CN114366730B - Application of gallic acid and pharmaceutical composition containing gallic acid in treatment of bacterial prostatitis - Google Patents
Application of gallic acid and pharmaceutical composition containing gallic acid in treatment of bacterial prostatitis Download PDFInfo
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- CN114366730B CN114366730B CN202210088367.8A CN202210088367A CN114366730B CN 114366730 B CN114366730 B CN 114366730B CN 202210088367 A CN202210088367 A CN 202210088367A CN 114366730 B CN114366730 B CN 114366730B
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- Prior art keywords
- gallic acid
- ciprofloxacin
- prostate
- prostatitis
- bacterial prostatitis
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims abstract description 128
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Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to application of gallic acid and a composition containing gallic acid and ciprofloxacin in preparing medicines for treating bacterial prostatitis. The composition comprises gallic acid and ciprofloxacin, and the content ratio of the gallic acid to the ciprofloxacin is 0.1:1 to 10:1 in terms of mass ratio.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a composition containing gallic acid and ciprofloxacin in preparation of a medicament for treating bacterial prostatitis.
Background
Prostatitis (prostatides) refers to a disease in which the prostate gland, under the action of pathogens and/or certain non-infective factors, is characterized by symptoms such as pain or discomfort in the pelvic area, abnormal urination, etc. Prostatitis is a common urinary system disorder, and in all male urinary tract disorders, the incidence of prostatitis is inferior to prostate cancer and benign prostatic hyperplasia. It is counted that nearly 16% of men report a history of prostatitis at some stage in their lives, with prostatitis accounting for nearly 25% of all urological visits.
The causative agent of bacterial prostatitis (bacterial prostatitis, BP) is mainly a pathogen infection, and its incidence is about 20% of all prostatis. BP can be classified into acute bacterial prostatitis (ABP, type I) and chronic bacterial prostatitis (CBP, type II) according to the etiology and pathogenesis. ABP is caused by low body resistance, strong bacteria or other pathogens infecting the prostate and rapidly growing and reproducing in large numbers, mostly blood-going infection or transurethral retrograde infection, and has the potential risk of causing more serious diseases due to abscess, septicemia and septic shock. CBP, on the other hand, is caused by a more resistant or less virulent pathogen, mainly by retrograde infections, and is particularly susceptible to recurrence, which can lead to decreased libido, erectile dysfunction and premature ejaculation, severely affecting the quality of life and mental health of the patient.
Currently, in clinical practice for treating BP, the most commonly used first-line drugs are antibiotics, such as quinolones like ciprofloxacin. However, the gram-positive bacteria in BP prostatic fluid have a drug resistance rate to ciprofloxacin as high as 45.54%. Increased difficulty in antimicrobial treatment (emergence of multi-resistant bacteria and ESBL bacteria producing ultra-broad spectrum beta-lactamase, production of bacterial biofilms, shift in bacterial etiology) and shift in treatment regimens have been reported to have attracted worldwide attention. In addition, quinolones such as ciprofloxacin also have the problem of cardiotoxicity causing QT interval prolongation. The prostate tissue structure is special, particularly in the inflammatory injury state, the interstitial is thickened to generate fibrosis, and the prostate capsule permeability is reduced, so that the medicine is difficult to cross the blood-prostate barrier, the medicine concentration in the target tissue is influenced, and the satisfactory treatment effect is difficult to obtain. Thus, finding new solid compounds or new therapeutic strategies to cope with BP has become a currently very critical task.
Disclosure of Invention
The invention aims to provide a medicament capable of effectively treating bacterial prostatitis. The inventor has found that gallic acid can effectively reduce the bacterial number in the prostate, reduce the prostate index, lower the body inflammatory factor level, and has remarkable curative effect on bacterial prostatitis. In addition, the composition of the gallic acid and the ciprofloxacin can achieve the aim of synergy through reasonable compatibility and application, and has good development prospect in the field of treating bacterial prostatitis.
Specifically, the present invention provides:
1. use of gallic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt is any one of the following salts:
1) Salts of gallic acid with sodium, potassium, magnesium, or calcium cations,
2) A salt of gallic acid with an organic base,
3) A salt of gallic acid with an amino acid,
4) Ammonium salts of gallic acid with ammonium cations.
