CN101780082B - Bisbenzylisoquinoline alkaloid is at the purposes prepared in anti-infectives synergist and pharmaceutical composition thereof - Google Patents
Bisbenzylisoquinoline alkaloid is at the purposes prepared in anti-infectives synergist and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention discloses the bisbenzylisoquinoline alkaloid shown in general formula (I) or its pharmaceutically acceptable salt at the purposes prepared in anti-infectives synergist and a kind of anti-infective pharmaceutical composition containing this synergist.
Description
Technical field
The present invention relates to anti-infectives synergist, specifically, the present invention relates to bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt as the purposes of anti-infectives synergist and pharmaceutical composition thereof.
Background technology
Drug resistance is the relevant antagonism of pathogen enantiopathy substance medicine.It is natural rule that pathogen produces drug resistance, and namely its generation is the inevitable outcome of drug resistant gene long-term evolution, not just occurs after anti-infectives asks city.Pathogen drug resistance is divided into intrinsic resistance (naturalresistance), obtains drug resistance (acquiredresistance), multidrug resistance (multi-drugresistance, MDR) and cross resistance (crossresistance).Intrinsic resistance also claims endogenous drug resistance (intrinsicresistance), and it determines the antimicrobial spectrum of anti-infectives.Drug resistant gene one is mediated by chromosome coding, namely caused by DNA or RNA sudden change.Another is mediated by plasmid (plasmid, also known as R-plasmid), and feature is mode many (transforms, transduction, combine and transposition), and incidence rate is high, usually shows and produce fermentoid or modification enzyme and drug resistance.After acquired resistance refers to sensitive pathogens contact anti-infectives, the drug resistance produced due to the change of genetic change, existence metabolic pathway.Multidrug resistance means that main mechanism is efflux pump gene mutation simultaneously to the drug resistance that multiple conventional anti-infectives occurs, and is secondly change and the super wide spectrum enzyme of generation of outer membrane permeability.Cross resistance refers to that the drug resistance between medicine transmits mutually, mainly occurs between the similar antibacterials of structure.
Find and apply anti-infectives synergist, both can reduce drug resistance, increasing the sensitivity of pathogen to medicine, the clinical efficacy of increase anti-infectives, the application cycle of anti-infectives can be delayed again.
The research of anti-infectives synergist is being carried out recently in decades always.The trimethoprim (TMP) used clinically is the synergist of the antibacterium medicines such as sulfonamides.China national patent " berberine is as the purposes of antifungal medicine synergist " (number of patent application 200410052989.7), " baicalin is as the purposes of antifungal medicine synergist " (number of patent application 200710041688.8), " reverse the medicinal plants synergist of azole drug antifungal activity multidrug resistance " (number of patent application 200610034165.6), " antifungal medicine synergist and its preparation method and application " (number of patent application 00121370.9) discloses some can as the structure of antifungal medicine synergist or material.
Bisbenzylisoquinoline alkaloid has multiple biological activity (He Liwen etc.Pharmacy is in progress, and 1996; 20:193.), antibacterial, antitumor, analgesia, blood pressure lowering etc. is comprised; Also find that bisbenzylisoquinoline alkaloid has activity (OnoMetal.CancerChemotherPharmacol, 1994 of reversal of multidrug resistance of tumor cells; 35:10.).The tetrandrine that Gao Aili, Zhang Hong etc. report Dibenzylisoquinolinealkaloids has synergistic activity (Chinese journal of dermatology .2008,41:31.) to fluconazole against Candida albicans.But there is not yet the report of bisbenzylisoquinoline alkaloid in addition as anti-infectives synergist.
