CN114288283A - Application of galangin in preparation of medicine for treating gonorrhea - Google Patents
Application of galangin in preparation of medicine for treating gonorrhea Download PDFInfo
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- CN114288283A CN114288283A CN202111429912.7A CN202111429912A CN114288283A CN 114288283 A CN114288283 A CN 114288283A CN 202111429912 A CN202111429912 A CN 202111429912A CN 114288283 A CN114288283 A CN 114288283A
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- galangin
- gonococci
- ceftriaxone
- gonorrhea
- resistant
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- VCCRNZQBSJXYJD-UHFFFAOYSA-N galangin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=CC=C1 VCCRNZQBSJXYJD-UHFFFAOYSA-N 0.000 title claims abstract description 90
- CIPSYTVGZURWPT-UHFFFAOYSA-N galangin Natural products OC1=C(Oc2cc(O)c(O)cc2C1=O)c3ccccc3 CIPSYTVGZURWPT-UHFFFAOYSA-N 0.000 title claims abstract description 45
- SUYJZKRQHBQNCA-UHFFFAOYSA-N pinobanksin Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(O)C1C1=CC=CC=C1 SUYJZKRQHBQNCA-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 206010018612 Gonorrhoea Diseases 0.000 title claims description 20
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- 238000002360 preparation method Methods 0.000 title claims description 5
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- 229960004755 ceftriaxone Drugs 0.000 claims description 26
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims description 26
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- 229960002129 cefixime Drugs 0.000 claims description 4
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- 229930003935 flavonoid Natural products 0.000 description 4
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- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 description 3
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- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
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- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
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- 206010034133 Pathogen resistance Diseases 0.000 description 1
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- 201000007100 Pharyngitis Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
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- 241000122973 Stenotrophomonas maltophilia Species 0.000 description 1
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- 239000001913 cellulose Substances 0.000 description 1
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- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
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- 238000012070 whole genome sequencing analysis Methods 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/12—Ketones
-
- 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
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of galangin in preparing antibacterial drugs, wherein the galangin is shown as a formula (1). The galangin has strong bactericidal activity on gonococcus in vitro, and shows that the galangin has wide application prospect in preparing medicaments for treating infectious diseases caused by the gonococcus.
Description
The application is a divisional application of an invention patent with the application number of CN202011532484.6 and the name of application of chalcone and flavonoid compounds in preparing antibacterial drugs.
Technical Field
The invention relates to the field of antibacterial drugs, in particular to application of galangin in preparation of a drug for treating gonorrhea.
Background
Gram-negative bacteria of the genus gonococcus are pathogenic bacteria of gonorrhea. Gonorrhea is the second most prevalent sexually transmitted disease worldwide, according to WHO statistics, there are 8800 to 1.06 billion new cases of gonorrhea worldwide each year [ see references: [1] WHO, emery of multi-drug resistant Neisseria gonorrhoeae-Threat of Global organ in untreated transported infection. fact Sheet RHR 11.14.2011: Geneva, Switzerland. [2] WHO, Global Action Plan to Control the Spread and Impact of anti-social Resistance of Neisseria gonorrhoeae.2012: Geneva, Switzerland. ], as an important public health issue, the health world organization (WHO) and many other international agencies are tightening the monitoring of gonorrhea. Gonococci often colonize the epithelial lining of the human urogenital mucosa and can also infect the urethra, throat, rectum and eyes of a human, and if not treated promptly, can cause serious complications such as pelvic inflammation, arthritis, dermatitis and endocarditis.
