CN104382901B - The antifungal products of amlodipine or flunarizine associating fluconazol and application thereof - Google Patents
The antifungal products of amlodipine or flunarizine associating fluconazol and application thereof Download PDFInfo
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Abstract
The invention discloses the antifungal products of amlodipine or flunarizine associating fluconazol and application thereof, valid density proportioning when amlodipine and fluconazole application: fluconazol: amlodipine=1:8 (μ g/ml)；Valid density proportioning fluconazol: flunarizine=1:16 (μ g/ml) when flunarizine and fluconazole application.During use in conjunction, amlodipine is respectively as follows: 8 μ g/ml, 1 μ g/ml with the minimum inhibitory concentration of fluconazol；The minimum inhibitory concentration of flunarizine and fluconazol is respectively as follows: 16 μ g/ml, 1 μ g/m.Calcium ion channel blocker is extensive use clinically, and it is to FLC antifungal potentiation, can expand its range of application, and reduces the minimal effective concentration of FLC, reduces the dosage of antifungal drug, thus reducing the generation of the untoward reaction of medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to antifungal products and the application thereof of amlodipine or flunarizine associating fluconazol.
Background technology
In recent years, along with increasing of hypoimmunity crowd (patient such as malignant tumor, acquired immune deficiency syndrome (AIDS), autoimmune disease), carrying out of the technology such as intubation catheter and organ transplantation, widely using of broad ectrum antibiotic, 17-hydroxy-11-dehydrocorticosterone and immunosuppressant, the sickness rate of fungal infection steeply rises (OddsFC.PathogenesisofCandidainfections.JAmAcadDermatol.1 994,31:S2 S5).Research shows, the fungal infection that AIDS (acquired immune deficiency syndrome (AIDS)) patient suffers late period, it separates bacterium and shows drug resistance phenomenon more than 1/3rd, particularly to azole drug, resistant rate is up to 65% (SaltanatH, LiH, GengXHetal.Clinicaldistributionanddrugresistanceofcandid ainfection.JournalofXingjiangMedicalUniversity2008,31 (8): 1058-1060).
New drug research and drug combination research are all the approach solving antifungal agent resistance.The new drug research cycle is long, and cost is high, and its early investment of drug combination is few, effect notable, receives concern both domestic and external.Drug combination research includes two kinds of antifungal agent associatings and non-antifungal agent is combined with antifungal agent.Owing to antifungal drug kind is limited, and the new drug price with antifungic action is expensive and side effect is obvious so that the use in conjunction research of non-antifungal drug and antifungal drug receives much concern.Fluconazol (FLC) as safely, effectively, cheap triazole antifungal agent thing, clinical practice widely, also leads to antifungal agent resistance rate simultaneously and constantly rises.Therefore, the effect of non-antifungal agent and FLC use in conjunction antagonism drug resistance fungal becomes the focus of research.
Current antifungal mechanism includes: suppress the synthesis of fungal cell wall；Suppress the synthesis of fungal cell membrane main component ergosterol and directly act on the structure of ergosterol, acting on fungal nucleic acid metabolism etc..In addition, find new antifungal approach from other aspects and also become the focus that researcheres give more sustained attention.
Chinese patent CN102626415A, discloses a kind of tetracycline medication use in conjunction fluconazol application in preparing antifungal products and products thereof.Its content is that antimycotic medicine fluconazol can produce collaborative antifungic action with Tetracyclines antibacterials doxycycline (DOX), minocycline (MINO) use in conjunction, and above two medication is had potentiation by non-selective calcium channel blocker benidipine (BEN), selectivity L-type calcium channel blocker nifedipine (NIF) and calcium ion chelator ethylenediaminetetraacetic acid (EDTA).Above-mentioned patent research finds that BEN, NIF and EDTA all can be remarkably reinforced FLC and the DOX/MINO associating antifungic action to Candida albicans, substantially reduce minimal effective concentration during FLC, MINO and DOX drug combination, strengthening the synergy of FLC and DOX/MINO, namely drug resistance Candida albicans medication combined is had significant lethal effect by three kinds.It addition, have been used in the medicine of clinic, a lot of examples show that similar drugs differs to establish a capital and has same effect.Such as penicillin medicine, various in style, but only part kind, as piperacillin has an effect of resisting pseudomonas aeruginosa, and major part kind to this bacterium without effect.