3. The use according to the above item 1 or 2, wherein the gallic acid or a pharmaceutically acceptable salt thereof is used in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable additive.
4. The use according to claim 3, wherein the additive comprises at least one selected from the group consisting of excipients, disintegrants and lubricants.
5. The use according to item 1 or 2 above, wherein the administration dose is 10 to 500mg/kg based on the mass of gallic acid or a pharmaceutically acceptable salt thereof.
6. A composition comprising gallic acid and ciprofloxacin, wherein the ratio of the content of gallic acid to ciprofloxacin is from 0.1:1 to 10:1 in terms of mass ratio.
7. The composition according to the above item 6, wherein the ratio of the content of gallic acid to ciprofloxacin is 1:1 to 5:1 in terms of mass ratio.
8. The composition according to item 6 or 7 above, further comprising a pharmaceutically acceptable additive.
9. The composition according to item 8 above, wherein the additive comprises at least one selected from the group consisting of an excipient, a disintegrant, and a lubricant.
10. Use of a composition according to any one of items 6 to 9 above in the manufacture of a medicament for the treatment of bacterial prostatitis.
Effects of the invention
According to the invention, the gallic acid can effectively reduce the bacterial quantity in the prostate, reduce the prostate index and lower the body inflammatory factor level, has obvious curative effect on bacterial prostatitis, and is expected to become a candidate medicament for treating the bacterial prostatitis. In addition, the gallic acid is easy to obtain, low in cost and small in toxic and side effects, and has obvious advantages compared with the similar medicines which are clinically applied at present.
In addition, according to the invention, the composition of the gallic acid and the ciprofloxacin can achieve the aim of synergy through reasonable compatibility application, accords with the clinical situation of combined use of Chinese and western medicines, and has good development prospect in the field of bacterial prostatitis.
Drawings
Fig. 1 shows a bar graph of the effect of gallic acid and ciprofloxacin-containing compositions on prostate index.
Figure 2 is a bar graph showing the effect of gallic acid and ciprofloxacin containing compositions on prostate colony count.
FIG. 3 is a bar graph showing the effect of gallic acid and ciprofloxacin-containing compositions on inflammatory factor TNF- α.
FIG. 4 is a bar graph showing the effect of gallic acid and ciprofloxacin-containing compositions on inflammatory factors IL-1. Beta.
Fig. 5 shows a photomicrograph of a histopathological analysis. The magnification is 100 times and the scale bar is 100 μm.
Note that, in fig. 1 to 4, # represents p compared to the control group<0.05； ## Represents p compared to the control group<0.01； * Representation compared to model set, p<0.05； ** Representation compared to model set, p<0.01。
Detailed Description
The present invention is described in detail below by way of description of specific embodiments, but this is not a limitation of the present invention, and various modifications or improvements may be made by those skilled in the art based on the basic idea of the present invention, but are within the scope of the present invention as long as they do not depart from the basic idea of the invention.
In a first aspect, the invention provides the use of gallic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of bacterial prostatitis.
Gallic acid(gallic acid, GA) also known as gallic acid or gallic acid, chemical name 3,4, 5-trihydroxybenzoic acid, chemical formula C 7 H 6 O 5 The structural formula is shown in the following chemical formula 1.
[ chemical formula 1]
Gallic acid is widely present in plants such as gallnut, phyllanthus emblica, pomegranate, grape, lily, rose, lacquer tree, rheum palmatum, eucalyptus robusta, cornus officinalis, tarragon, rhodiola rosea, etc. Modern pharmacological research shows that gallic acid has various pharmacological activities of resisting oxidation, resisting cancer, reducing blood sugar, resisting inflammation, protecting cardiac and cerebral vessels, protecting liver and the like. Gallic acid can be used as a potential food additive and an effective component of cosmetics, and has important medical effect. At present, no related research report on the treatment of bacterial prostatitis by gallic acid exists.
In the present invention, gallic acid may be used as a single compound extracted from a plant, or may be used as a commercially available product, for example, commercially available from Hubei Xingzheng technology Co., ltd.
In the present invention, salts of gallic acid may be used. The salt may be a pharmaceutically acceptable salt. Specifically, there may be mentioned: salts with metal cations such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine, or ammonium salts.
