CN115414487B - Application of stephanine combined with macrolide antibiotics in preparation of antibacterial products - Google Patents
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- CN115414487B CN115414487B CN202211089890.9A CN202211089890A CN115414487B CN 115414487 B CN115414487 B CN 115414487B CN 202211089890 A CN202211089890 A CN 202211089890A CN 115414487 B CN115414487 B CN 115414487B
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses an application of stephanine combined with macrolide antibiotics in preparation of antibacterial products, and belongs to the technical field of medicines. According to the invention, the chessboard method is adopted to evaluate the in-vitro antibacterial activity of the stephanine and the erythromycin on the drug-resistant group B streptococcus, and researches show that the combination of the stephanine and the erythromycin shows a synergistic effect on the drug-resistant group B streptococcus, so that the dosage of the erythromycin can be obviously reduced while the same antibacterial effect is achieved. The research result shows that the drug combination is expected to be applied to clinic and provides thought for overcoming the current situation of clinical drug resistance of group B streptococcus.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of stephanine combined with macrolide antibiotics in preparation of antibacterial products.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Group B Streptococcus (GroupBStreptococcus, GBS), also known as group B Streptococcus or Streptococcus agalactiae (S.agalactiae), is one of the beta hemolytic aerobic gram-positive cocci. Group B streptococcus can cause infection in pregnant women, dysplasia in premature fetus (low weight infants), premature rupture of membranes, late abortion, etc., and can also cause septicemia, pneumonia, meningitis, and even death in newborns. At present, the prevention scheme of GBS at home and abroad mainly adopts antibiotic prevention, and beta-lactam antibiotics are mostly selected, and macrolide antibiotics are commonly used for replacing patients with allergic physique or slight infection. However, the use of macrolide antibiotics has increased significantly worldwide, resulting in the emergence of a large number of resistant strains. The problem of resistance of GBS to macrolide antibiotics, especially erythromycin, in China is also becoming serious, which brings great difficulty to clinical treatment and control of nosocomial infection.
Cepharanthine (Cepharanthin) is alkaloid separated from Cepharanthine plant, and is a leukocyte increasing drug with effect in promoting peripheral leukocyte proliferation, and also has certain platelet proliferation effect, and can be used for treating leukopenia caused by chemotherapy, radiotherapy, etc. In addition, cepharanthine has recently been reported as a potential drug for treating viral infections. However, no antibacterial combination of cepharanthine and antibiotics has been reported so far.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide the application of stephanine combined with macrolide antibiotics in preparing antibacterial products. The invention adopts a chessboard method to evaluate the in-vitro antibacterial activity of the stephanine and the erythromycin on the drug-resistant group B streptococcus, and researches show that the combination of the stephanine and the erythromycin shows a synergistic effect on the drug-resistant group B streptococcus, and the dosage of the stephanine and the erythromycin can be obviously reduced while the same antibacterial effect is achieved. The research result shows that the drug combination is expected to be applied to clinic and provides thought for overcoming the current situation of clinical drug resistance of group B streptococcus.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in a first aspect, there is provided the use of stephanine in combination with a macrolide antibiotic for the manufacture of an antibacterial product.
Cepharanthine (Cepharanthin) is alkaloid separated from Cepharanthine plant, and is a leukocyte increasing drug with effect in promoting peripheral leukocyte proliferation, and also has certain platelet proliferation effect, and can be used for treating leukopenia caused by chemotherapy, radiotherapy, etc. In addition, cepharanthine has recently been reported as a potential drug for the treatment of viral infections, but there is currently no report on the treatment of group B streptococci. The invention discloses a combination of stephanine and macrolide antibiotics, which can improve the sensitivity of drug-resistant group B streptococcus to erythromycin and has good drug-resistant group B streptococcus curative effect.
And the research of the invention shows that the combination of the stephanine and the erythromycin can obviously reduce the dosage of the erythromycin.
Preferably, the macrolide antibiotics comprise erythromycin, erythromycin ethylsuccinate, azithromycin and roxithromycin.
Further preferably, the macrolide antibiotic is erythromycin.