Summary of the invention
The purpose of the present invention is contemplated to provide antifungal products and the application thereof of a kind of amlodipine or flunarizine associating fluconazol.
To achieve these goals, the present invention adopts the following technical scheme that
A kind of antifungal products of amlodipine or flunarizine associating fluconazol, valid density proportioning when amlodipine and fluconazole application: fluconazol: amlodipine=1:8 (μ g/ml)；Valid density proportioning fluconazol: flunarizine=1:16 (μ g/ml) when flunarizine and fluconazole application.
During use in conjunction, amlodipine is respectively as follows: 8 μ g/ml, 1 μ g/ml with the minimum inhibitory concentration of fluconazol；The minimum inhibitory concentration of flunarizine and fluconazol is respectively as follows: 16 μ g/ml, 1 μ g/m.
It is shown that it is all effective with the fluconazole application more than 1 μ g/ml more than 8 μ g/ml amlodipines；All effective with the fluconazole application more than 1 μ g/ml more than 16 μ g/ml flunarizine.
Described fungus is Candida albicans.
The said goods application in antifungal.
Beneficial effects of the present invention:
The clinical conventional cell calcium oscillations (amlodipine and flunarizine) of quantitative assessment of the present invention combines antifungic action with FLC's, analyzes its effect of enhanced sensitivity to FLC, and has carried out static and dynamic system evaluation.
The present invention adopts drug resistance albicans cell to study, and utilizes liquid quantitative method, measures minimal effective concentration when FLC and AML and FNZ drug combination, and selects optimal drug combined concentration with FICI method and evaluate the effect of combination therapies；The present invention also adopts time-kill curve method to evaluate the dynamic antifungic action of drug combination.
The present invention is the therapeutic scheme that clinic provides that drug combination infects as treatment drug resistance fungal.It addition, the potentiation that different types of calcium channel blocker is to fluconazol, disclosing its synergism mechanism and be likely to relevant with intracellular calcium, the novel targets for Effect of Anti fungi-medicine effect provides thinking.
Present invention demonstrates that, when FLC and AML or FNZ coupling, it is possible to produce collaborative antifungic action.Albicans strain (MIC to fluconazole resistantFLC> 512 μ g/ml), drug combination can make its minimum inhibitory concentration substantially reduce, and FNZ and the 1 μ g/mlFLC of the AML or 16 μ g/ml of 8 μ g/ml share the fungus that all can kill more than 80%, and concentration increases again, and effect is higher.
Present invention demonstrates that, destroying intracellular Ca2+ balance and be probably the mechanism of associating antifungic action, the research direction providing possible is newly used in exploitation and old medicine for new drug.
Present invention demonstrates that, calcium ion channel blocker is extensive use clinically, and it is to FLC antifungal potentiation, its range of application can be expanded, and reducing the minimal effective concentration of FLC, reducing the dosage of antifungal drug, thus reducing the generation of the untoward reaction of medicine.
Accompanying drawing explanation
Fig. 1 is the antifungal time-kill curve during application of fluconazole amlodipine；
Fig. 2 is the antifungal time-kill curve during application of fluconazole flunarizine.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1FLC and CCB combines antifungic action and measures
1. material
1.1 medicines and reagent
Fluconazol (fluconazole, FLC), Shandong Cheng Chuan medical sci-tech Development Co., Ltd；
Amlodipine (minocycline, AML), logical sequence biology company limited of U.S.；
Flunarizine (flunarizinehydrochloride, FNZ), National Institute for Food and Drugs Control；
Kerma (unit of kinetic energy) praises Candida chromogenic medium, Zhengzhou Bo Sai biological engineering company limited；
TTC-sand Borrow's agar, sky, Hangzhou and microorganism reagent company limited；
Sodium hydroxide, state-run Shandong Dan County Organic Chemical Plant, lot number 940420；
Potassium dihydrogen phosphate, Shanghai is precious Fine Chemical Works newly, lot number 200602132；
Dimethyl sulfoxide (DMSO), Tianjin Guang Cheng chemical reagent company limited；
RPMI1640 raw material medicated powder, GIBCO company of 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, Shanghai development chemical industry one factory, lot number 200209510；
XTT (3; 3'-[1-(phenylamino acyl group)-3; 4-tetrazole]-two (4-methoxyl group-6-nitro) benzene sulfonic acid sodium salt) preparation of-menadione solution: take XTT powder 0.0500g; it is dissolved in the sterilized ringer's solution of 100ml and is made into the solution of 0.5mg/ml, filter sterilizing with 0.22 μm of filter membrane；Adding the menadione acetone soln (take menadione 0.0860g and be dissolved in 5ml acetone) of the 10mmol/L of 10 μ l so that it is final concentration of 1 μm of ol/L, shake up, 2 DEG C～8 DEG C keep in Dark Place.