Summary of the invention
On the one hand, the object of this invention is to provide the bisbenzylisoquinoline alkaloid shown in general formula (I) or its pharmaceutically acceptable salt is preparing the purposes in anti-infectives synergist:
In formula, R
1it is the straight or branched alkyl of 1-10 carbon atom;
R
2and R
3hydrogen, or R
2and R
3be O together;
R
4and R
5hydrogen, methoxyl group, acetyl group, or R
4and R
5be O together;
X1, X2, X3, X4 can be identical or different, and are straight or branched alkoxyl or the acyloxy of halogen atom or 1-10 carbon atom independently of one another, and n is the integer of 0 to 3.
We find to have anti-infectives synergistic activity by the bisbenzylisoquinoline alkaloid shown in general formula (I) and derivant thereof on the basis of great many of experiments, and they can be used as anti-infectives synergist as active component.Synergist of the present invention uses together with anti-infectives, forms a kind of compositions, makes medicine, health product, cosmetics, medical apparatus and instruments, sterilizing article, hygienic article and sell, use, thus facilitates the crowd of some occasion.
In the present invention, anti-infectives synergist can be anti-fungal infection medicament synergistic agent, bacterial-infection resisting medicine synergist, viral infection resisting medicament synergistic agent, anti-actinomycotic infection medicament synergistic agent, anti-mycoplasma infection medicine synergist, anti-chlamydia infection medicament synergistic agent, anti-spirochaete infection medicament synergistic agent, rickettsicidal infection medicine synergist, protozoacide infection medicine synergist or anthelmintic infection medicine synergist.
Anti-infectives synergist of the present invention can for the various pathogen causing infection, comprise and can cause animal, the fungus of plant constitutional or secondary infection, antibacterial, virus, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsia, protozoon, helminthic infection, especially eukaryotic microorganisms fungus, prokaryotic micro-organisms antibacterial, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsia.。
Except the above-mentioned pathogen enumerated, also comprise other animal pathogen newfound, phytopathogen.
Anti-infectives synergist of the present invention can as the synergist of following anti-infectives, as antibacterium, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsial antibiotic and other infectious agents matter, including, but not limited to following anti-infectives, as long as this anti-infectives reduces by the impact of anti-infectives synergist of the present invention: antibiotic such as beta-lactam, Macrolide, lincomycin class, polypeptide class, Tetracyclines, chloromycetin, quinolones, aminoglycosides; Sulfonamides and other antibacterials; Antifungal drug (nitrogen azole but not containing fluconazol, Allylamines, Thiourea, antibiotics is as polyenoid class, lipopeptid class, glycolipid class, class lipopeptid, class glycolipid, peptidyl nucleosides, amino acids, polycyclic aromatic class, morpholine class, 5-FU class, echinocandin class, Nikemycin class); Antiviral drugs (ucleosides, non-nucleoside, nucleoside reverse transcriptase inhibitors); Anti-parasite medicine (antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug, vermifuge).But do not comprise the potentiation of tetrandrine to fluconazole against Candida albicans, do not comprise the potentiation of tetrandrine to the anti-Echinococcus Granulosus Cysts of albendazole, Echinococcus multilocularis.
Anti-infectives synergist of the present invention associating anti-infectives can be adopted to treat, prevent the pathogenic infection of animal, plant, to obtain better effect, reduce drug resistance.
Under some concrete occasion, preferably, anti-infectives synergist of the present invention is selected from as the one in next group material or its pharmaceutically acceptable salt: tetrandrine, ITET, BrTET, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine.
Under some specific occasion, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine can be adopted as anti-infectives synergist of the present invention.
Anti-infectives can be (but being not limited to) more specifically: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
On the other hand, the invention provides a kind of anti-infective pharmaceutical composition, this pharmaceutical composition comprises:
(a) one or more the bisbenzylisoquinoline alkaloid as shown in general formula (I) or its pharmaceutically acceptable salt:
In formula, R
1it is the straight or branched alkyl of 1-10 carbon atom;
R
2and R
3hydrogen, or R
2and R
3be O together;
R
4and R
5hydrogen, methoxyl group, acetyl group, or R
4and R
5be O together;
X
1, X
2, X
3, X
4can be identical or different, and be straight or branched alkoxyl or the acyloxy of halogen atom or 1-10 carbon atom independently of one another, and n is the integer of 0 to 3;
And
(b) one or more anti-infectives.
