CN113318100A - Application of honokiol in preparation of antifungal product - Google Patents
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Abstract
The invention discloses an application of honokiol in preparing an antifungal product, wherein the honokiol and echinocandin medicaments are combined to prepare the antifungal product, the fungi are candida, the fungi comprise candida albicans, candida tropicalis, candida krusei, candida glabrata and candida parapsilosis, and the echinocandin medicaments comprise caspofungin. The invention combines honokiol and echinocandins, has pharmacodynamic complementation, can improve antifungal curative effect, improve medicament effectiveness and safety and relieve the occurrence of medicament resistance to a certain extent, and can properly reduce the dosage of caspofungin, thereby reducing certain economic burden for patients and giving consideration to medicinal and economic factors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of honokiol in preparation of antifungal products.
Background
In recent years, the incidence of deep fungal infections has been on the rise year by year due to the excessive use of broad-spectrum antibiotics and immunosuppressants. Candida species account for the highest percentage of deep fungal infections in China (91%), with Candida albicans, Candida tropicalis, Candida glabrata, and Candida parapsilosis accounting for 95% of the total Candida species. However, the treatment effect of the existing antifungal medicines on the systemic candidiasis or candidemia is not satisfactory. Once patients suffer from systemic mycosis, the fatality rate is higher. How to effectively treat deep fungal infection has become a problem which needs to be solved urgently in clinic.
Echinocandins are an inhibitor of fungal cell wall beta-1, 3-D-glucan synthase, inhibiting fungal cell wall synthesis. The medicine is a bactericide against candida. The main drugs of this type are: caspofungin, micafungin, anidulafungin. Among them, caspofungin is already on the market at home. At present, caspofungin is clinically recommended to be used as a first-line medicament for treating invasive mycosis, shows good treatment effect on patients suffering from oral invasive fungal infection and esophageal fungal infection, and is also used as a remedy when other antifungal medicaments fail to treat. However, in recent years, the reports of different levels of drug resistance of candida to echinocandin drugs are increasing, and the mechanism of the drug resistance is mainly the base mutation of the FKS hot spot region of a coding gene of candida glucan synthase, so that the affinity of echinocandin to glucan synthase is reduced, and the drug resistance is generated. In addition, the fungal infection is relatively stubborn and the treatment time is long, and echinocandin medicaments are expensive, so that huge economic burden is brought to patients. Therefore, there is a need to find a synergist for echinocandin drugs to improve antifungal efficacy, reduce the amount and frequency of echinocandin drugs, and alleviate the occurrence of drug resistance.
Disclosure of Invention
In order to solve the defects mentioned in the background technology, the invention aims to provide the application of honokiol in preparing antifungal products, the honokiol and echinocandins are combined to prepare the antifungal products, the combination of the honokiol and echinocandins has the complementation of pharmacokinetics or pharmacodynamics, the antifungal curative effect can be improved to a certain extent, the effectiveness and the safety of the medicine can be improved, the occurrence of drug resistance can be relieved, and the dosage of caspofungin can be properly reduced.
The purpose of the invention can be realized by the following technical scheme:
the application of honokiol in preparing antifungal products is characterized in that the honokiol and echinocandin medicaments are combined to prepare the antifungal products, the fungi are candida, the fungi comprise candida albicans, candida tropicalis, candida krusei, candida glabrata and candida parapsilosis, and the echinocandin medicaments comprise caspofungin.
Furthermore, the usage amount of honokiol is 8-32 mug/ml and the usage amount of caspofungin is 0.08-0.32 mug/ml when preparing antifungal products.
Furthermore, the usage amount of honokiol is 16 mug/ml and the usage amount of caspofungin is 0.16 mug/ml when the product for resisting candida albicans is prepared.
Furthermore, when the product of candida albicans for resisting azole drugs is prepared, the usage amount of honokiol is 16 mu g/ml, and the usage amount of caspofungin is 0.16 mu g/ml.
Furthermore, when preparing the product of anti-echinocandin drug-resistant candida albicans, the usage amount of honokiol is 16 mug/ml, and the usage amount of caspofungin is 2 mug/ml.
Furthermore, the usage amount of honokiol is 16 mug/ml and the usage amount of caspofungin is 0.16 mug/ml when the product for resisting candida tropicalis is prepared.
Furthermore, the amount of honokiol used in the preparation of the anti-candida krusei product is 16 mug/ml, and the amount of caspofungin used is 0.32 mug/ml.