Gonococci are extremely prone to develop drug resistance, and nowadays, the gonococci have developed drug resistance to all the previously and currently used antibiotics, and treatment of gonorrhea in the future may become extremely challenging, ceftriaxone is the only first-line recommended drug that can successfully cure urogenital and pharyngeal gonococcal infections at present, however, the level of susceptibility of the gonococci in some countries is continuously decreasing, and the results of 7 drug resistance monitoring points in 2013to 2016 in China show that the rate of low susceptibility of the gonococci ceftriaxone is as high as 10.8% [ see reference: [3] yin Y P, Han Y, Dai X Q, et al, science of Neisseria gonorrhoeae to azomycin and cellulose in China, a retroactive study of the national surveyability data from 2013to 2016[ J ], PLOS Medicine,2018,15 ], the drug resistance of a clinical strain of gonococci in 2019 of a hospital in the hangzhou region has more reached 30% [ see reference: [4] yan J, Chen Y, Yang F, et al, high performance of the center, ria-resistant Neisseria gonorrhoeae FC428 clone, isolates from a single host in Handzhou, China [ J ] Journal of analytical chemistry, 2021 ].
Even more alarming, the FC428 clone (MIC 0.5mg/L), a ceftriaxone high-resistant strain originally found in japan, has been successfully propagated internationally, the most important feature of the FC428 clone is that the determinant of ceftriaxone high-resistance is its mosaic penA allele 60.001, and the global propagation of the FC428 clone will have a major impact on the formulation of treatment guidelines in various countries in the future. In China, FC428 clones have been successfully propagated to several geographically distinct areas, such as Beijing, Hangzhou, Suzhou, Changsha, Shanghai, and Chengdu, with frequent cases of initial treatment failure and a last line of defense that also becomes at risk.
Therefore, the development of new drugs against gonococci, especially against cefuroxime axetil gonococci, is imminent.
Disclosure of Invention
The invention aims to provide the application of galangin in preparing a medicament for treating gonorrhea, and the natural compound has extremely high antibacterial activity on neisseria gonorrhoeae and wide application prospect.
The invention adopts the following specific technical scheme:
the application of galangin in preparing a medicine for treating gonorrhea is disclosed, wherein the galangin is shown as a formula (1):
galangin has excellent gonococcus resisting activity and minimum bacteriostasis concentration not higher than 32 micron.
The gonorrhea is an infectious disease caused by gonococcus; the gonococcus is resistant to ceftriaxone, cefixime, azithromycin, penicillin, ciprofloxacin or tetracycline, multiple drug resistance and high resistance to ceftriaxone.
The infectious diseases are infections of genitourinary tract, rectum, throat or eyes.
The invention also provides a pharmaceutical composition, which comprises the galangin and pharmaceutically acceptable auxiliary materials.
The dosage form of the pharmaceutical composition is emulsion, gel, capsule, suppository, tablet, solvent or suspension.
The medicine composition of the invention is applied to mammals and human beings through oral administration, rectal administration and genital tract administration, and is applied to the preparation of medicines for preventing and treating genital tract, rectal administration, eye infection and throat infection diseases caused by gonococci.
The galangin and the pharmaceutical composition containing the galangin in the invention show strong bactericidal activity against gonococci.
Compared with the prior art, the invention has the following beneficial effects:
(1) the galangin of the present invention is used as a novel antibacterial compound, and compared with the existing antibiotics and derivatives thereof, the galangin is sensitive to drug-resistant bacteria.
(2) The galangin is used as a novel antibacterial compound, and is not easy to form drug resistance.
(3) The galangin of the invention is used as a novel antibacterial compound, and is economical and practical.
Drawings
Fig. 1 is a plot of the minimum inhibitory concentration profile of galangin against clinically isolated multiple drug resistant gonococcal strains (n 100);
FIG. 2 is a graph showing the minimal inhibitory concentration profile of galangin against clinically isolated ceftriaxone highly gonococci (n-9);
FIG. 3 shows the time-bactericidal activity of galangin against gonococci and the control ceftriaxone sodium against gonococci, wherein (A) represents the time-bactericidal activity of galangin against gonococci and (B) represents the time-bactericidal activity of control ceftriaxone sodium against gonococci.
Detailed Description
Specific embodiments of the present invention are described in detail in the following examples. These are illustrative of the invention and do not limit the scope of the invention. All reagents were commercially available unless otherwise indicated.