In above-mentioned pharmaceutical composition, anti-infectives and synergist of the present invention mix, formed as the medicine of one, health product, cosmetics, medical apparatus and instruments, sterilizing article, hygienic article and sell, use, thus facilitate patient or other crowds of some occasion.In above-mentioned pharmaceutical composition, anti-infectives and synergist of the present invention also can separate priority and use.
Preferably, in pharmaceutical composition of the present invention, anti-infectives synergist is selected from the one as in next group material or its pharmaceutically acceptable salt: tetrandrine, ITET, BrTET, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine, anti-infectives is then selected from the material as next group: Beta-lactam medicine, Macrocyclolactone lactone kind medicine, lincomycin class medicine, polypeptide drug, tetracycline medication, chloromycetin medicine, quinolones, aminoglycoside drug, disulfonamide, do not comprise the nitrogen azole drug of fluconazol, Allylamines medicine, thiourea medicine, antibiotics is as polyenes, fat peptide medicament, sugar lipid drug, class lipopeptid medicine, class glycolipid medicine, peptidyl nucleosides medicine, amino acid drug, polycyclic aromatic class medicine, morpholine class medicine, 5-FU class medicine, echinocandin class medicine, Nikemycin class medicine, nucleoside medicine, non-nucleoside medicine, nucleoside reverse transcriptase inhibitors, antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug and vermifuge.
Under some concrete occasion, above-mentioned anti-infectives can be selected from the material as next group: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
In pharmaceutical composition of the present invention, the bisbenzylisoquinoline alkaloid shown in general formula (I) or its pharmaceutically acceptable salt can be any stereoisomers of its C (1) and C (1 ').
Certainly, pharmaceutical composition of the present invention may further include one or more pharmacologically acceptable excipient.Its excipient used is also not particularly limited, the dosage form taked also is not particularly limited, can both be the exterior-applied formulation of topical therapeutic, preventive effect equally, as ointment, solution, gel, liniment, aerosol, lotion etc., or be the dosage form of whole body therapeutic, preventive effect, as containing agent, tablet, capsule, pill, syrup, suspending agent, chewing gum, wafer, injection or other be conducive to drug absorption utilize dosage form.
The synergist and anti-infectives that reverse anti-infectives drug resistance use by the present invention simultaneously, the pathogenic infection for the treatment of, prevention animal, plant, not only can increase the effective percentage for the treatment of, prevention, reduce case fatality rate, the using dosage of anti-infectives can also be reduced simultaneously, alleviate its untoward reaction.
Synergist of the present invention can be used from experimental prediction tools with anti-infectives one, as anti-infectives sensitivity tests.
Synergist of the present invention and anti-infectives one are used from treatment and the prevention of pathogenic infection, but do not comprise the potentiation of tetrandrine to fluconazole against Candida albicans, do not comprise the potentiation of tetrandrine to the anti-Echinococcus Granulosus Cysts of albendazole, Echinococcus multilocularis.
Below, in conjunction with the detailed description of the invention of pharmacological evaluation, zoopery, clinical trial and synergist of the present invention and anti-infective medicament composition, further describe the present invention, but these describe just for explaining the present invention, instead of limit the invention to these modes.
Detailed description of the invention
The present inventor, to having studying for a long period of time containing the natural materials of general formula (I) or synthesis of derivatives and clinical practice thereof of anti-infectives synergistic activity, finds that they are in laboratory and the effect all clinically with good reverse anti-infectives drug resistance.