In the present invention, gallic acid or a pharmaceutically acceptable salt thereof may be used in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable additive.
In the above pharmaceutical composition, gallic acid or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable additive to obtain a pharmaceutical composition which can be orally or parenterally administered. The pharmaceutical compositions may be formulated by conventional methods.
The administration may be carried out in a dosage form for oral administration (e.g., tablet, capsule, granule, powder, liquid preparation, etc.), or in a dosage form for parenteral administration (e.g., injection, etc.).
As the solid composition for oral administration, tablets, pills, powders, granules, capsules and the like can be used. In such solid compositions, gallic acid or a pharmaceutically acceptable salt thereof is admixed with at least one additive. The above additives include excipient, disintegrating agent, lubricant, etc.
Excipients include, for example, lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium aluminum silicate, and the like.
Disintegrants include cellulose (e.g., calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, or crystalline cellulose), starch (e.g., cornstarch, pregelatinized starch, or sodium carboxymethyl starch), cross-linked polyvinylpyrrolidone, and the like.
Lubricants include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid esters, talc, polyethylene glycol and the like.
The solid formulation of the present invention may optionally contain other additives in appropriate amounts, depending on the purpose. Such additives include binders, plasticizers, coating agents, deflocculants, solubilizing agents, sweeteners, acidulants, flavoring agents, pH modifiers, co-solvents, colorants, flavoring agents, and the like. The binder includes sodium alginate, gelatin, dextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. The plasticizer comprises triethyl citrate, glycerol fatty acid ester, polyethylene glycol, etc. The coating agent comprises ethyl cellulose, hydroxypropyl methylcellulose, etc. Deflocculant includes talc, calcium stearate, and the like. The solubilizer comprises sucrose fatty acid ester, sorbitan monostearate, sodium dodecyl sulfate, etc. The sweetener comprises saccharin, dipotassium glycyrrhizinate, stevia, etc. The acidulant includes citric acid, malic acid, ascorbic acid, fumaric acid, etc. Flavoring agents include 1-menthol, sodium chloride, sucrose, etc. The pH regulator comprises citrate, phosphate, carbonate, acetate, etc. The cosolvent comprises cyclodextrin, arginine, lysine, and triaminomethane. The colorant comprises ferric oxide yellow, ferric oxide, sodium copper chlorophyllin, etc. Flavoring agents include orange oil, lemon oil, peppermint oil, eucalyptus oil, and the like.
The tablets of the invention may be prepared according to conventional methods in tablet manufacture, for example, by the steps of: i) Preparing a mixture comprising gallic acid or a pharmaceutically acceptable salt thereof, and one or more additives selected from the group consisting of excipients, disintegrants, lubricants, binders, plasticizers, coating agents, deflocculating agents, solubilizing agents, sweeteners, acidulants, flavoring agents, pH adjusting agents, co-solvents, colorants and flavoring agents, and then ii) compression molding the mixture obtained in i) above.
Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the nonaqueous solvent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, alcohols such as ethanol, and tween 80. The formulation may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or dissolution aids. For example, can be sterilized by filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. Alternatively, the sterile solid may be prepared and used after dissolution or suspension in sterile water or sterile injectable solvent prior to use.
For oral administration, a suitable 1-day dose is about 10 to 500mg/kg, preferably 50 to 200mg/kg, per body weight, and the dose is taken once or 2 to 4 times. The administration dose is appropriately selected according to the circumstances, taking into consideration symptoms, age, sex, and the like.
In a second aspect the invention provides a composition comprising gallic acid and ciprofloxacin as major components. The term "main component" refers to a component having a content of 90% or more (mass fraction) of the total mass of the composition, preferably 95% or more, and more preferably 99% or more of the total mass of the composition.
Ciprofloxacin (CIP) with chemical name 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7 (1-piperazinyl) -3-quinolinecarboxylic acid, formula C 17 H 18 FN 3 O 3 Molecular weight 331.34, structural formula is shown in the following chemical formula 2.
