalent site) that therefore medicine is alone or coupling produces identical drug effect compares.Its analytical method is mark Mlc index method (fractionalinhibitoryconcentrationindex, FICI), is expressed as follows:
ΣFIC=FIC
A+FIC
B=C
A/MIC
A+C
B/MIC；
MIC
aand MIC
bbe respectively medicine A and B alone time minimal inhibitory concentration, C
awith C
brespective concentration when reaching identical drug effect when being two medicine couplings.Synergy effect assessment standard is according to the suggestion of Odds: FICI≤0.5 is collaborative, and FICI>4 is antagonism, for being added or haveing nothing to do between 0.5 with 4.
3. result
Experimental result shows that FLC and FK506 coupling shows as synergism to all Candida glabratas and Candida krusei.24h and 48h evaluation of effect result is summed up as shown in Table 1 and Table 2.
The MIC value of the alone and coupling 24h of table 1FLC and FK506 and act on result of determination
The MIC value of the alone and coupling 48h of table 2FLC and FK506 and act on judgement
The CK synergism of FLC and FK506 coupling to the CG of drug resistance and high drug resistance is better as can be seen from the above table, and FICI value is much smaller than 0.5.Wherein in FLC and FK506 coupling is measured the drug sensitive experiment of CK9, add XTT lucifuge and hatch the photo after 2h as shown in Figure 1.Can find out the synergism that two medicines are stronger significantly from figure, FK506 adds the MIC that can make CK9
80%drop to 16 μ g/ml from 256 μ g/ml, have dropped 4 gradients.
For showing FK506 and FLC coupling more intuitively to the effect degree of the non-white candidiasis of drug resistance, the Δ E(of associating drug sensitive detection data based on BI theory is grown percent difference) model analysis.E is conk percent, Δ E=E
theoretical-E
actual.Wherein, E
theoretical=E
a× E
b, for when medicine A and B coupling under without interactional hypothesis theoretic conk percent, E
awith E
bbe respectively the conk percent of reality when two kinds of medicines are applied separately; E
actualfor actual growth percent corresponding under each group drug combination concentration.Drug interaction effect is evaluated with the difference-Δ E of the theoretical value of conk percent under each concentration of medicine and experiment value, and the combination of each drug combination all can obtain a Δ E value.With the mapping of Matlab data analysis software, be respectively X-axis and Y-axis with two concentrations of use in conjunction, Δ E value is Z axis, can form a 3-D view, in 0 plane or under peak represent respectively and work in coordination with or antagonism, 0 plane indicates to be distinguished without statistically significant.When FK506 and FLC coupling is to the interpretation of CK924h result, the 3-D view that the Δ E value that coupling drug regimen is corresponding is formed as shown in Figure 2.Both coupling CK9 to high drug resistance present stronger synergism as seen from Figure 2, and have higher Δ E value in effective drug level scope, figure camber is higher, and synergistic action effect is better.
4. conclusion
Antifungal drug is less and occur the present situation of drug resistance phenomenon in the clinical practice, the antifungal drug of development of new is one of approach addressed this problem, and increase fungus to the sensitivity of medicine by the mode of drug combination is also a kind of selection preferably simultaneously.FLC and FK506 coupling can reach in vivo to the Candida glabrata of SDD with to the FK506 concentration of the Candida krusei onset of the low drug resistance of FLC; Be difficult in vivo reach to the FK506 concentration of the CG of drug resistance and the CK onset of high drug resistance, can only at indivedual internal organs as liver perhaps can reach.But meaningfully, there is the Candida glabrata of bibliographical information drug resistance only to account for 9%; The Candida krusei (MIC > 64 μ g/ml) of high drug resistance account for 40%, and the Candida krusei of low drug resistance account for 57%.The CG of proportion more than drug resistance that account for of the CG of SDD and the CK of low drug resistance and the CK of high drug resistance as can be seen from the above data, FLC and FK506 therapeutic alliance non-white monilial infection has certain application prospect clinical.
Embodiment 2FLC and FK506 combines antifungal dynamic action and measures
1. material
1.1 bacterial strain
Experiment bacterial strain uses therefor is Candida glabrata CG4 and the Candida krusei CK4 of clinical separation, praises yeast differential medium and differentiates to confirm, Secondary Culture on solid medium through Kerma (unit of kinetic energy).