Furthermore, the usage amount of honokiol is 32 mug/ml and the usage amount of caspofungin is 0.16 mug/ml when the product for resisting candida glabrata is prepared.
Furthermore, the usage amount of honokiol is 32 mug/ml and the usage amount of caspofungin is 0.16 mug/ml when the product for resisting candida parapsilosis is prepared.
The invention has the beneficial effects that:
according to the invention, honokiol and echinocandin drugs are combined for application to prepare antifungal products, echinocandins can inhibit the synthesis of fungal cell walls, honokiol has obvious and lasting antibacterial, antioxidant, anti-inflammatory and anti-tumor effects, central muscle relaxation and nerve inhibition effects, honokiol has obvious anti-candida activity, the minimum inhibitory concentration MI C is 16-64 mu g/ml, honokiol and echinocandin drugs are combined for use, the pharmacokinetics and pharmacodynamics complementation is achieved, the antifungal curative effect can be improved to a certain extent, the drug effectiveness and safety are improved, the occurrence of drug resistance is relieved, the dose of caspofungin can be properly reduced, certain economic burden is reduced for patients, and the pharmaceutical economic factors can be considered.
Drawings
The invention will be further described with reference to the accompanying drawings.
FIG. 1 is a schematic diagram showing the effect of honokiol in combination with echinocandin drugs on the growth inhibition of Candida albicans in the example of the present invention.
FIG. 2 is a schematic representation of the time-growth inhibitory effect of Candida albicans CA10 against azole-resistant drugs in combination with echinocandin drugs in an example of the present invention;
FIG. 3 is a schematic diagram showing the growth inhibition effect of the combination of honokiol and echinocandin drugs on Candida tropicalis, Candida krusei, Candida glabrata and Candida parapsilosis in the example of the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides an application of honokiol in preparing antifungal products, and the honokiol and echinocandin medicaments are jointly applied to prepare the antifungal products.
The usage amount of honokiol is 8-32 μ g/ml and the usage amount of caspofungin is 0.08-0.32 μ g/ml when preparing antifungal product.
When the product for resisting candida albicans is prepared, the usage amount of honokiol is 16 mu g/ml, and the usage amount of caspofungin is 0.16 mu g/ml.
When the product of candida albicans for resisting azole drugs is prepared, the usage amount of honokiol is 16 mug/ml, and the usage amount of caspofungin is 0.16 mug/ml.
When the product of the candida albicans for resisting the echinocandin medicaments is prepared, the usage amount of honokiol is 16 mu g/ml, and the usage amount of caspofungin is 2 mu g/ml.
When the product for resisting candida tropicalis is prepared, the usage amount of honokiol is 16 mu g/ml, and the usage amount of caspofungin is 0.16 mu g/ml.
When the anti-candida krusei product is prepared, the usage amount of honokiol is 16 mu g/ml, and the usage amount of caspofungin is 0.32 mu g/ml.
When the product for resisting candida glabrata is prepared, the usage amount of honokiol is 32 mu g/ml, and the usage amount of caspofungin is 0.16 mu g/ml.
When the product for resisting candida parapsilosis is prepared, the usage amount of honokiol is 32 mu g/ml, and the usage amount of caspofungin is 0.16 mu g/ml.
Example 1:
the Candida is activated twice in YPD culture solution, and is subjected to shaking culture at 30 ℃ and 200rpm to enable the fungi to be in the later exponential growth phase. Taking the bacterial liquid to 1ml, centrifuging, resuspending with normal saline, counting blood cells, and adjusting bacterial density to 108cfu/ml. Diluting the bacterial liquid with YPD to 1-5 × 106cfu/ml, and divided into 4 portions of 20ml for use, the following four sets of experiments were performed:
experimental group 1: adding 16 μ g/ml honokiol to one of the liquids, culturing at 30 deg.C, and measuring after 0, 24 and 48 hr, respectively;
experimental group 2: to one of the aliquots was added 0.16. mu.g/ml caspofungin, followed by incubation at 30 ℃ and measurements after 0, 24 and 48 hours, respectively;
experimental group 4: one of the liquids was incubated without the addition of the antimicrobial agent at 30 ℃ and measured after 0, 24 and 48 hours, respectively.