Pharmacological evaluation
The present inventor finds, the natural plant extracts tetrandrine containing general formula (I), when 2-30 μ g/ml, can have potentiation, in table 1 to ketoconazole, miconazole, amphotericin B, terbinafine antifungal.Tetrandrine, when 2-30 μ g/ml, can have potentiation, in table 2 to ketoconazole, bifonazole, the anti-trichophyton of terbinafine.Tetrandrine, when 20-30 μ g/ml, can have potentiation, in table 3 to ceftriaxone, erythromycin anti-Staphylococcus aureus.Tetrandrine, when 20-30 μ g/ml, can have potentiation, in table 4 to ciprofloxacin, the anti-escherichia coli of gentamycin.Radix Stephaniae Tetrandrae A prime, when 20-30 μ g/ml, can have potentiation, in table 5 to doxycycline, penicillin antigen core microorganism Ureaplasma urealyticum, Actinomyces israelii, star-shaped nocardia.And when with tetrandrine conbined usage after, the MIC terminal of anti-infectives is clear, " conditions of streaking " disappear.
Table 1
MIC1 is the MIC of antifungal drug to Candida albicans; MIC to tested bacterium when MIC2 is antifungal drug associating tetrandrine (2 μ g/mL).
CA-1 ~ CA-16 is Candida albicans strain number.
Table 2
MIC1 is the MIC of antifungal drug to trichophyton; MIC to tested bacterium when MIC2 is antifungal drug associating tetrandrine (2 μ g/mL).
TR-1 ~ TR-4 is strain number.
Table 3
MIC1 is the MIC of anti-infectives to staphylococcus aureus; MIC to tested bacterium when MIC2 is anti-infectives associating tetrandrine (20 μ g/mL).STA-1 ~ STA-4 is Candida albicans strain number.
Table 4
MIC1 is the MIC of anti-infectives to escherichia coli; MIC to tested bacterium when MIC2 is anti-infectives associating tetrandrine (20 μ g/mL).ECO-1 ~ ECO-4 is escherichia coli strain number.
Table 5
MIC1 is the MIC of anti-infectives; MIC to tested bacterium when MIC2 is anti-infectives associating tetrandrine (20 μ g/mL).UU-1, UU-2 are Ureaplasma urealyticum, and A-1 is Actinomyces israelii, and N-4 is star-shaped nocardia.
The present inventor also finds, the ITET containing general formula (I), BrTET, when 2-20 μ g/ml, significantly can strengthen anti-infectives to the antibacterial of pathogen or bactericidal action in experiment in vitro.Table 6 is results of part Experiment.
Table 6
MIC1 is the MIC of anti-infectives to pathogen; MIC2 be anti-infectives associating ITET or BrTET time MIC to tested bacterium.
CA-1, CA-2, CA-3, TR-1, STA-1, STA-2, ECO-1, ECO-2, UU-1, UU-2, A-1, N-4 are strain number.
The present inventor adopts flow cytometer and spectrofluorophotometer respectively, measure 16 strains and come from same parent but the Candida albicans different to fluconazole-sensitive, when without tetrandrine and tetrandrine 30 μ g/ml (non-cell toxicity dosage), after accumulation/outer row's experiment, the change of Rh123 fluorescence intensity in the change of Rh123 positive cell rate and cell.Then this 16 strain Candida albicans total serum IgE is extracted respectively, before adopting RT-PCR to compare tetrandrine effect and after effect 24h, multi-efflux pumps gene M DR1, FLU1, CDR1, CDR2 expression in fluconazole-sensitive/dose dependent sensitivity/persister.Found that, during without tetrandrine and tetrandrine 30 μ g/ml, after accumulation experiment, 16 strain Candida albicans Rh123 positive cell rate are respectively 26.65% and 70.99%, and in cell, Rh123 average fluorescent strength is respectively 11.34,18.00; After outer row's experiment, its Rh123 positive cell rate is respectively 1.79% and 42.57%, and in cell, Rh123 average fluorescent strength is respectively 0.74,2.19.When without tetrandrine, the difference of MDR1, FLU1, CDR1, CDR2 expression between fluconazole-sensitive/dose dependent sensitivity/persister all has statistical significance (P < 0.05); With compared with tetrandrine person after tetrandrine 30 μ g/ml24h, MDR1 in fluconazole resistant strain, FLU1 in fluconazol dose dependent sensitivity/persister, the difference of CDR1 and CDR2 