1.2 medicines and reagent
FLC and FK506 crude drug; Dimethyl sulfoxide DMSO; PBS buffer; 0.1mol/LNaOH solution; CHROMagar (France); RPMI1640(GIBCO, the U.S., containing L-glutaminate, not containing sodium bicarbonate, adjusts pH to 7.0 with MOPS buffer); Yeast extract-peptone-glucose (YPD) agar culture medium.
1.3 instrument
MMM-55L constant incubator (Germany); MMM-55L dry heat sterilizer (Germany); THZ-C constant temperature oscillator; HS-9041 desk-type steam sterilizer (Korea S); The ultra-clean operating board of ESCO (Korea S).
2. content and method
This experiment adopts Experimental agents obtainable concentration in body, sets up medicine alone with drug combination effect system, at 35 DEG C of shaken cultivation 48h.From system, draw a small amount of bacterium liquid at 0h, 6h, 12h, 24h, 48h respectively, after serial dilution, fall plate count, measure the dynamic antibacterial activity size of medicine.
The foundation of 2.1 systems
4 effect systems are set up in experiment: alone group of growth control group, FK506, alone group of FLC and FLC and FK506 coupling group.
2.1.1 experimental bacteria liquid and the preparation of testing medicinal liquid
Be taken at CG4 and CK4 of twice that YPD culture medium goes down to posterity, the single comparatively macrocolony of picking, makes bacteria suspension with PBS buffer, and adopt Chinese turbidity standard to carry out than turbid, initial concentration is 4.5 × 10
6cFU/mL, is suitably diluted to working concentration with RPMI1640 fluid medium.Under the microscope with blood counting chamber checking work bacterial concentration.
Get the mother liquid medicine prepared with method with embodiment 1, doubling dilution is carried out with RPMI1640, with reference to the obtained concentration of medicine in human body and last point of static drug sensitive experiment result, preparation work medicinal liquid, the concentration of medicine in time-kill curve work system is respectively: FLC-10 μ g/mL, FK506-0.5 μ g/mL(CG4); FLC-10 μ g/mL, FK506-0.25 μ g/mL(CK4).
2.1.2 the preparation of system and cultivation
Preparation growth control group, alone group of FK506, alone group of FLC and FLC and FK506 coupling group four systems, each system is 5mL, and often group adds 0.5mL bacterium liquid, and concrete preparation method is in table 3.
Table 3 drug effect system preparation method
By system complete for preparation in 35 DEG C of shaken cultivation 48h.
Dynamic Determination of Antibacterial Activity during 2.2 drug combination
After the preparation of effect system, 0h, 6h, 12h, 24h and 48h respectively after Establishing draw a certain amount of bacteria suspension from each group, and after series 10 times dilution, adopt colony counting method to measure the dynamic antibacterial activity of the alone and coupling of medicine.Experiment repetition is averaged for 3 times.
3. result
This part experiment coupling evaluating drug effect standard is as follows: if compared with the composition the strongest with activity, and the common logarithm drop-out value of drug combination system every milliliter of CFU is more than or equal to 2 for synergism; Compared with the composition that activity is minimum, the common logarithm lift-off value of every milliliter of CFU is more than or equal to 2 for antagonism; Other situations are irrelevant effect.According to different time points colony counting result, draw FLC respectively with time-kill curve to CG4 and CK4 in FK506 coupling 48h, as shown in Figure 3.As can be seen from Figure 3, for Candida glabrata CG4 and Candida krusei CK4, alone group of FK506 compares almost without antifungic action with growth group, alone group of FLC has certain antifungic action, FLC with FK506 coupling group is compared with alone group of FLC, the drop-out value commonly using logarithm value during 24h has all exceeded 2, and curve has good separation, and collaborative antifungic action is stronger.
4. conclusion
Dynamic action result on strain subject impact when time-kill curve method can provide medicine alone or coupling, is widely used in evaluating antibacterial effect during the alone and coupling of antibacterials.After these research trends antibacterial experiment result shows FLC and FK506 coupling, synergism is presented to Candida glabrata CG4 and Candida krusei CK4, this is consistent with a upper chapter experimental result, and the concentration of FLC and FK506 applied is the drug level that can reach in vivo.