The determination method adopts a viable bacteria counting method: mu.l of each tube of the culture broth was diluted 10-fold with 0.9% physiological saline, and 5. mu.l of each tube of the culture broth was dropped on the surface of YPD solid medium. The number of colonies was counted after culturing the plates in a 30 ℃ fungal incubator for 48 hours, with the number of colonies growing on YPD plates reaching 1 as the minimum. Viable colony numbers (CFU) were calculated.
Evaluation of the effect of the combination: compared with the single antifungal drug with the strongest activity, the fungus concentration reduction value after the two drugs are used together is more than or equal to 2Log10The two medicines are confirmed to have synergistic effect when CFU/ml; compared with the single antifungal drug with the highest activity, the reduction value of the concentration of the fungus after the two drugs are used together is less than or equal to 2Log10CFU/ml confirmed that the two drugs had independent effects.
Taking candida albicans SC5314 as an example, as shown in figure 1 (1-A is an apparent picture of a culture dish after 24h, 1-B is an apparent picture of a culture dish after 48h, 1-C is the number of viable colonies after 24h, and 1-D is the number of viable colonies after 48 h), caspofungin has a certain inhibiting effect on candida albicans after 24h at a concentration of 0.16 mug/ml, but cannot completely kill the candida albicans. The antibacterial effect of honokiol at the concentration of 16 mu g/ml is very weak, and the growth of candida albicans is almost the same as that of a control group. But the combined application of the two medicines greatly enhances the antibacterial effect, the combined medicines are detected in a sterile manner, and the bacterial concentration is reduced after the two medicines are combined>2Log10CFU/ml. The experimental results suggest that the combined application of honokiol and caspofungin has synergistic effect. After the drug acts for 48 hours, the antibacterial activity of the caspofungin is obviously reduced, but the antibacterial activity of the combined drug group is still strong, the bacterial colony detection is lower than the lowest detection line (the bacterial colony is still detected), and the bacterial concentration reduction value is reduced after the two drugs are combined>2Log10CFU/ml. The experimental results again suggest that the combined application of honokiol and caspofungin has synergistic effect.
Example 2:
candida albicans CA10 was activated twice in YPD medium, and cultured at 30 ℃ and 200rpm with shaking to keep the fungus in late exponential phase of growth. Taking the bacterial liquid to 1ml, centrifuging, resuspending with normal saline, counting blood cells, and adjusting bacterial density to 108cfu/ml. Diluting the bacterial liquid with YPD to 1-5 × 106cfu/ml, and divided into 4 portions of 20ml for use, the following four sets of experiments were performed:
experimental group 1: adding 16 μ g/ml honokiol to one of the liquids, culturing at 30 deg.C, and measuring after 0, 1, 2, 3, 4, 5, and 6 days;
experimental group 2: to one of the aliquots was added 0.16. mu.g/ml caspofungin, followed by incubation at 30 ℃ and measurements after 0, 1, 2, 3, 4, 5, and 6 days, respectively;
experimental group 4: one of the liquids was incubated without the addition of an antimicrobial agent at 30 ℃ and measured after 0, 1, 2, 3, 4, 5, and 6 days, respectively.
The assay method was as described in example 1. The efficacy of the combination was evaluated as described in example 1.
Taking candida albicans CA10 as an example, caspofungin has a certain effect of inhibiting the growth of candida albicans compared with a control group in the first 24 hours at the concentration of 0.16 mu g/ml as shown in fig. 2, but cannot completely kill the candida albicans. However, after 2 days, the antifungal effect of caspofungin was almost lost. The inhibitory effect of honokiol is very weak at the concentration of 16 mug/ml, and the growth of candida albicans is almost the same as that of a control group. But the combined application of the two medicines greatly enhances the antibacterial effect, and the antifungal effect can be prolonged to 5 days and 6 days of Log10The obvious rebound exists only when the CFU/ml is used, and the bacterial concentration is reduced after the two medicines are used together>2Log10CFU/ml. The experimental results suggest that the combined application of honokiol and caspofungin has long-term synergistic effect. Honokiol can significantly prolong the antifungal effect time and intensity of caspofungin.
Example 3:
different candida species were activated twice in YPD medium and cultured with shaking at 30 ℃ and 200rpm to keep the fungus in late exponential growth phase. Taking the bacterial liquid to 1ml, centrifuging, resuspending with normal saline, counting blood cells, and adjusting bacterial density to 108cfu/ml. Diluting the bacterial liquid with YPD to 1-5 × 106cfu/ml, and each Candida was divided into 4 portions of 20ml for use, and the following 4 experiments were conducted, respectively：
(1) The classification for candida krusei CK3 was 4 groups:
experimental group 1: adding 16 μ g/ml honokiol into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 2: adding caspofungin 0.32 μ g/ml into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 4: one of the liquids was assayed without the addition of antibacterial agents and incubated at 30 ℃ for 48 h.