expression in fluconazole-sensitive/dose dependent sensitivity/persister all has statistical significance (P < 0.05).These materials illustrate, tetrandrine can suppress Candida albicans drug efflux systems in vitro, reduce drug efflux, and its effect link is relevant with the expression of suppression multi-efflux pumps gene M DR1, FLU1, CDR1, CDR2.These materials also illustrate, the potentiation of tetrandrine is not only relevant with drug efflux systems, also have other mechanism of action.Such as, we find, the mRNA level in-site Relative quantification of the target enzyme gene ERG11 that RT-PCR is detected, and apply SPSS13.0 software kit and analyze, found that, the no significant difference (P > 0.05) of the expression of Candida albicans ERG11 between fluconazole-sensitive/dose dependent sensitivity/Resistant strain before ITET effect, and after ITET effect 24h, in sensitivity/dose dependent sensitive strain, the expression difference of ERG11 has statistical significance (P < 0.05), now, the expression of ERG11 is on a declining curve.Illustrate that the potentiation of tetrandrine is not only relevant with drug efflux systems, also relevant with target enzyme gene.
The present inventor finds again, during with flow cytomery, one-parameter histogram analysis is produced according to 10000 cells obtained in FITC road, do not add and the person that adds tetrandrine, after accumulation experiment, staphylococcus aureus Rh123 positive cell rate is respectively 22.40% and 78.92% (χ 2=60432, P=0.000), after therefore adding tetrandrine, in aureus cell, Rh123 savings significantly increases.And when not adding and add tetrandrine, outer row tests rear staphylococcus aureus Rh123 positive cell rate and is respectively 3.12% and 63.50% (χ 2=77127, P=0.000), after therefore adding tetrandrine, Rh123 arranges remarkable minimizing outward.
Zoopery
The zoopery that the present inventor carries out finds, when using ITET 13mg/kg body weight, can strengthen the oidiomycotic effect of Oral Treatment With Ketoconazole mouse vagina, mycological cure rate reaches 98%, and without obvious local excitation, avirulence.Table 7 gives the experimental result of the potentiation (mouse vagina candidiasis model) of ITET to ketoconazole.
Table 7
F: non-medication; KCZ: ketoconazole; ITET: ITET.Under be designated as dosage (mg/kg)
The present inventor also finds, compared with alone ampicillin (AMP), combine ampicillin treatment Dou Kou with BrTET (BrTET) and not exclusively block the rabbit Experimental Sinusitis Model adding staphylococcus aureus induction, can curative effect be significantly improved.Latter 2nd day of inoculation, each treated animal bacterial loads is 22.68 ± 1.63 × 10
4~ 23.12 ± 2.86 × 10
4cFU/ml (x ± s), group difference not statistically significant (P > 0.05).Inoculation after the 6th day, AMP20+BrTET20 group compared with AMP20 group, AMP10+BrTET20 group compared with AMP10 group, bacterial loads difference has statistical significance (P is respectively 0.003,0.016).AMP10+BrTET10 group is (P=0.646), AMP20+BrTET10 group (P=0.834) bacterial loads no significant difference compared with AMP20 group compared with AMP10 group.
Clinical experiment
The clinical trial that the present inventor carries out finds, tetrandrine can strengthen the antifungal activity of ketoconazole, terbinafine, reverses the drug resistance of ketoconazole, terbinafine antifungal activity, thus improves the mycotic effect for the treatment of.Table 8 gives tetrandrine and ketoconazole, terbinafine use the Preliminay clinical trials result for the treatment of people's fungal infection simultaneously.Specific practice is: according to the principle of simple random sampling, and the patient choosing equivalent amount uses antifungal drug treatment group (A group), antifungal drug+tetrandrine treatment group (B group) respectively as simple.Observe its mycological cure rate, clinical cure rate, total effective rate, relapse rate.