[ chemical formula 2]
CIP is a synthesized third-generation quinolone antibacterial drug, has broad-spectrum antibacterial activity, and has antibacterial effect on enterobacter, pseudomonas aeruginosa, haemophilus influenzae, gonococcus, streptococcus, legionella and staphylococcus aureus. CIP can kill pathogenic bacteria, but is easy to cause bacterial drug resistance, so that repeated infection of the urinary tract occurs, and the clinical effect of single application is not ideal.
In the above composition, the ratio of the content of gallic acid to ciprofloxacin is 0.1:1 to 10:1, preferably 1:1 to 5:1, and more preferably 2:1 to 4:1 in terms of mass ratio. When the ratio of gallic acid to ciprofloxacin content is within the above range, bacterial prostatitis can be effectively treated.
Gallic acid and ciprofloxacin may be mixed with pharmaceutically acceptable additives to obtain a pharmaceutical composition which may be administered orally or parenterally. The pharmaceutical compositions may be formulated by conventional methods.
The administration may be carried out in a form for oral administration (for example, tablet, pill, capsule, granule, powder, liquid preparation, etc.), or in a form for parenteral administration (for example, injection, suppository, eye drop, eye ointment, transdermal liquid preparation, ointment, transdermal patch, transmucosal liquid preparation, transmucosal patch, inhalant, etc.). Preferably, the dosage form for oral administration is a tablet, capsule, or granule.
The preparation method of each dosage form can be similar to the preparation method of the dosage form containing gallic acid.
For oral administration, a suitable 1-day dose is about 10 to 500mg/kg, preferably 100 to 250mg/kg, more preferably 150 to 250mg/kg, per body weight, and the dose is administered once or 2 to 4 times. The amount to be administered is appropriately selected depending on the conditions, in consideration of symptoms, age, sex, and the like.
In addition, the preparation of the above-described pharmaceutical composition of the present invention may be used in combination with other therapeutic agents for bacterial prostatitis. When used together, the administration may be simultaneous, or may be performed sequentially, or at desired intervals.
A third aspect of the invention relates to the use of a composition according to the second aspect described above for the treatment of bacterial prostatitis.
The pharmaceutical composition containing gallic acid and ciprofloxacin can achieve the aim of synergy through reasonable compatibility application, and can be effectively used for treating bacterial prostatitis.
Examples
The following examples further illustrate or describe the invention but should not be construed as limiting the scope of the invention.
Various reagents and the like used in the following examples are known in the art and are commercially available.
1. Cultivation of bacteria
Standard pathogenic Escherichia coli ATCC25922 (Lot Number:70027805, north Nanoorganism, beijing) was used and cultured in TSB (Trypticase soy broth) trypsin soybean broth medium at 37℃for 12 hours. Before inoculation, the bacterial solution is diluted to 1.0X10 by using sterilized normal saline 8 CFU/mL suspension.
2. Establishment of bacterial prostatitis rat model
The bacterial prostatitis rat model was replicated with reference to the following prior document 1. Male Wistar rats, SPF grade (SCXK (jin) 2016-0011, beijing Fukang Biotechnology Co., ltd.), weight 250-300 g, after adaptive feeding for one week, 10%Chloral hydrate was anesthetized by intraperitoneal injection and the genital area was cleaned with 70% alcohol. Under aseptic conditions, an incision of about 1.5cm was made in the middle of the lower abdomen of the rat, and the abdominal wall and peritoneum were incised to expose the bladder. The toothless forceps gently lift the bladder, exposing the prostate. A suspension of Escherichia coli (ATCC 25922) (1.0X10) was injected at both sides of the prostate by 0.05mL 8 CFU/mL), the blank group was infused with 0.05mL of physiological saline, and then the peritoneum and skin were sutured layer by layer.
Document 1: inci M, davarci M, inci M, et al anti-inflammatory and antioxidant activity of thymoquinone in a rat model of acute bacterial pro-stics Hum Exp Toxicol.2013;32 (4):354-361.