Example 1
The in vitro activity of the compounds of the invention can be assessed according to the EUCAST test Standard for drug sensitivity in the European Union (EUCAST; www.eucast.org). According to the test standard, the Minimum Inhibitory Concentrations (MICs) of galangin and flavonoid control compounds of the invention to different pathogenic bacteria are detected by adopting an agar plate dilution method, and the specific operations are as follows:
recovering gonococcus, enterobacter cloacae, stenotrophomonas maltophilia, escherichia coli, pseudomonas aeruginosa and listeria monocytogenes from an ultra-low temperature refrigerator, inoculating the standard strains on a GC agar plate containing 1% of microbial inoculum, placing the plate in a constant temperature incubator at 37 ℃, and culturing in a 5% CO constant temperature incubator2Under the condition (1), performing inverted culture for 14-18 h until the strain state is good, scraping a proper amount of bacteria by an inoculating loop to 1mL of GC liquid culture medium, mixing uniformly, and diluting to OD600After pipetting 5. mu.L of the suspension in a 0.01 suspension using a micro-pipette, the suspension was spotted on a plate containing a gradient of (256. mu.M, 128. mu.M, 64. mu.M, 32. mu.M, 16. mu.M, 8. mu.M, 4. mu.M, 2. mu.M, 1. mu.M, 0.5. mu.M, 0.25. mu.M) drug, air-dried, placed in a 37 ℃ incubator with 5% CO2And (5) carrying out inverted culture for 24-48h under the condition, and recording the MIC values of the medicaments to different types of standard strains.
The MIC values of galangin and control analogues of the compounds of the present invention against different pathogenic bacteria are shown in table 1. Therefore, the galangin has better narrow-spectrum bactericidal effect on gonococci compared with other flavonoid compounds.
TABLE 1 minimum inhibitory concentration (MIC, μ M) of flavonoids against different pathogenic bacteria
Example 2
Since the use of antibiotics for treating gonorrhea in 1938, antibiotics have been the preferred drugs for treating gonorrhea, however, gonococci are highly susceptible to the evolution of drug resistance, and most antibiotics cannot be used any further due to the production of resistant strains of gonococci.
Here, in order to confirm the effectiveness of galangin against multidrug-resistant gonococci, we tested the minimum inhibitory concentration against galangin of 100 clinically isolated gonococci samples by agar plate dilution method according to EUCAST (EUCAST; www.eucast.org), and the antibiotic sensitivity of the total samples is shown in Table 2. As can be seen from Table 2, there were 34 strains resistant to azithromycin (MIC >0.5mg/L) in the sample population, among which 21 strains (21%) were included in the azithromycin highly resistant strains. In addition, 12 strains were resistant to ceftriaxone (MIC >0.125mg/L), and 34 strains had decreased susceptibility to ceftriaxone (MIC ═ 0.125 mg/L). Of particular importance is the inclusion of a clinical isolate in the sample population that is resistant to all tested antibiotics (cefixime 0.25mg/L, ceftriaxone 0.25mg/L, ciprofloxacin 32mg/L, penicillin 2mg/L and tetracycline 32 mg/L). The specific operation is as follows:
recovering gonococcus and quality testing ATCC 49226 standard strain from ultralow temperature refrigerator, inoculating to GC agar plate containing 1% proliferation agent, and placing in 37 deg.C constant temperature incubatorIn 5% CO2Under the condition (1), performing inverted culture for 14-18 h until the strain state is good, scraping a proper amount of bacteria by an inoculating loop to 1mL of GC liquid culture medium, mixing uniformly, and diluting to OD6000.01, using a microsyringe to aspirate 5 μ L of the suspension and sample the suspension on a galangin drug plate with a gradient concentration, air-drying the suspension, placing the plate in a 37 ℃ incubator with 5% CO2And (5) carrying out inverted culture for 24-48h under the condition, and observing and recording the MIC value of galangin on multiple drug-resistant bacteria.