Drug solution: fluconazol sterile distilled water dissolves, other drug dmso solution is made into the storing solution of 2560 μ g/ml respectively, filters (0.22 μm) subpackage.All medicinal liquids are in-20 DEG C of Refrigerator stores, standby.
PBS (phosphate buffer): by the PBS phosphate buffer (powder) of Beijing prosperity Bioisystech Co., Ltd of ancient cooking vessel state, fractional pack one bag is dissolved in 1L distilled water, namely 0.01M it is made into, the PBS phosphate buffer of PH7.4,121 DEG C of High Temperature High Pressure moist heat sterilization 20min, cool down standby.
RPMI (RoswellParkMemorialInstitute) 1640 liquid medium: take RPMI1640 (containing L-glutaminate, without sodium bicarbonate) powder 2.08g, add 10% glucose solution 40ml (sugary final concentration 2%) and MOPS (3-(N-morpholinyl) propane sulfonic acid) powder 6.906g, add distilled water to 200ml, pH is adjusted to be 7.0 ± 0.1 at 22 DEG C by the NaOH solution of 1mol/L after mix homogeneously, before use with 0.22 μm of composite fibre membrane filtration sterilizing.
1.2 instruments
1.3 experimental strains
Quality-control strains: Candida albicans ATCC10231, pharmacology teaching and research room of Shandong University is so kind as to give；
Experimental strain: the Candida albicans that provincial hospital, Qianfo Mount hospital clinical separate；
Identification of strains: experiment bacterial strain is cultivated 48 hours at the good Candida chromogenic medium 35 DEG C of Kerma (unit of kinetic energy), bacterium colony is green or emerald green all bacterial strains, is accredited as Candida albicans then through Shandong Center for Disease Control & Prevention's microbe research room with standard microbiology method.
Bacterium solution preparation: the Candida albicans thawed at room temperature preserved at-20 DEG C, is inoculated on TTC-sand Borrow's agar culture medium, cultivates 24～48h, takes well-developed single bacterium colony and again inoculate for 35 DEG C, cultivates 24h for 35 DEG C, to ensure that bacterial strain is in trophophase.Choosing some single relatively macrocolonies, PBS is configured to bacteria suspension, turbid with China's bacterial turbidity standard pipe ratio after vortice shaken well, adjusts sample cell consistent with standard pipe turbidity, and now the bacteria concentration of Candida albicans is about 4.5 × 106CFU/ml, namely serial dilution obtains work bacterium solution, and carries out concentration checking with count plate.
2. content and method
2.1 fluconazol measure with the antifungic action of combining of amlodipine or flunarizine
2.1.1 micro-dilution method
Chessboard method according to CLSIM27-A3 scheme, 4 times of working concentrations are become with RPMI-1640 fluid medium dilute liquid medicine, screening AML and FNZ or FLC concentration range of application, namely the final concentration of AML and FNZ respectively 32～0.5 μ g/ml, FLC are 64～0.125 μ g/ml.Azole medicinal liquid 50 μ l is drawn by concentration order from low to high, it is separately added into the 2nd～12 row of 96 hole flat boards, amlodipine and flunarizine medicinal liquid 50 μ l is drawn by concentration order from low to high, it is separately added into G～A row of 96 hole flat boards, except A12, each hole adds 100 μ l bacterium solution more respectively, and all the other hole RPMI-1640 culture fluid less than 200 μ l are supplied.Wherein H1 is growth control, and containing only bacterium solution not drug containing, A12 is blank, containing only medicinal liquid without bacterium solution.96 hole flat boards are put after 35 DEG C of constant incubators cultivate 24h, with measuring with microplate reader after XTT load and recording result.All experiments are in triplicate.
2.1.2 time-kill curve method
Fluconazol and amlodipine, flunarizine medicine storage liquid that concentration is 2560 μ g/ml are diluted to 10 times of working concentrations with RPMI1640 fluid medium.
