CN116236496A - Method for resisting candida glabrata by combining ambroxol and amphotericin B - Google Patents
Method for resisting candida glabrata by combining ambroxol and amphotericin B Download PDFInfo
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- CN116236496A CN116236496A CN202310237219.2A CN202310237219A CN116236496A CN 116236496 A CN116236496 A CN 116236496A CN 202310237219 A CN202310237219 A CN 202310237219A CN 116236496 A CN116236496 A CN 116236496A
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- amphotericin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention discloses an aromatic plant extract combined with amphotericin B, which uses ambroxol as an active ingredient, opens up a new application for ambroxol, and can be used as a synergist of antifungal drugs to reduce the dosage of the antifungal drugs, thereby reducing the toxic and side effects of the drugs, in particular to amphotericin B, and effectively reducing the Minimum Inhibitory Concentration (MIC) of amphotericin B; the antifungal effect of the amphotericin B is obviously improved, so that the dosage of the amphotericin B in the treatment process is reduced, and the toxic and side effects of the amphotericin B are further reduced.
Description
Technical Field
The invention relates to the field of antifungal treatment, in particular to application of ambroxol and amphotericin B composition in preparation of antifungal medicines.
Background
Fungal pathogens have profound effects on global human health, food safety, and biodiversity. Opportunistic fungal pathogens have become a major cause of human death, particularly in individuals with potential health or undergoing immunosuppressive therapy, with annual mortality rates of about 150 tens of thousands. Major pathogens include candida, aspergillus and cryptococcus. Candida glabrata accounts for about 15% of all candida-related systemic blood infections worldwide. Candida glabrata has become the second candida albicans pathogen next to candida albicans in some countries and regions, and infections caused by this species lead to higher morbidity and mortality (50%), with mortality rates of up to 100% in bone marrow transplant patients.
Microorganisms have a significant ability to develop resistance to antimicrobial drugs, threaten the efficacy of limited antimicrobial drug libraries, and become a serious public health crisis. This is particularly a concern for fungal pathogens, which can cause devastating invasive infections, and the therapeutic regimen is that, in addition to 5-fluorocytosine (5 FC), there are only three classes of antifungal drugs currently in clinical use, namely azoles, polyenes and echinocandins, and therefore the emergence of resistance of fungal pathogens to these drugs makes fungal diseases a global human health problem.
One major obstacle in the discovery of antifungal agents is the determination of important targets in fungi where molecules lacking host toxicity can specifically participate. One promising strategy to expand the drug targeting space is to explore combination therapies. This approach is the basis for the treatment of aids, malaria and tuberculosis, and has a number of advantages including reduced drug resistance, improved efficacy, reduced host toxicity and an expanded therapeutic range. Pharmaceutical combinations may also be used to target the drug resistance mechanism itself, in particular mechanisms involving drug resistance.
Robbins et al screened six sub-inhibitory concentrations of antifungal agents, combined with approximately 3600 small molecules, against four fungi. This study established that several small molecules, including FDA approved drugs, could enhance the efficacy of antifungal agents, and even enhance the activity of antifungal agents in resistant strains. Combinations of screening can also be performed directly with drug resistant strains to identify compounds useful in the treatment of drug resistant organisms and to reduce the identification of cross-drug resistant molecules. Screening with candida albicans resistant to echinocandin showed that the metal chelator DTPA is an enhancer of caspofungin activity, and that the combination treatment of DPTA and caspofungin significantly improved survival in mice vaccinated with echinocandin compared to each drug alone.
The high cost and serious side effects limit the combination of antifungal agents. In addition, contradictory results of synergistic or antagonistic effects of various antifungal combinations have also been reported. Thus, the focus of research has shifted to examining combinations of typical antifungal agents and non-antifungal agents.
Amphotericin B (AmB) is a polyene antifungal drug with strong antifungal activity, is the first choice for treating many life-threatening deep fungal infections, has a broad antifungal spectrum, definite curative effect and long half-life, is known as the 'gold standard' for treating the deep fungal infections, but has the defects of non-negligible Amphotericin B, large toxicity and more adverse reactions, and serious nephrotoxicity, hepatotoxicity and hemolytic toxicity are usually caused by common injection administration patients, and symptoms such as chills, chill, nausea and vomiting are accompanied. These serious side effects severely limit the clinical range of use of amphotericin B.