As can be seen from fig. 1, galangin had relatively consistent bactericidal effects against clinically isolated multidrug-resistant gonococci, with the MIC value of galangin against 49 gonococci strains being 16 μ M and the MIC value against the remaining 51 strains being 32 μ M among 100 clinical isolates, and more importantly, clinical isolates that showed resistance to all antibiotics were still sensitive to galangin (cefixime ═ 0.25mg/L, ceftriaxone ═ 0.25mg/L, ciprofloxacin ═ 32mg/L, penicillin ═ 2mg/L and tetracycline ═ 32mg/L), and the MIC value being 16 μ M. The galangin has no cross resistance to antibiotic-resistant gonococcus, and has potential application in gonorrhea treatment.
TABLE 2 clinical gonococcal isolate (n ═ 100) antibiotic susceptibility
Example 3
Gonorrhea is a second epidemic disease in the world, and at present, ceftriaxone is a single antibacterial therapy which is only stored in the first line of clinic and can successfully cure the gonococcal infection of pharyngeal and urogenital systems, however, in recent years, cases of treatment failure related to ceftriaxone drug-resistant strains are frequently released, and ceftriaxone is at risk as a first-line medicament. Among these, the high drug resistance FC428 clone of ceftriaxone (MIC of 0.5mg/L) originated in japan plays an important role, and FC428 clone has a mosaic type penA 60.001 allele containing a311V and T483S polymorphisms associated with the high drug resistance of ceftriaxone, and has been shown to spread to various parts of the world, such as europe, australia, north america, etc., and in china, FC428 clones were detected in multiple geographically distinct regions, such as beijing, hangzhou, suzhou, changsha, shanghai, and chengdu, etc.
The 9 ceftriaxone high-resistant strains from Hangzhou and Suzhou multi-hospital 2016-2019 are collected, whole genome sequencing technology and phylogenetic analysis prove that the 9 ceftriaxone high-resistant strains are highly related to FC428, and related drug-resistant genotyping results and antibiotic sensitivity are shown in table 3, wherein infection symptoms of 8 patients are not relieved after the patients initially receive oral cephalosporin treatment, which indicates that the initial treatment is not successful, the reason for treatment failure is that ceftriaxone is not recommended as a treatment scheme according to the guideline on one hand, and the application of oral cephalosporin medicines is greatly limited by the spread of the ceftriaxone high-resistant strains on the other hand.
TABLE 3 genotype and antibiotic susceptibility of the clinically isolated 9 FC 428-related gonococcal strains
Here, in order to confirm the effectiveness of galangin against the world-wide spread of strains associated with high resistance to FC428 by ceftriaxone, we tested the minimum inhibitory concentration of the 9 FC 428-associated gonococcal strains against galangin by agar plate dilution according to the EUCAST test standard (EUCAST; www.eucast.org), which was the same as the above:
FC428 related strain and quality test ATCC 49226 standard strain clinically separated from ultra-low temperature refrigerator resuscitation are inoculated on GC agar plate containing 1% proliferation agent, and 5% CO is added at 37 deg.C2Under the conditions of (1) performing inverted culture for 14-18 h, scraping a proper amount of bacteria into 1mL of GC liquid culture medium, and diluting the obtained product into OD600Sucking 5 μ L of the sample to 0.01, dropping on galangin-containing plate with gradient concentration, air drying, and drying at 37 deg.C with 5% CO2Inverted culture is carried out for 24-48h under the conditionMIC values of FC 428-associated bacteria were observed and recorded.
As shown in figure 2, the MIC value of galangin on 3 FC 428-related strains (SZ 20, SRRSH 180 and SRRSH 214) is 16 mu M, and the MIC value of galangin on the other 6 FC 428-related strains (SRRSH 203, SRRSH 204, SRRSH 205, SRRSH 207, SRRSH 229 and SRRSH 240) is 32 mu M, which indicates that the galangin also has a strong bactericidal effect on the FC 428-resistant strains of ceftriaxone which are prevalent in the world, and indicates that the galangin has a very high application value at the present stage.
