CN101032486B - Medical plants synergist having antifungal activity and drug tolerance of reversion azole antifungal agents - Google Patents
Medical plants synergist having antifungal activity and drug tolerance of reversion azole antifungal agents Download PDFInfo
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Abstract
The present invention discloses the application of tetrandine, matrine, ligustrazine or elemene as synergist for reverting the activity of azole medicines for treating mycotic infection of mammal in resisting fungal drug resistance, and corresponding medicine composition containing the synergist. The botanic medicine synergist of tetrandine, matrine, ligustrazine or elemene is applied together with antifungal azole medicine for treating mycotic infection of mammal, and this can raise treating effect and reduce the dosage of antifungal azole medicine and corresponding untoward reaction.
Description
Technical field
The present invention relates to the application of medicinal plants aspect reverse azole drug antifungal activity multidrug resistance (MDR), the present invention also further relates to medicinal plants synergist that reverses azole drug antifungal activity multidrug resistance and the antifungal medicine composition that comprises this synergist.
Background technology
In recent years, along with being extensive use of of broad ectrum antibiotic, corticosteroid hormone, immunosuppressant, chemotherapeutics, extensively the carrying out of organ transplantation and microcatheter technology, and the sharp increase of HIV number of the infected, infection rate of fungus and fatality rate also significantly increase.Alvarez-Lerma etc. to 1562 cases of 641 intensive care unit(ICU) investigation find have that 15.9% patient is separable to go out pathomycete, the concurrent fungus clinical infection of 7.7% patient, wherein Candida albicans accounts for 68.9%.Wisplinghoff etc. to the case of 24179 routine blood infectioies in 49 hospitals of the U.S. investigation find have 9.5% case to cause by fungal infection.
At present, azole drug is considered to treat a line medicine of multiple superficial mycosis, subcutaneous mycosis and deep mycosis, such medical instrument have clinical efficacy significantly, advantage such as safety, taking convenience, tissue permeability is good, prevent clinically and treat various fungal infection to play an important role.Existing triazole antifungal agent thing comprises fluconazol, itraconazole, ketoconazole, voriconazole etc.But along with azole drug long-term, be extensive use of, engendered the drug-fast bacterial strain of azole drug, and showed increased trend arranged, also grow with each passing day because of Resistant strain infects the treatment failure that causes.Wroblewska etc. find from clinical isolating 851 strain Candida albicanss, 37.2% bacterial strain are arranged to the fluconazol drug resistance, and 47.6% bacterial strain is to the itraconazole drug resistance.Gomez-Lopez etc. find from clinical isolating 338 strain aspergillosis, 3.8% bacterial strain are arranged to the itraconazole drug resistance.
Therefore, be necessary to provide a kind of synergist, reverse the drug resistance of fungus, improve the sensitivity of fungus azole drug to azole drug.
Summary of the invention
The present inventor is on the basis of a large amount of experiments, unexpectedly find, medicinal plants such as tetrandrine, matrine, ligustrazine, elemene etc., can be at external downward modulation mammal azole drug antifungal activity multidrug resistance (multidrug resistance, MDR) expression of gene mRNA, messenger drug thing efflux pump P glycoprotein (P-glycoprotein, P-gp) synthetic minimizing, antifungal drug is pumped out minimizing, drug accumulation increases in the cell, thereby has reversed the drug resistance of the fungal cell of P-gp mediation to azole drug.Thereby this class medicinal plants has the function that reverses azole drug antifungal activity multidrug resistance (MDR), can adopt this class medicinal plants to reverse azole drug antifungal activity multidrug resistance and treat fungal infections in mannals.
Therefore, on the one hand, the invention provides tetrandrine, matrine, ligustrazine and/or elemene etc. in treatment during fungal infections in mannals, be used to reverse the purposes aspect the azole drug antifungal activity multidrug resistance.