Ambroxol belongs to labdane diterpene family, is reduced by sclareolide, is a precursor of ammonia oxide, is usually used as an important intermediate for synthesizing ambroxol, but has certain bioactivity. Georgieva and the like find that ambroxol can reverse hypokinesia caused by reserpine, can enhance hypokinesia caused by low-dose apomorphine, enhance motility, and has more remarkable long-term treatment effect; ambroxol can increase secretion of cortisol and ACTH; studies in the effect of ambroxol on convulsive seizures have shown that the use of low doses of ambroxol has a protective effect on convulsions caused by alopecuroxin and dicrotic alkali and prolonged incubation periods for convulsions.
In conclusion, although ambroxol has good biological activity, reports on ambroxol and polyene antifungal drugs as antifungal drug compositions are not seen so far, so that the development of new antifungal drug compositions has good practical significance.
Disclosure of Invention
The invention aims at providing a new application of ambroxol as an antifungal pharmaceutical composition.
The invention aims at providing an antifungal composition, which aims at solving the problems of lack of antifungal drug combination and great toxic and side effects of the antifungal drugs in the prior art.
The invention provides an amphotericin B synergist, which takes ambroxol as an active ingredient and can also comprise a pharmaceutically acceptable carrier.
The present invention provides an antifungal composition comprising amphotericin B and ambroxol.
Preferably, the mass ratio of ambroxol to amphotericin B in the composition is (0.195-100): (0125-0.5); preferably, the mass ratio of ambroxol to amphotericin B is 0.781:0.25; more preferably, the mass ratio of ambroxol to amphotericin B is (6.25-50): 0.125.
The invention also provides application of the composition in preparation of antifungal medicines.
Preferably, the antifungal agent is an anti-candida glabrata (candida glabrata atcc 2001) agent.
In addition, the antifungal pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.
Compared with the defects and the shortcomings of the prior art, the invention has the following beneficial effects:
the invention discloses a synergistic antifungal method of ambroxol and amphotericin B composition, which opens up a new application for ambroxol, and can effectively reduce the Minimum Inhibitory Concentration (MIC) of ambroxol B as a synergist of antifungal drugs; the antifungal effect of the amphotericin B is obviously improved, so that the dosage of the amphotericin B in the treatment process is reduced, and the toxic and side effects of the amphotericin B are further reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the present invention will be given by way of examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
It should be noted that the experimental methods used in the following examples are conventional methods unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
Ambroxol is available from Shanghai Seiyaku Biotechnology Inc. (product number: B21372).
Candida glabrata (candidaglabra atcc 2001) was purchased from the beijing north narrative biotechnology institute.
Amphotericin B was purchased from Shanghai Ala Biotechnology Co., ltd (product code: A105482).
Example 1 ambroxol and amphotericin B were tested for antifungal activity in combination.
The antifungal activity of ambroxol and amphotericin B in combination was tested using checkerboard dilution (Candida glabrata ATCC 2001).
1. Candida glabrata was inoculated on YM plates and incubated at 28 ℃ for 48 hours at 80% humidity.
2. Ambroxol and amphotericin B are dissolved in DMSO to concentrations of 20mg/ml and 0.8mg/ml respectively, and stored in a refrigerator at-80deg.C for use.
3. Determination of Minimum Inhibitory Concentration (MIC)
(1) Reference is made to International Association of clinical and laboratory standardization (Clinical and Laboratory Standards Institute: CLSI) version M27-A3, the "protocol for the" Yeast broth dilution method "anti-fungal drug sensitivity test protocol. The stock 20mg/ml ambroxol and 0.8mg/ml amphotericin B solution were formulated into a series of diluted concentrations of ambroxol and amphotericin B solutions using the liquid medium recommended in the protocol (RPMI 1640).