3. Preparation of dosing solutions
Gastric lavage solutions of gallic acid (GB 720, CAS:149-91-7,Solarbio Science&Technology Co, ltd., beijing) and ciprofloxacin (SH-C482500-50 g, CAS:85721-33-1,Toronto Research Chemicals,Toronto,Canada) were prepared separately using physiological saline. The solution concentrations were as follows:
ciprofloxacin solution (5 mg/mL), low concentration gallic acid solution (5 mg/mL), medium concentration gallic acid solution (10 mg/mL), high concentration gallic acid solution (20 mg/mL), low concentration gallic acid+ciprofloxacin solution (5 mg/mL+5 mg/mL), medium concentration gallic acid+ciprofloxacin solution (10 mg/mL+5 mg/mL), high concentration gallic acid+ciprofloxacin solution (20 mg/mL+5 mg/mL).
4. Experimental grouping and administration
After 24 hours of molding, rats were randomly divided into 9 groups: control (Control), model (Model), gallic acid low dose (ga_l), gallic acid medium dose (ga_m), gallic acid high dose (ga_h), CIP, gallic acid low dose CIP, gallic acid medium dose CIP (ga_m+cip), gallic acid high dose CIP (ga_h+cip). Each group of 10. Each dosing group was dosed once daily for 7 days of drug treatment. Details are shown in Table 1.
Table 1 experimental grouping and administration
5. Sampling and detecting index
5.1 prostate organ coefficients
The prostate organ factor (prostate viscera coefficient, PVC) is an important factor in assessing the progression of prostatitis, reflecting the extent of prostatitis. PVC increases with the progression of inflammation. Referring to the following prior document 2, rats were anesthetized with 10% chloral hydrate, the abdominal cavity was opened under aseptic conditions, the prostate tissue was removed, and the prostate tissue was cleaned, weighed, and the calculation of the viscera coefficient of the prostate was performed according to the following formula.
Prostate index = total wet weight of prostate tissue/rat mass
Document 2: yang Y, huang C, su X, et al Deciphering the multicomponent synergy mechanism from a systems pharmacology perspective: application to Gualou Xiebai Decoction for coronary heart disease.J function Foods,2018;47:143-155.
5.2 bacterial colony culture
To further investigate the effect of bacillus cephalocathartic on the colonization of the bacteria within the prostate, each group of prostate tissue was cultured in McConkey agar dishes and the colony numbers were examined. Referring to the following prior document 3, prostate tissue of the same region of each rat was weighed under a sterile environment, and the prostate tissue was minced with sterile tissue scissors to prepare a prostate tissue homogenate. The tissue fluid supernatants were plated on McConkey agar plates by 10-fold dilution, 100uL each, and colonies were counted after incubation at 37℃for 24 hours. Bacterial counts are expressed as a logarithmic average of the total number of colonies per gram of prostate tissue (Log CFU/g of prostate tissue).
Document 3: xiong Y, qia X, shi W, et al anti-inflammatory and antioxidant effect of modified Bazhengsan in a rat model of chronic bacterial pro-statis J Etenopharmacol.2017; 198:73-80.
5.3ELISA method for detecting expression of tissue inflammatory factor TNF-alpha and IL-1 beta
TNF-alpha is an important pro-inflammatory cytokine that plays an important role in the development and progression of chronic inflammation of the prostate. TNF-alpha can be used as an index for diagnosing the local immunoreaction intensity of the prostate and the chronic prostatitis and detecting the illness state, and the reduction of the level of the proinflammatory cytokine TNF-alpha has important significance for preventing organ injury. In bacterial prostatitis, TNF-a is usually associated with IL-1β, and thus ELISA was used to detect the expression of the tissue inflammatory factors TNF- α, IL-1β. Details can be found in the following prior documents 4 to 6.
Document 4: sun Yiming, liu Li, li Yinglin, etc. effect of prostatic watered pills on serum IL-6 and TNF-alpha levels in rats with chronic bacterial prostatitis J.Zhonghua Men's journal, 2006 (05): 470-472.
Document 5: wang Shoufu, zhang Huijian, li Jiansheng, etc. effects of Xionqing granule on inflammatory factor of multiple organ injury of aged rats with bacterial pneumonia [ J ]. J.J.J.of Chinese laboratory prescription, 2011,17 (06): 165-169.
Document 6: lang MD, nickel JC, olson ME, et al Rat model of experimentally induced abacterial pro-statis. Prostate.2000;45 (3):201-206.