Table 5
In this research, the antifungal drug of application is ketoconazole, terbinafine.Administering mode: 150mg, qw.The course for the treatment of: vaginal candidiasis 3 weeks, tinea pedis 4 weeks, tinea corporis and tinea cruris 2 weeks, tinea unguium 16 weeks.Observe the time of mycological cure rate, clinical cure rate, total effective rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are after drug withdrawal 14 days, tinea unguium is after drug withdrawal 4 weeks.Observe time of relapse rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are after drug withdrawal 12 weeks, tinea unguium is after drug withdrawal 24 weeks.Tetrandrine is cream or suppository, is external.
The present inventor also finds, with alone 0.5% neomycin solution or compared with, with 1% ITET combine 0.5% the soak of neomycin solution treatment impetigo, can curative effect be significantly improved.After medication the 6th day, the clinical recovery rate of two groups of patients was respectively 8/13 (alone 0.5% neomycin solution) and 13/13 (1% ITET+0.5% neomycin solution), and the latter's inflammatory resolution is more rapid.
Preparation embodiment
Following examples illustrate formula of the present invention and preparation scheme.
The Suitable dosage ranges of compound of the present invention or natural materials depends on compound used and the disease of patient, also depends on especially and absorbs effect and administration frequency and approach.
Different according to route of administration, can be according to the following formulation containing the natural of general formula (I) or synthesis of derivatives synergist.In order to by any administration, the compounds of this invention or derivant can be prepared, be preferably mixed with unit dosage forms, or human patients can with the dosage form of single dose to self-administer.For the purpose of favourable, the compounds of this invention or compositions be applicable to oral, parenteral route, locally, rectum, intravenous, muscle, Intradermal, subcutaneous, submucosal administration.Preparation can be designed and be beneficial to active ingredient slow releasing.
1. local application:
(1) the natural or synthesis of derivatives containing general formula (I) is made into ointment with 0.01-5% ratio and fat-soluble medium (as vaseline) and is coated with affected part outward; Or add appropriate emulsifying agent (as phospholipid, medicine: phospholipid=10-100: 1) with same ratio and be made into aqueous solution and be coated with outward or rinse ill portion; Or make other dosage form, as gel, liniment, spray, lotion, containing agent etc.
(2) containing the preparation of the natural of general formula (I) or synthesis of derivatives ointment: the medicinal natural or synthesis of derivatives powder containing general formula (I) choosing purification, with the vaseline of heating and melting according to 1% (w: ratio w) makes ointment.
(3) containing the preparation of the natural of general formula (I) or synthesis of derivatives liniment: the medicinal natural or synthesis of derivatives powder containing general formula (I) choosing purification, by itself and phospholipid in 50: 1 ratio mix, add water and make aqueous solution, become liniment, use for focus local.
2. Systemic administration:
(1) containing the natural of general formula (I) or synthesis of derivatives tabletting (containing coated tablet), or will make capsule, pill, syrup, suspending agent, chewing gum, wafer, powder, solution, every sheet content of dispersion is 50-500mg; Or make injection.
(2) prepared by the capsule containing the natural or synthesis of derivatives of general formula (I): the medicinal natural or synthesis of derivatives powder containing general formula (I) choosing purification, with medicinal glucose powder according to 1: 10 ratio mix, make capsule, in order to orally using.
3. the preparation of medicinal natural or synthesis of derivatives+anti-infectives containing general formula (I):
(1) the medicinal natural or synthesis of derivatives powder containing general formula (I) choosing purification respectively and anti-infectives powder, (w: ratio w) makes ointment, for the use of focus local according to 1% respectively with the vaseline of heating and melting.Also various Topical application forms as above can be made.