Above-mentioned fungal infection had both comprised the superficial mycosis of former or secondary, also comprised deep mycosis.Wherein, the superficial mycosis of former or secondary includes but not limited to: tinea such as tinea capitis, tinea corporis, tinea cruris, tinea pedis, hands tinea; Mucocutaneous candidiasis; Other mycosis of skin such as tinea versicolor, pityrosporum furfur folliculitis, piedra, tinea barbae, black tinea, tinea imbricata, the infection of capital spore, tinea unguium etc.Deep mycosis includes but not limited to: cryptococcosis, sporotrichosis, candidiasis, chromoblastomycosis, phaeohyphomycosis, hyalohyphomycosis, aspergillosis, mucormycosis, blastomycosis, penicilliposis marneffei, Paecilomyces varioti disease, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, uncle sieve mycosis, rhinosporidiosis, entomophthoromycosis or Prototheca disease.Except the above-mentioned fungal infection of enumerating, comprise that also newfound pathogen is other fungal infections in mannals of fungus.
On the other hand, the present invention also provides a kind of synergist that reverses azole drug antifungal activity multidrug resistance, comprise in this synergist one or more, be selected from the material in tetrandrine, matrine, ligustrazine and the elemene.Herein, tetrandrine, matrine, ligustrazine and elemene etc. both can be the monomers (as the chemical purification thing) of these materials, also can be the monomeric source plants of these materials.
Further, synergist of the present invention can also comprise acceptable excipient on one or more the pharmacology.This excipient does not have special restriction, and the dosage form of synergist also is not particularly limited, can be for playing the exterior-applied formulation of topical therapeutic effect, as ointment, solution, gel, liniment, aerosol, lotion etc., also can be play the dosage form of whole body therapeutic effect, as containing agent, tablet, capsule, pill, syrup, suspending agent, chew chewing gum, wafer, injection or other helps the dosage form of drug absorption utilization.
Synergist of the present invention can be used with antifungal medicament.
On the one hand, the present invention further provides a kind of antifungal medicament compositions again, this pharmaceutical composition comprises:
(a) one or more is selected from material in tetrandrine, matrine, ligustrazine and the elemene; And
(b) one or more triazole antifungal agent thing.
In above-mentioned pharmaceutical composition, triazole antifungal agent thing and synergist of the present invention mix, and sell, use as the medicine of one, thereby made things convenient for the patient of some occasion.Preparation triazole antifungal agent thing can be fluconazol, itraconazole, ketoconazole, voriconazole, triazole or glyoxaline compound or other triazole antifungal agent thing, as long as its medicine efflux pump P glycoprotein (P-gp) synthetic influenced by tetrandrine, matrine, ligustrazine, elemene etc. and reduce.
Similarly, above-mentioned pharmaceutical composition may further include acceptable excipient on one or more the pharmacology.Its used excipient does not have special restriction yet, the dosage form of being taked also is not particularly limited, can both be the exterior-applied formulation of topical therapeutic effect equally, as ointment, solution, gel, liniment, aerosol, lotion etc., perhaps be the dosage form of whole body therapeutic effect, as containing agent, tablet, capsule, pill, syrup, suspending agent, chew chewing gum, wafer, injection or other helps the dosage form that drug absorption is utilized.
Medicinal plants synergist and azole drug antifungal drug that the present invention will reverse azole drug antifungal activity multidrug resistance use simultaneously, the treatment fungal infections in mannals, not only can increase the effective percentage of treatment, reduce case fatality rate, can also reduce simultaneously the using dosage of azole drug antifungal drug, alleviate its untoward reaction.
Below, the specific embodiment in conjunction with pharmacological evaluation, zoopery, clinical experiment and synergist of the present invention and pharmaceutical composition, describe the present invention in further detail, but these descriptions just are used to explain the present invention, rather than limit the invention to these modes.
The specific embodiment
The present inventor studies for a long period of time to having the medicinal plants synergist and the clinical practice thereof that reverse azole drug antifungal activity multidrug resistance, finds that they are at laboratory and all have good reverse azole drug antifungal activity effect clinically.