Preferably, the bacteria include, but are not limited to, group B streptococcus; further preferably, the group B streptococcus comprises drug-resistant group B streptococcus.
In a second aspect, a pharmaceutical composition comprises stephanine and a macrolide antibiotic.
Preferably, in the pharmaceutical composition, the minimum inhibitory concentration of stephanine is 8-32 mug/mL, and the minimum inhibitory concentration of erythromycin is 0.0625-1 mug/mL.
In some embodiments of the present invention, a combination of stephanine and erythromycin is used to inhibit drug-resistant group B streptococcus, wherein the combination of stephanine and erythromycin has the following concentration to achieve the lowest inhibitory concentration: the minimum inhibitory concentration of stephanine is 8-32 mug/mL, and the minimum inhibitory concentration of erythromycin is 0.0625-1 mug/mL. According to the experimental result, the bacterial infection caused by drug-resistant group B streptococcus clinically can achieve the effect of synergetically resisting the drug-resistant group B streptococcus when the erythromycin concentration is more than 0.0625-1 mug/mL and the stephanine concentration is more than 8-32 mug/mL.
Preferably, the effective concentration ratio of the stephanine and the erythromycin is as follows: erythromycin = 8-50:0.0625-10; the preferable proportion is 8-32:0.0625-1.
In a third aspect, the use of a pharmaceutical composition according to the second aspect for the manufacture of a medicament for the prevention and treatment of a group B streptococcus mediated disease.
Preferably, the disease includes, but is not limited to, neonatal group B streptococcal disease, adult group B streptococcal disease.
Wherein the neonatal group B streptococcal disease is of both early onset and late onset types; the neonatal onset time of early onset is within seven days of birth, including pulmonary infection, bacteremia, meningitis, and sepsis; late onset neonatal morbidity, mostly within seven to three months after birth, includes meningitis, endocarditis, arthritis, osteomyelitis, cellulitis, and sepsis.
The adult group B streptococcal disease includes maternal and other adult infections; maternal infections include chorioamniosis, endometritis, urinary infections, meningitis, endocarditis, and sepsis; other adult infections include pneumonia, meningitis, endocarditis, skin soft tissue infections, and sepsis.
In the medicine, the stephanine and the macrolide antibiotics are combined to be used as active ingredients, the active ingredients account for 60-99% of the weight of the medicine, and the rest is pharmaceutically acceptable carrier, diluent or solution or salt solution.
The present invention does not exclude the combination of one or more components having the same or similar activity as the pharmaceutical composition, which combination would in a large way reduce the amount of the pharmaceutical composition in the composition, such as 1-60% of the total weight, and also, when the combination is very effective, would in a large way reduce the amount of the composition, such as down to less than 1% of the total weight, the person skilled in the art can obtain the desired amount by routine experimentation, depending on the situation.
The medicaments of the present invention may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.
These pharmaceutical compositions are generally safe, non-toxic and biologically desirable, and therefore, the pharmaceutically acceptable carriers or excipients described herein are non-toxic and safe. Pharmaceutically acceptable carriers and excipients described herein are generally well known to those skilled in the art or can be determined by those skilled in the art depending on the actual situation.
Such pharmaceutically acceptable excipients include, but are not limited to, excipients, carriers, and the like. One skilled in the art can select a suitable excipient depending on the purpose for which the excipient has. Such as a common excipient such as a solvent, a solubilizer, a surfactant, a preservative, a filler, an emulsifier, a binder, a disintegrant, a stabilizer, a flavoring agent, an antioxidant, a colorant, a diluent, a pH adjustor, a pressure adjustor, or the like, or a combination of two or more of these, or the like, depending on the pharmaceutical properties or mode of administration.
The pharmaceutical composition may be administered in unit dosage form. The dosage form may be conventional, such as liquid, e.g. emulsion, colloidal, true solution, particulate, mixed spin; such as other conventional forms, e.g., tablets, capsules, drops, aerosols, pills, oral liquids, powders, injections, solutions, suspensions, emulsions, granules, clathrates, landfill agents, etc. These dosage forms may be prepared according to conventional preparation methods in the pharmaceutical arts, such as mixing, granulating, tabletting, filling, dissolving, or suspension-dispersing, and the like.
The pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by intravenous injection, oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.
In a fourth aspect, a method of treating a group B streptococcus infection, the method comprising using the pharmaceutical composition of the second aspect.
Compared with the prior art, the invention has the beneficial effects that:
the stephanine is mainly used for treating leucopenia caused by various reasons such as chemotherapy, radiotherapy and the like clinically, and has not been reported in the field of resisting group B streptococcus at present. The invention provides the combination of stephanine and macrolide antibiotics for antibacterial treatment for the first time, and is expected to provide thought for the development of antibacterial drugs.
The research on the combined application of stephanine and erythromycin shows that the combination of stephanine and erythromycin has obvious effect on drug-resistant group B streptococcus. Researches show that the stephanine can remarkably improve the sensitivity of drug-resistant group B streptococcus to erythromycin, can greatly reduce the dosage of erythromycin if being expected to be applied to clinic, and has great clinical significance.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described in the background, the problem of GBS resistance to macrolide antibiotics, particularly erythromycin, is becoming increasingly serious, which presents significant difficulties in clinical treatment and control of nosocomial infections. The invention establishes that the combination of stephanine and erythromycin has good in-vitro antibacterial activity on the group B streptococcus through a chessboard method, and shows a synergistic effect.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1
Synergistic effect of stephanine and erythromycin on drug-resistant group B streptococcus
1 materials and methods
1.1 reagents and instruments
Erythromycin (HPLC. Gtoreq.98%) was purchased from Dalian Mei Lun Biotechnology Co., ltd;
cepharanthine (HPLC > 98%) was purchased from Source leaf Biolimited;
THB medium, mueller-Hinton agar medium, were purchased from Haibo Biotechnology Co., ltd;
HKM-9802 infrared seed sterilizer Guangdong Cryptographic microorganism Co., ltd;
DHP-81508 electrothermal incubator, nanfu Laibo scientific instruments Co., ltd;
VORTEX-GENIE2 VORTEX oscillator, scientific industries, U.S.A.;
the STAR-VF-20 pure water meter is arranged on a gravel tripod water treatment equipment company;
pipettor Eppendorf company, usa;
BSA124S electronic balance Sartorius, germany.
1.2 Strain
Group 3 streptococcus (groupbstretococcus): GBS2, GBS3, GBS4;
2 Experimental methods
2.1 chessboard method
2.1.1 operating procedure
Referring to the CLSIM100-30 scheme, the medicine stock solution is diluted to 2 times concentration by THB liquid culture medium (the final concentration range of medicine is erythromycin 0.0625-32 mug/mL, stephanine 0.5-32 mug/mL). The operation is carried out according to the following method: taking 50 mu L of erythromycin diluted by a ratio from high concentration to low concentration, and sequentially adding columns 2-11 of a 96-well plate; taking 50 mu L of stephanine solution diluted by a ratio from low concentration to high concentration, and sequentially adding the stephanine solution into G-A rows of a 96-well plate. 100. Mu.L of the bacterial suspension (10) was added to each well except line 12 6 CFU/mL), and wells based on less than 200 μl of liquid were incubated with THB liquid. Wherein, H1 holes are positive growth control holes, and 12 rows of holes are blank control holes. Culturing at 35 deg.c under constant temperature and humidity for 18 hr, and taking the lowest concentration well with sterile growth with naked eye as the lowest inhibitory concentration (MIC).
2.1.2 method for evaluating the Effect of drug combination
The results were evaluated in this experiment using the FICI method. The method is an nonparametric method model developed based on Loeweadditivity (LA) theory. The formula is as follows:
MIC/a at combined use of FICI = MIC at combined use of mic+b at combined use of MIC/B at combined use of MIC at single use.
The experimental result is judged by adopting the criterion that FICI is less than or equal to 0.5 and less than or equal to 1.0 and less than or equal to 0.5 as synergistic effect and FICI is less than or equal to 1.0 and less than or equal to 2.0 as irrelevant effect and FICI is more than 2.0 as antagonistic effect.