(2) Candida glabrata (Candida glabrata ATCC 2001) was inoculated into 96-well plates with 100. Mu.L (about 2X 10) per well 4 Individual cells), 50 μl ambroxol and amphotericin B liquid medicine were added respectively, the combination of the liquid medicine is as follows:
the amphotericin B of the first drug is longitudinally distributed on a 96-well plate according to the dilution concentration from top to bottom (the amphotericin B concentration of all test wells in each horizontal row is the same), and each well is 50 mu L; the second drug ambroxol was arranged in diluted concentrations in a left to right lateral direction (the ambroxol concentration was the same for all test wells in each column) with 50 μl per well. The concentration of amphotericin B and ambroxol in each test group was recorded, test wells were simultaneously set with separate additions of solutions containing different concentrations of ambroxol and ambroxol B, 100 μl of each well was added, and a blank group without any drug was set, and three parallel 96 well plates were made and the results averaged.
(3) The 96-well plates were incubated at 37℃for 24 hours.
(4) MIC values were defined as the lowest drug concentration at which no fungal growth was seen with clear visual observation of the test wells.
The following definitions are set forth herein: whether the two drugs A and B are synergistic, additive or antagonistic is determined by the inhibition concentration coefficient FICI.
Wherein, fici= (MIC A in pharmaceutical combination /MIC A is A alone )+(MIC B in pharmaceutical combination /MIC B is B alone ) If the FICI value is less than or equal to 0.5, the synergy between the drugs A and B is shown; if the FICI value is between 0.5 and 4.0, the activities of the drugs A and B are added; if FICI values > 4.0, antagonism is indicated between drugs A and B.
By the above definition, the interaction of ambroxol and amphotericin B was detected, since ambroxol itself had poor anti-Candida glabrata activity (MIC Ambroxol in pharmaceutical combination /MIC Ambroxol glycol ) Negligible, the results are shown in table 1.
TABLE 1 FICI after ambroxol and amphotericin B combination
As can be seen from the above table, the final concentration of amphotericin B was 0.25. Mu.g/mL and the final concentration of ambroxol was 0.781. Mu.g/mL; amphotericin B final concentration is 0.125 μg/mL and ambroxol final concentration is 6.25 μg/mL; amphotericin B final concentration is 0.125 μg/mL, ambroxol final concentration is 12.5 μg/mL; amphotericin B final concentration is 0.125 μg/mL and ambroxol final concentration is 25 μg/mL; the final concentration of amphotericin B is 0.125 mug/mL, and the final concentration of ambroxol is 50 mug/mL, and in five groups of drug combinations, the amphotericin B and ambroxol have synergistic antifungal effect. Wherein the synergistic anti-candida glabrata activity of amphotericin B and ambroxol is continuously enhanced with increasing ambroxol concentration.
The fungi which can be inhibited by the pharmaceutical composition of the invention have wide sources, including but not limited to shallow fungi which are less harmful to organisms and deep fungi which are seriously harmful, and the optimal inhibition effect of the pharmaceutical composition on the fungi can be obtained by determining the optimal mixing ratio between the two by the implementation method.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (4)
1. Use of a composition comprising amphotericin B and ambroxol for the manufacture of an antifungal medicament, said fungus being candida glabrata (candidaglabrata atcc 2001).
2. The composition according to claim 1, wherein the mass ratio of amphotericin B to ambroxol is in the range of (0.125-0.5): (0.195-100).
3. Use of a composition comprising amphotericin B and ambroxol in a mass ratio of 0.25 in a composition comprising candida glabrata ATCC 2001: 0.781.
4. use of a composition comprising amphotericin B and ambroxol in a mass ratio of amphotericin B to ambroxol of 0.125 in a composition comprising candida glabrata ATCC 2001: (6.25-50).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310237219.2A CN116236496A (en) | 2023-03-13 | 2023-03-13 | Method for resisting candida glabrata by combining ambroxol and amphotericin B |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310237219.2A CN116236496A (en) | 2023-03-13 | 2023-03-13 | Method for resisting candida glabrata by combining ambroxol and amphotericin B |
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| CN116236496A true CN116236496A (en) | 2023-06-09 |
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| CN202310237219.2A Pending CN116236496A (en) | 2023-03-13 | 2023-03-13 | Method for resisting candida glabrata by combining ambroxol and amphotericin B |
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