Take the experimental strain (CA10) of twice of going down to posterity on TTC-sand Borrow's agar culture medium, the single relatively macrocolony of picking, makes bacteria suspension with PBS, adopts China's bacterial turbidity standard to carry out ratio turbid, when standard pipe is consistent with sample cell concentration, bacterium solution initial concentration is about 4.5 × 106CFU/ml, dilutes bacterium solution for 10 times of working concentrations with RPMI-1640, and carries out concentration checking by viable bacteria counting method.
The medicinal liquid 500 μ l taking above-mentioned preparation joins in corresponding test tube, and adding RPMI1640 fluid medium to total liquid volume is 4.5ml；Now take the bacterium solution 500 μ l prepared as stated above and join in this 4.5ml culture medium containing (or without) medicine, concussion mixing.This experiment is divided into four groups, it may be assumed that alone group of growth control group (not dosing), amlodipine pharmaceutical, alone group of flunarizine medicine, alone group of fluconazol, amlodipine and flunarizine medicine and fluconazole medication group, totally 10 individual system.Every individual system cumulative volume is 5ml, and the final concentration of fluconazol, amlodipine and flunarizine respectively 2 μ g/ml, 8 μ g/ml and 16 μ g/m in system, in system, bacterium solution final concentration is about 4.5 × 103CFU/ml.Complete system will be prepared in 35 DEG C of quiescent culture, in pharmaceutically-active 0th, 6,12,24, the point in time sampling of 48h measures.
2.2 evaluation methodologys judge with result
2.2.1LA theoretical
Basic thought theoretical for Loeweadditivity (LA) thinks that medicine can not interact with itself, and the concentration (equivalence site) that therefore alone for medicine or coupling produce identical drug effect compares.It analyzes method mark Mlc index method (fractionalinhibitoryconcentrationindex, FICI), is expressed as follows:
Σ FIC=FICA+FICB=CA/MICA+CB/MICB
MICAAnd MICBBe respectively medicine A and B alone time minimal inhibitory concentration, CAWith CBRespective concentration during identical drug effect is reached when being two medicine couplings.FICI > 4 is antagonism, and FICI is for being added or unrelated effect between 0.5 with 4, and FICI≤0.5 is defined as synergism.
2.2.1XTT method (dimethoxy azoles Huang colorimetry)
At sampling time point, each system is mixed on spiral agitator, draw the bacteria suspension in 100 μ l systems and join in 96 hole flat-bottomed plates, when with the 100 aseptic RPMI1640 fluid mediums of μ l for blank, the 100 μ l XTT-menadione solution prepared is added again respectively in the hole after each application of sample, culture plate lucifuge at 35 DEG C is cultivated 2 hours, microplate reader arranges single hole blank, the OD value in each hole is surveyed at 492nm place, every individual system does three groups, averaging record result, test repeats 3 times.
3. result
3.1 fluconazol combine antifungic action result with non-antibacterials
3.1.1 fluconazol and non-antibacterial medication combined minimum effective bacteria concentration
In each hole, the computational methods of fungus growth percent are:
Fungus growth percent=(each hole OD value-blank control wells OD value)/growth control hole OD value
Calculating each hole fungus growth percent in flat board by above-mentioned formula, taking the minimum coupling drug level that can suppress fungus growth 80% is interpretation terminal, if fungus rate of growth is not exactly equal to 20%, taking immediate medication combined hole with it is interpretation terminal.
The associating antifungic action of FLC and AML and FNZ, sensitive strain is inconspicuous, it mostly is unrelated, and to persister, then presents strong synergism.Wherein the growth percent experimental result in persister CA10 flat board is as shown in table 1.
Table .1. chessboard represents that the drug combination overriding resistance Candida albicans CA10 of FLC and AML and FNZ grows percentage rate (marking with the medicine the best use of combination Lycoperdon polymorphum Vitt of FICI method conversion).
3.1.2FICI method evaluates the synergism of FLC/AML or FNZ
Three repeated experiment acquired results are in Table 2.From measurement result, during AML or FNZ and FLC use in conjunction, to the effect FICI of drug resistance Candida albicans all < 0.5, present synergism, wherein the coupling better effects if of FLC/AML.To the FICI value of sensitive Candida albicans then between 0.5 and 2, present unrelated effect.