2.2 experimental results
2.2.1 chessboard method Experimental results
TABLE 1 synergistic effects of the combination of Cepharanthine and erythromycin on drug resistant group B Streptococci
The chessboard method experiment result shows that: when the stephanine and the erythromycin are combined to be used for the drug-resistant strain of the group B streptococcus, the MIC of the stephanine and the erythromycin is reduced, the sensitivity of the strain to the erythromycin is enhanced, the sensitivity of the strain is changed from drug resistance (MIC is more than or equal to 4), the MIC of the erythromycin after the combination is 0.0625-1 mug/mL, and the MIC of the stephanine is reduced to 8-32 mug/mL (table 1). Based on the MIC value, FICI values were calculated after the combination of the two drugs and judged to be synergistic or additive.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The application of stephanine combined with macrolide antibiotics in preparing antibacterial products;
the macrolide antibiotic is erythromycin; the bacteria are drug-resistant group B streptococcus, wherein the concentration of stephanine is 8 mug/mL, and the concentration of erythromycin is 1 mug/mL.
2. The medicine composition for preventing and treating drug-resistant group B streptococcus induced diseases is characterized by comprising stephanine and erythromycin; in the medicine combination, the concentration of stephanine is 8 mug/mL, and the concentration of erythromycin is 1 mug/mL.
3. The use of the pharmaceutical composition according to claim 2 for the preparation of a medicament for the prevention and treatment of diseases caused by drug-resistant group B streptococcus.
4. The use of a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and treatment of a drug-resistant group B streptococcus disease, wherein the disease comprises a neonatal drug-resistant group B streptococcus disease, an adult drug-resistant group B streptococcus disease;
wherein the neonatal drug-resistant group B streptococcal disease comprises two types, early onset and late onset; the neonatal onset time of early onset is within seven days of birth, including pulmonary infection, bacteremia, meningitis, and sepsis; neonatal onset of late onset, mostly within seven to three months after birth, includes meningitis, endocarditis, arthritis, osteomyelitis, cellulitis, and sepsis;
the adult drug-resistant group B streptococcus diseases comprise pregnant and lying-in women infection and other adult infections; maternal infections include chorioamniosis, endometritis, urinary infections, meningitis, endocarditis, and sepsis; other adult infections include pneumonia, meningitis, endocarditis, skin soft tissue infections, and sepsis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105457084A (en) * | 2015-12-17 | 2016-04-06 | 张德信 | Surgical suture with analgesic and antibacterial effect and preparation method thereof |
| CN106167493A (en) * | 2016-07-06 | 2016-11-30 | 河北大学 | The preparation method of novel cepharanthine and the application on medicine thereof |
| US9539305B1 (en) * | 2014-03-14 | 2017-01-10 | Fleurir Abx Llc | Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof |
| CN110448554A (en) * | 2019-09-12 | 2019-11-15 | 济南市儿童医院（山东大学齐鲁儿童医院） | Application of D-penicillamine and fluconazole in preparation of antifungal product |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9539305B1 (en) * | 2014-03-14 | 2017-01-10 | Fleurir Abx Llc | Pristinamycin compositions, LpxC compositions, their improvements, and combinations thereof |
| CN105457084A (en) * | 2015-12-17 | 2016-04-06 | 张德信 | Surgical suture with analgesic and antibacterial effect and preparation method thereof |
| CN106167493A (en) * | 2016-07-06 | 2016-11-30 | 河北大学 | The preparation method of novel cepharanthine and the application on medicine thereof |
| CN110448554A (en) * | 2019-09-12 | 2019-11-15 | 济南市儿童医院（山东大学齐鲁儿童医院） | Application of D-penicillamine and fluconazole in preparation of antifungal product |
Non-Patent Citations (1)
| Title |
|---|
| "Reversal of Tetracycline Resistance by Cepharanthine, Cinchonidine, Ellagic Acid and Propyl Gallate in a Multi-drug Resistant Escherichia coli";Darko Jenic et al;《Nat Prod Bioprospect》;第11卷(第3期);345–355 * |
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