The expression of the inflammatory factors TNF- α, IL-1β in the tissues was examined separately and the experiment was repeated 3 times according to the instructions of the ELISA kit for TNF- α (CSB-E11987 r, cusabio Biotech Co., ltd, wuhan), IL-1β (CSB-E08055 r, cusabio Biotech Co., ltd, wuhan) and the test results were expressed in ng/mL.
5.4 histopathological analysis
The most immediate indicator of prostatitis is a pronounced inflammation of the prostate tissue. The pathological observation can accurately judge the severity of prostatitis, and an optical microscope is used for observing whether inflammatory cells infiltrate, inflammatory cell types, tissue oedema, glandular epithelium necrosis, shedding and glandular epithelium disappearance. Referring to the following prior document 7, prostate tissue of the same region of each rat was fixed in a 4% tissue fixing solution, dehydrated, sectioned by conventional paraffin embedding, stained with 5 μm in section thickness and H & E, and subjected to histological scoring. The severity of prostatitis was scored based on three parameters, chronic inflammatory cell infiltration, acinar changes and interstitial fibrosis, of the representative area, as observed under light microscopy.
Document 7: wang W, navied M, baig MMFA, et al experimential rodent models of chronic prostatitis and evaluation criterion, biomed pharmacother.2018;108:1894-1901.
6. Test results
6.1 Effect of gallic acid and ciprofloxacin-containing composition on prostate index
Swelling of the prostate tissue is one of the features of prostatitis. The prostate index is often used as a detection index of BP, and can reflect the tissue inflammation degree to a certain extent.
The test results are shown in table 2 and are visually shown in fig. 1.
As shown in table 2, the prostate index of the rats in the model group was significantly increased (P < 0.01) compared to the rats in the control group, indicating that the prostate tissue had obvious inflammatory symptoms in the disease state.
As shown in fig. 1, the prostate index of ciprofloxacin group rats was significantly reduced (P < 0.01) compared to model group rats; the prostate index of the rats in the low, medium and high dose groups of gallic acid is significantly reduced (P < 0.01) and dose dependency is presented; the rat prostate index of the combination of low, medium and high doses of gallic acid and ciprofloxacin also showed a significant dose-dependent decrease (P < 0.01), respectively. The results show that both gallic acid monomers and compositions comprising gallic acid and ciprofloxacin can significantly improve the swelling and inflammatory states of prostate tissue.
TABLE 2 influence of gallic acid and ciprofloxacin-containing compositions on prostate index in rats
Note that: ## represents p compared to the control group<0.01； ** Representation compared to model set, p<0.01
6.2 Effect of gallic acid and compositions comprising gallic acid and ciprofloxacin on the number of bacteria in the prostate
The test results are shown in table 3 and are visually shown in fig. 2.
As shown in fig. 2, no bacterial colony was observed in the prostate tissue of the control group rats.
The number of bacteria in the prostate of rats in the model group was significantly increased compared to the control group.
Compared with the model group, the colony count of the prostate tissue of the ciprofloxacin group rat is obviously reduced; the colony count of the gallic acid low dose group rats and the combined group rats of gallic acid low dose and ciprofloxacin was not significantly reduced, but there was a tendency to be reduced; prostate tissue colony counts were significantly reduced in gallic acid medium dose group rats and gallic acid high dose group rats; the prostate tissue colony count of rats with the combined dosage of gallic acid and ciprofloxacin and rats with the combined dosage of gallic acid and ciprofloxacin is also obviously reduced respectively.
TABLE 3 influence of gallic acid and ciprofloxacin-containing compositions on the number of bacteria in the prostate
Note that: ## represents p compared to the control group<0.01； * Representation compared to model set, p<0.05； ** Representation compared to model set, p<0.01
6.3 Effect of gallic acid and ciprofloxacin-containing composition on prostate tissue inflammatory factor
(1) Inflammatory factor TNF-alpha levels
The test results are shown in table 4 and are visually shown in fig. 3.
As shown in fig. 3, the tissue inflammatory factor TNF- α levels were significantly elevated in rats in the model group compared to the control group.
Tissue inflammatory factor TNF- α levels were significantly reduced in ciprofloxacin group rats compared to model group rats; TNF-alpha is also significantly reduced in low, medium and high dose groups of gallic acid rats, respectively, and shows dose dependency; the reduction of TNF-alpha in rats with low doses of gallic acid and ciprofloxacin was not significant, but the reduction of TNF-alpha in rats with medium doses of gallic acid and ciprofloxacin was significant.