Pharmacological evaluation
The present inventor finds, reverses the medicinal plants synergist tetrandrine of azole drug antifungal activity multidrug resistance〉during 2 μ g/mL, candida albicans hyphal there is inhibitory action mutually, and is concentration dependent, see Table 1.During tetrandrine 〉=4.5 μ g/mL, tried survival rate≤8.6% of bacterium; During tetrandrine≤2 μ g/mL, the survival rate of bacterium〉95%, visual method is observed its turbidity and normal growth control wells zero difference.When uniting use separately and with tetrandrine, fluconazol seen Table 2 to respectively trying bacterium mycelia MIC mutually.When 16 strain candida albicans hyphal phases, fluconazol reached associating tetrandrine (2 μ g/mL) separately, its MIC scope was respectively 0.250～64 μ g/mL or 0.125～8 μ g/mL, through paired t-test, and t=2.088, P=0.054, difference not statistically significant.But after uniting use with tetrandrine, the MIC terminal point of fluconazol is clear, and " conditions of streaking " disappears, and microscopically counting candida albicans hyphal phase suppression ratio is greater than 95%.16 strain Candida albicanss when following table 1 uses separately for tetrandrine (CA-1, CA-2 ..., CA-17) viable count of mycelia phase and survival rate, table 2 is fluconazol and unites the MIC (μ g/mL) of tetrandrine to the candida albicans hyphal phase.
Table 1
Table 2
MIC1 is the MIC of this measuring fluconazol to 16 strain candida albicans hyphal phases; MIC2 in this experiment during fluconazol associating tetrandrine (2 μ g/mL) to being tried the MIC of bacterium.
The present inventor also finds, when detecting (table 3-5) with flow cytometer, produce the one-parameter histogram analysis according to 10000 cells that obtain in the FITC road, do not add and add the tetrandrine person, accumulate experiment back Candida albicans yeast phase Rh123 positive cell rate be respectively 26.47% and 70.98% (removed the background positive rate, χ 2=62921, P=0.000), therefore after adding tetrandrine, the Rh123 savings significantly increases in the Candida albicans yeast phase cell.And do not add and when adding tetrandrine, efflux experiment back Candida albicans yeast phase Rh123 positive cell rate be respectively 6.72% and 60.00% (removed the background positive rate, χ 2=77127, P=0.000), therefore after adding tetrandrine, Rh123 effluxes remarkable minimizing.Wherein, table 3 is for adding and not adding the cell Rh123 positive rate comparison (%) mutually of tetrandrine 16 strain Candida albicans yeast, table 4 has provided accumulates two kinds of method Candida albicans yeast phase Rh123 positive cell rate experimental results of experiment, and table 5 has provided and effluxed two kinds of method Candida albicans yeast phase Rh123 positive cell rate experimental results of experiment:
Table 3
C is the background contrast; A1, A2 accumulate experiment and efflux each bacterium Rh123 positive cell rate of experiment back when not adding tetrandrine; B1, B2 are when adding tetrandrine, accumulate experiment and efflux each bacterium Rh123 positive cell rate of experiment back.
Table 4
Table 5
Zoopery
The zoopery that the present inventor carries out is found, when using tetrandrine 13mg/kg body weight, can strengthen the oidiomycotic effect of Fluconazole treating mouse vagina, and the mycology cure rate reaches 90%, and does not have tangible local excitation, avirulence.Table 6 has provided the experimental result of tetrandrine to the potentiation (mouse vagina candidiasis model) of fluconazol.
Table 6
10 of every treated animals, respectively at administration in the 0th, 3,7 day 3 times, dosage is as in the table.In the table the 8th day result.
Human experimentation
The present inventor finds when carrying out preliminary human experimentation, tetrandrine, matrine, ligustrazine, elemene can strengthen the azole drug antifungal activity really, reverse azole drug antifungal activity multidrug resistance, treat mycotic effect thereby improve azole drug.Table 7 has provided the medicinal plants synergist and the triazole antifungal agent thing that reverse azole drug antifungal activity multidrug resistance and has used the preliminary clinical test results for the treatment of people's fungal infection simultaneously.Specific practice is: according to the principle of simple random sampling, patient's number of choosing equivalent amount is respectively as simple azole drug treatment group (A group), the azole drug+plant synergist treatment group (B group) of using.Observe its mycology cure rate, clinical cure rate, total effective rate, relapse rate.