(2) the medicinal natural or synthesis of derivatives powder containing general formula (I) and the anti-infectives powder of purification is chosen, the two is in after the ratio mixing of 1: 10 ~ 1: 20, again with medicinal glucose powder according to 1: 10 ratio mix, make capsule, in order to orally using.Also various Systemic administration dosage form as above can be made.
Claims (6)
1.5-bromine tetrandrine or its pharmaceutically acceptable salt are preparing the purposes in anti-infectives synergist, wherein, described BrTET or its pharmaceutically acceptable salt are as such as next organizes the synergist of anti-infectives: ketoconazole, amphotericin B, terbinafine, erythromycin, ciprofloxacin and penicillin.
2. purposes as claimed in claim 1, wherein, described BrTET or the valid density of its pharmaceutically acceptable salt are 2-20 μ g/ml.
3. purposes as claimed in claim 1, wherein, described BrTET or the valid density of its pharmaceutically acceptable salt are 20 μ g/ml.
4. an anti-infective pharmaceutical composition, this pharmaceutical composition comprises:
(a) BrTET or its pharmaceutically acceptable salt: and
(b) one or more anti-infectives;
Wherein, described anti-infectives is selected from the material as next group: ketoconazole, amphotericin B, terbinafine, erythromycin, ciprofloxacin and penicillin.
5. anti-infective pharmaceutical composition as claimed in claim 4, wherein, described BrTET or the valid density of its pharmaceutically acceptable salt are 2-20 μ g/ml.
6. anti-infective pharmaceutical composition as claimed in claim 4, wherein, described BrTET or the valid density of its pharmaceutically acceptable salt are 20 μ g/ml.
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| JP5976810B2 (en) * | 2011-08-19 | 2016-08-24 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー．Ｈａｎｇｚｈｏｕ Ｂｅｎｓｈｅｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | 5-substituted tetrandrine derivatives, their preparation and their use |
| CN103635475B (en) * | 2011-08-19 | 2016-06-08 | 杭州本生药业有限公司 | Tetrandrine derivant that 5-position carbon replaces, and its preparation method and application |
| CN102600159A (en) * | 2012-03-09 | 2012-07-25 | 深圳松乐生物科技有限公司 | Composition comprising tetrandrine, tetrandrine-based ramification and fluoroquinolones and application of composition |
| CN103910741B (en) * | 2014-03-26 | 2016-04-13 | 山东师范大学 | Bisbenzylisoquinolincompounds trimethyl-glycine and preparation method thereof and the application in antitumor drug preparation |
| CN103923092B (en) * | 2014-03-26 | 2016-05-11 | 山东师范大学 | Tetrandrine derivative and preparation method thereof and the application in antineoplastic preparation |
| CN103910739B (en) * | 2014-03-26 | 2016-08-17 | 山东师范大学 | A kind of Bisbenzylisoquinolincompounds glycine betaine and preparation method thereof and the application in preparing antitumor drug |
| CN114028453B (en) * | 2021-12-07 | 2023-05-30 | 北京中医药大学 | Broad-spectrum antiviral medicine, its medicinal composition and application |
| CN115770245A (en) * | 2022-12-28 | 2023-03-10 | 华南农业大学 | Application of dibenzyl isoquinoline alkaloid in preparation of drug for preventing and treating African swine fever virus |
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| US5025020A (en) * | 1989-09-28 | 1991-06-18 | Cancer Biologics Of America, Inc. | Use of tetrandrine and its derivatives to treat malaria |
| US5332747A (en) * | 1989-09-28 | 1994-07-26 | Cancer Biologics Of America, Inc. | Method for potentiating primary drugs in treating multidrug resistant parasitic disease cells |
| JP2000143523A (en) * | 1998-11-02 | 2000-05-23 | Kaken Shoyaku Kk | Resistance overcoming agent chloroquine-resistant malaria protozoan and antimalarial composition |
| CN101032486B (en) * | 2006-03-08 | 2011-05-11 | 张宏 | Medical plants synergist having antifungal activity and drug tolerance of reversion azole antifungal agents |
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