Claims (1)
1. tacrolimus associating fluconazol is preparing the application in antifungal drug, it is characterized in that: described fungus is Candida krusei.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310499539.1A CN103520157B (en) | 2013-10-22 | 2013-10-22 | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310499539.1A CN103520157B (en) | 2013-10-22 | 2013-10-22 | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103520157A CN103520157A (en) | 2014-01-22 |
| CN103520157B true CN103520157B (en) | 2015-05-20 |
Family
ID=49922748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310499539.1A Expired - Fee Related CN103520157B (en) | 2013-10-22 | 2013-10-22 | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103520157B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104382901B (en) * | 2014-11-24 | 2016-07-20 | 山东省千佛山医院 | The antifungal products of amlodipine or flunarizine associating fluconazol and application thereof |
| CN105497026B (en) * | 2015-12-14 | 2017-11-10 | 山东省千佛山医院 | Application of benzenebutanoic acid joint antifungal drug in triazole class and products thereof |
| CN106619621B (en) * | 2016-12-14 | 2019-04-23 | 山东省千佛山医院 | Licofelone combines antifungal products and its application of Fluconazole |
| CN113384570B (en) * | 2021-07-13 | 2022-08-26 | 山东省妇幼保健院 | Application of caffeic acid methyl ester and triazole composition in preparation of antifungal products |
| CN115671293B (en) * | 2022-11-01 | 2024-02-23 | 攀枝花市中西医结合医院 | Antifungal pharmaceutical composition and application thereof |
-
2013
- 2013-10-22 CN CN201310499539.1A patent/CN103520157B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103520157A (en) | 2014-01-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103520157B (en) | Application of combination of tacrolimus and fluconazole in preparing antifungal drugs | |
| Gomes et al. | Mucormycosis caused by unusual mucormycetes, non-Rhizopus,-Mucor, and-Lichtheimia species | |
| CN105801670A (en) | Polypeptide with antibacterial activity and application thereof | |
| Wang et al. | Susceptibilities of Malassezia strains from pityriasis versicolor, Malassezia folliculitis and seborrheic dermatitis to antifungal drugs | |
| Dogra et al. | Mucormycosis amid COVID-19 crisis: pathogenesis, diagnosis, and novel treatment strategies to combat the spread | |
| Mada et al. | Trichosporon asahii septic thrombophlebitis following lower extremity amputation in an immunocompetent host | |
| CN103007287A (en) | Application of rhamnolipid as oral medicine absorbent accelerant | |
| CN111419841B (en) | Anti-candida albicans combined medicine | |
| Pagalavan | Melioidosis: the johor bahru experience | |
| CN102274215A (en) | Synergist with synergetic antifungal effect with fluconazole | |
| CN106309526B (en) | A kind of composition and its application of the arasaponin and Fluconazole of antifungal antibody-resistant bacterium | |
| CN101301289A (en) | Uses of berberine and analog thereof in pump for reversing multidrug resistance | |
| CN108478566A (en) | Application and products thereof of the butylphenyl phthaleine in preparing antifungal products | |
| CN106974914B (en) | Linezolid combines antifungal products and its application of Fluconazole | |
| CN104188962A (en) | Application of magnolol and azole medicines to preparation of antifungal combined medicines | |
| CN103040852B (en) | Application of lysine as synergist for preparing antifungal drug | |
| Palmore et al. | Fusarium proliferatum soft tissue infection at the site of a puncture by a plant: recovery, isolation, and direct molecular identification | |
| Ukekwe et al. | Candidiasis, a rare cause of gastric perforation: a case report and review of literature | |
| Chen et al. | Enhancement in serum (1–3)-β-D-glucan level by cutaneous alternariosis: A case report and literature review | |
| CN105998011B (en) | Antifungal medicine composition and application thereof | |
| CN101816646B (en) | Application of theaflavin as synergist of antifungal medicine | |
| CN101816666B (en) | Use of forsythiaside as synergist of antifungal agents | |
| CN104474550A (en) | Pharmaceutical composition capable of killing drug-resistant aspergillus fumigatus and method for killing drug-resistant aspergillus fumigatus | |
| CN101961328B (en) | Application of sodium houttuyfonate as synergist of antifungal medicament | |
| CN103690554B (en) | Kill compositions and the method for drug resistance Aspergillus fumigatus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150520 Termination date: 20181022 |