Table 7 reverses the medicinal plants synergist and the triazole antifungal agent thing while of azole drug antifungal activity multidrug resistance
Use the preliminary clinical test results of treatment people fungal infection
The triazole antifungal agent thing of using in this research is a fluconazol, administering mode: 150mg, qw.The course of treatment: 3 weeks of vaginal candidiasis, 4 weeks of tinea pedis, tinea corporis and 2 weeks of tinea cruris, 16 weeks of tinea unguium.Observe the time of mycology cure rate, clinical cure rate, total effective rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are after the drug withdrawal 14 days, and tinea unguium is 4 weeks after the drug withdrawal.Observe the time of relapse rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are 12 weeks after the drug withdrawal, and tinea unguium is 24 weeks after the drug withdrawal.Tetrandrine, matrine, ligustrazine, elemene are cream or suppository, are external.
Embodiment
According to the route of administration difference, the pharmaceutical composition that reverses the medicinal plants synergist of azole drug antifungal activity multidrug resistance and contain this synergist can be prepared by following prescription:
1, local application:
(1) the medicinal plants synergist that will reverse azole drug antifungal activity multidrug resistance is made into ointment with 0.01-5% ratio and fat-soluble medium (as vaseline) and is coated with affected part outward; Or with same ratio add an amount of emulsifying agent (as phospholipid, medicine: phospholipid=10-100:1) be made into aqueous solution to be coated with or to wash ill portion outward; Perhaps make other dosage form, as gel, liniment, spray, lotion, containing agent etc.
(2) preparation of tetrandrine ointment: choose the medicinal tetrandrine powder of purification, make ointment according to the ratio of 1% (w:w) with the vaseline of heating and melting.
(3) preparation of tetrandrine liniment: choose the medicinal tetrandrine powder of purification, itself and phospholipid in the ratio mixing of 50:1, are added water and make aqueous solution, become liniment, be used for that focus is local to be used.
2, system's medication:
(1) will reverse the medicinal plants synergist tabletting (containing coated tablet) of azole drug antifungal activity multidrug resistance, or make capsule, pill, syrup, suspending agent, chew chewing gum, wafer, every content of dispersion is 50-500mg; Or make injection.
(2) preparation of ligustrazine capsule: choose the medicinal ligustrazine powder of purification,, make capsule, in order to orally using with the ratio mixing of medicinal glucose powder according to 1:10.
3, the preparation of medicinal plants synergist+triazole antifungal agent:
(1) chooses the medicinal tetrandrine powder and the fluconazol powder of purification respectively, make ointment according to the ratio of 1% (w:w) respectively, be used for that focus is local to be used with the vaseline of heating and melting.
(2) choose the medicinal tetrandrine powder and the fluconazol powder of purification, after the two presses the mixed of 1:10～1:20, with the ratio mixing of medicinal glucose powder, make capsule again, in order to orally using according to 1:10.
Claims (5)
1. tetrandrine reverses the purposes of the chemical sproof medicine of medicine more than the fluconazol class medicine antifungal activity when being used for the treatment of the mammal pathogenic fungi and infecting in that preparation is a kind of; Wherein, described pathogenic fungi infects and is vaginal candidiasis, tinea pedis, tinea cruris or tinea unguium.
2. an antifungal medicament compositions is characterized in that, this active ingredient in pharmaceutical is:
(a) tetrandrine; And
(b) one or more triazole antifungal agent thing; Described triazole antifungal agent thing is fluconazol, itraconazole, miconazole, econazole, clotrimazole, bifonazole, ketoconazole or voriconazole.
3. pharmaceutical composition as claimed in claim 1 or 2 is characterized in that, described pharmaceutical composition further comprises acceptable excipient on one or more the pharmacology.
4. pharmaceutical composition as claimed in claim 2 is characterized in that, the dosage form of described pharmaceutical composition is ointment, solution, gel, liniment, aerosol or lotion.
5. pharmaceutical composition as claimed in claim 2 is characterized in that, the dosage form of described pharmaceutical composition for containing agent, tablet, capsule, pill, syrup, suspending agent, chew chewing gum, wafer or injection.
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