TABLE 4 influence of gallic acid and ciprofloxacin-containing compositions on prostate tissue inflammatory factor TNF-alpha
Note that: ## represents p compared to the control group<0.01； ** Representation compared to model set, p<0.01
(2) Inflammatory factor IL-1 beta levels
The test results are shown in table 5 and are visually shown in fig. 4.
As shown in fig. 4, the inflammatory factor IL-1β levels were significantly elevated in the rats of the model group compared to the control group.
Compared with the model group, the inflammatory factor IL-1 beta level of the ciprofloxacin group rats is not changed significantly; the IL-1 beta level dose dependence of the rats in the gallic acid medium dose group and the rats in the gallic acid medium dose and ciprofloxacin combination group and the rats in the gallic acid high dose and ciprofloxacin combination group is obviously reduced.
The results show that the gallic acid monomer and the composition containing the gallic acid and ciprofloxacin have remarkable curative effects on the bacterial prostatitis, and are expected to become candidate medicaments for treating the bacterial prostatitis.
TABLE 5 influence of gallic acid and ciprofloxacin-containing compositions on prostate tissue inflammatory factor IL-1 beta
Note that: ## represents p compared to the control group<0.01； * Representation compared to model set, p<0.05； ** Representation compared to model set, p<0.01
6.4 Effect of gallic acid and compositions comprising gallic acid and ciprofloxacin on prostate histopathology
The test results are shown in FIG. 5.
Normal control group (Con): rat prostate epithelial cells are orderly arranged, smooth and flat, no obvious hyperplasia is caused, the endocrine of the cavity is pink, and inflammatory cells in the interstitium are few.
Model control group (Mod): the prostate gland of the rat is obviously reduced, the gland epithelial tissues are destroyed to different degrees, the gland epithelium is shed, fused or thinned into a single layer, the gland cavity is disappeared, and a large amount of inflammatory cells infiltrate.
Gallic acid low dose group (ga_l) and gallic acid low dose and CIP combined group (ga_l+cip): the number of acinus is small, the acinus expands to different degrees, the interstitial tissue is obviously widened, a small amount of secretion exists in the acinus, even no secretion exists, and more inflammatory cells are infiltrated.
Ciprofloxacin group (CIP): the gland epithelium tissue is still damaged to different degrees, the number of acinus is larger than that of the model group, but the gland epithelium is thinned into a single layer, and inflammatory cells infiltrate.
Gallic acid medium dose group (ga_m) and gallic acid high dose group (ga_h): the glandular epithelium is seen to proliferate to a degree, there is a degree of fibrosis in the interstitium, and infiltration of inflammatory cells is greatly reduced compared to the model group, but it is still seen to be scattered.
Gallic acid medium dose and CIP combined (ga_m+cip) and gallic acid high dose and CIP combined (ga_h+cip): the glandular epithelium has no obvious hyperplasia, the acinus structure is basically normal, the shape is smoother and regular, the interstitium has no obvious edema, a small amount of inflammatory cells are distributed in the interstitium, no obvious fibrosis is generated, and the chronic inflammation degree is greatly reduced compared with that of a model group and others.
Claims (5)
1. The use of gallic acid or a pharmaceutically acceptable salt thereof as the sole active ingredient in the manufacture of a medicament for the treatment of bacterial prostatitis.
2. The use of claim 1, wherein the gallic acid or pharmaceutically acceptable salt thereof is used in combination with a pharmaceutically acceptable additive in the form of a pharmaceutical composition.
3. The use according to claim 2, wherein the additive comprises at least one selected from excipients, disintegrants, lubricants.
4. The use according to claim 1, wherein the dosage is 10-500 mg/kg based on the mass of said gallic acid or pharmaceutically acceptable salt thereof.
5. Use of a composition comprising gallic acid and ciprofloxacin as active ingredients for the preparation of a medicament for the treatment of bacterial prostatitis, wherein the ratio of gallic acid to ciprofloxacin content is from 1:1 to 5:1 in terms of mass ratio.
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