(2) The candida tropicalis CT2 was divided into the following 4 groups:
experimental group 1: adding 16 μ g/ml honokiol into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 2: adding caspofungin 0.16 μ g/ml into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 4: one of the liquids was assayed without the addition of antibacterial agents and incubated at 30 ℃ for 48 h.
(3) The groups for candida parapsilosis CP1 were 4:
experimental group 1: adding 32 μ g/ml honokiol into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 2: adding caspofungin 0.16 μ g/ml into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 4: one of the liquids was assayed without the addition of antibacterial agents and incubated at 30 ℃ for 48 h.
(4) The following groups 4 were assigned to candida glabrata CG 1:
experimental group 1: adding 32 μ g/ml honokiol into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 2: adding caspofungin 0.16 μ g/ml into one part of the liquid, and culturing at 30 deg.C for 48 hr;
experimental group 4: one of the liquids was assayed without the addition of antibacterial agents and incubated at 30 ℃ for 48 h.
The assay method was as described in example 1. The efficacy of the combination was evaluated as described in example 1.
For Candida krusei CK3, Candida tropicalis CT2, Candida parapsilosis CP1 and Candida glabrata CG1, as shown in figures 3A, 3B, 3C and 3D, after 48 hours of action, the bacteria concentration of the combined drug combination has decreased compared with that of the single drug>2Log10CFU/ml. The experimental results suggest that the combined application of honokiol and caspofungin has synergistic effect.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.
Claims (9)
1. The application of honokiol in preparing antifungal products is characterized in that the honokiol and echinocandin medicaments are combined to prepare the antifungal products, the fungi are candida, the fungi comprise candida albicans, candida tropicalis, candida krusei, candida glabrata and candida parapsilosis, and the echinocandin medicaments comprise caspofungin.
2. Use of honokiol according to claim 1 in the preparation of an antifungal product, wherein the amount of honokiol used in the preparation of the antifungal product is from 8 to 32 μ g/ml and the amount of caspofungin used is from 0.08 to 0.32 μ g/ml.
3. Use of honokiol according to claim 2 in the preparation of antifungal products, wherein the honokiol is used in an amount of 16 μ g/ml and caspofungin is used in an amount of 0.16 μ g/ml in the preparation of an antifungal product against candida albicans.
4. The use of honokiol according to claim 2 in the manufacture of an antifungal product, wherein the honokiol is used in an amount of 16 μ g/ml and the caspofungin is used in an amount of 0.16 μ g/ml in the manufacture of an anti-azole drug-resistant candida albicans product.
5. The use of honokiol according to claim 2 in the manufacture of an antifungal product, wherein the amount of honokiol used is 16 μ g/ml and the amount of caspofungin used is 2 μ g/ml in the manufacture of an echinocandin-resistant Candida albicans product.
6. Use of honokiol according to claim 2 in the preparation of antifungal products, wherein the honokiol is used in an amount of 16 μ g/ml and caspofungin is used in an amount of 0.16 μ g/ml in the preparation of products against candida tropicalis.
7. Use of honokiol according to claim 2 in the preparation of an antifungal product, wherein the product is prepared against candida krusei with a honokiol usage of 16 μ g/ml and caspofungin usage of 0.32 μ g/ml.
8. Use of honokiol according to claim 2, in the preparation of antifungal products, characterized in that when the product is prepared against candida glabrata the amount of honokiol used is 32 μ g/ml and caspofungin is 0.16 μ g/ml.
9. Use of honokiol according to claim 2 in the preparation of antifungal products, wherein the product against candida parapsilosis is prepared using honokiol at 32 μ g/ml and caspofungin at 0.16 μ g/ml.
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| CN104188962A (en) * | 2014-08-14 | 2014-12-10 | 东南大学 | Application of magnolol and azole medicines to preparation of antifungal combined medicines |
| WO2016144979A1 (en) * | 2015-03-09 | 2016-09-15 | The Children's Mercy Hospital | Dermatophytosis prophylaxis and treatment |
| CN112689758A (en) * | 2017-08-01 | 2021-04-20 | Essenlix公司 | Device and method for examining the effect of a drug on microorganisms |
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