Example 4
Recovering gonococcus and quality testing ATCC 49226 standard strain from ultralow temperature refrigerator, inoculating to GC agar plate containing 1% proliferation agent, placing in 37 deg.C constant temperature incubator under 5% CO2Under the condition (1), carrying out inverted culture for 14-18 h until the strain state is good, scraping a proper amount of bacteria into a GC liquid culture medium containing 1% of a microbial inoculum by using an inoculating loop, uniformly mixing and diluting the bacteria into OD600To the suspension of 1, 120. mu.L of the bacterial suspension was added to 12mL of a GC liquid medium containing 1% of the growth-enhancing agent (10%7CFU/mL), placing in a constant temperature shaking table at 37 ℃ for natural growth for 1 hour at 200rpm/min, adding galangin with different concentrations (1 MIC, 2 MIC, 4 MIC) for continuous culture for 8 hours, taking ceftriaxone with the same times as a positive control, sampling at initial stage, 0.5 hour, 1 hour, 2 hours, 4 hours and 8 hours respectively, diluting to proper concentration by 10 times, uniformly spreading 100 muL of diluent on a GC agar plate containing 1% of microbial inoculum, placing in a constant temperature incubator at 37 ℃, and culturing in 5% CO for 1 hour2Culturing the cells under the conditions of (1) for 24-48h, and observing and recording the clone number (CFU).
The results are shown in fig. 3, 4 × MIC indicates that the final concentration of the drug added to the GC broth was 4 times the Minimum Inhibitory Concentration (MIC) for the gonococcal standard strain (ATCC 49226), and the rest were similar. Results are expressed as mean ± SD of triplicate biological replicates and dashed lines as lower detection limits.
Compared with ceftriaxone sodium, galangin can rapidly and effectively kill gonococci at concentrations of 4 × MIC and 2 × MIC, has a similar sterilization rate to that of the clinical first-line medicament ceftriaxone, and can kill more than 90% of gonococci within a detection period at 1 × MIC, which shows that galangin has extremely high bactericidal activity to the gonococci at both high concentrations and low concentrations.
Claims (8)
1. The application of the natural compound in preparing the medicine for treating gonorrhea is characterized in that the natural compound is galangin shown as a formula (1):
2. the use of claim 1, wherein the gonorrhea is an infectious disease caused by gonococci.
3. The use of claim 2, wherein said gonococci are those resistant to ceftriaxone, cefixime, azithromycin, penicillin, ciprofloxacin or tetracycline.
4. The use of claim 3, wherein the gonococcus is an internationally prevalent strain of gonococcus that is highly resistant to ceftriaxone.
5. The use according to claim 2, wherein the infectious disease is an infectious disease of the urogenital tract, rectum, throat or eye.
6. A pharmaceutical composition is characterized by comprising galangin and pharmaceutically acceptable auxiliary materials.
7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of an emulsion, gel, capsule, suppository, tablet, solvent, or suspension.
8. Use of a pharmaceutical composition according to claim 6 or 7 for the preparation of a medicament for the treatment of gonorrhea, wherein gonorrhea is an infectious disease caused by gonococci.
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| CN1059563C (en) * | 1994-06-02 | 2000-12-20 | 中国人民解放军三○二医院 | Gonorrhoea eliminating and bacteriostatic bathing liquor containing Chinese drug and its preparing method |
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| MS HIFNAWY ET AL: "Phenolic contents and in vitro free radical scavenging activity of alcoholic extract of the fruits of Tribulus terrestris L", 《THE PHARMA INNOVATION JOURNAL》, vol. 4, 31 December 2015 (2015-12-31), pages 7 * |
| PATRICK S.RUDDOCK, MSC ET AL: "AntimicrobialActivity of FlavonoidsFrom Piper lanceaefolium and Other Colombian Medicinal Plants Against Antibiotic Susceptible and Resistant Strains of Neisseria gonorrhoeae", 《SEXUALLY TRANSMITTED DISEASES》, vol. 38, 31 December 2011 (2011-12-31), pages 4 * |
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