Table 2 comments FLC/AML or FNZ drug combination antifungic action with FICI method
3.1.3 time-kill curve method evaluates FLC/AML or FNZ synergistic result
The result that each time point combines antifungic action is connected into curve, the dynamic action effect after observable drug combination, as shown in Figure 1, 2: 4.5 × 103Bacterium solution in before 6h the change of dosing group and matched group OD value little, compared with matched group, after 6h, each group containing fluconazol starts growth delay occur, and the fungus growth delay that wherein FLC/AML coupling group processes becomes apparent from.Compared with in the of alone with fluconazol group, each coupling group is best to the inhibition of fungus at effect 24h, and final effect slowly dies down over time.
4. conclusion
Antifungal drug is less and the present situation of drug resistance phenomenon occur in the clinical practice, and the antifungal drug of development of new is one of approach solving this problem, and increase the fungus sensitivity to medicine by the mode of drug combination is also a kind of select preferably simultaneously.AML or FNZ is as the conventional cardiovascular drugs of clinic, and its safety and effectiveness is widely recognized, and itself is without antifungic action, but can reduce the MIC value of FLC significantly with FLC coupling overriding resistance Candida albicans, shows strong synergism.And existing lot of documents is reported, Ca2+ oscillations conducting system is at antifungal agent resistance important role.Whether the synergism mechanism as the AML or FNZ and FLC of calcium channel blocker is also relevant with have impact on Ca2+ oscillations conduction, needs to be studied further.Chinese patent CN102626415A mentioned calcium channel blocker nifedipine and benidipine can strengthen the associating antifungic action of FLC and DOX/MINO.
Fact proved that each big class material differs to establish a capital and has identical effect, such as cephalosporins, the main resisting gram-positive bacteria of generation cephalo, three, the four main against gram-negative bacteria of generation cephalosporin, and third generation cephalosporin kind only partly and four generation cephalos just have the effect of resisting pseudomonas aeruginosa；In like manner, can not infer that all calcium channel blockers all have associating antifungic action with FLC.Chinese patent CN102626415A, finds during qualitative screening that BEN, NIF and EDTA and FLC also have certain associating antifungic action, but does not carry out systematic quantification evaluation.This time, the synergy of two kinds of calcium antagonists (AML and FNZ) of our quantitative assessment early stage not test (N.T.) and FLC.Result shows, although AML and FNZ and FLC has associating antifungic action, but when AML and the FNZ concentration of coupling is 8 μ g/ml simultaneously, can make respectively the concentration of FLC from MIC > 512 μ g/ml drop to coupling time 1 μ g/ml and 32 μ g/ml, namely the AML of 8 μ g/ml can make FLC become sensitive, and FNZ then can only make it become intermediary.Therefore, combine antifungic action from a kind of calcium channel blocker with FLC and can not infer that all of calcium channel blocker all has identical FLC potentiation.
The specific embodiment of the present invention is described although above-mentioned in conjunction with the embodiments; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme, those skilled in the art need not pay various amendments or deformation that creative work can make still within protection scope of the present invention.
Claims (3)
1. the antifungal products of an amlodipine associating fluconazol, it is characterized in that, the valid density proportioning of amlodipine and fluconazol: fluconazol: amlodipine=1:8, during use in conjunction, amlodipine is respectively as follows: 8 μ g/ml, 1 μ g/ml with the minimum inhibitory concentration of fluconazol, and described fungus is drug resistance Candida albicans.
2. the antifungal products of a flunarizine associating fluconazol, it is characterized in that, the valid density proportioning fluconazol of flunarizine and fluconazol: flunarizine=1:16, during use in conjunction, flunarizine is respectively as follows: 16 μ g/ml, 1 μ g/m with the minimum inhibitory concentration of fluconazol, and described fungus is drug resistance Candida albicans.
3. product as claimed in claim 1 or 2 is in preparation for the application in antifungal medicine, and described fungus is drug resistance Candida albicans.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626415A (en) * | 2012-03-21 | 2012-08-08 | 山东省千佛山医院 | Application of combination of tetracycline medicine and fluconazole in preparation of antifungal product, and product thereof |
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626415A (en) * | 2012-03-21 | 2012-08-08 | 山东省千佛山医院 | Application of combination of tetracycline medicine and fluconazole in preparation of antifungal product, and product thereof |
| 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 (1)
| Title |
|---|
| 钙通道及钙通道阻断剂对白念珠菌生物膜的影响;喻其林等;《2012年中国菌物学会学术年会会议摘要》;20120810;第89页 * |
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