CN114469923B - Application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparation of liver injury drugs - Google Patents
Application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparation of liver injury drugs Download PDFInfo
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- -1 bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester Chemical class 0.000 title claims abstract description 26
- 206010067125 Liver injury Diseases 0.000 title claims abstract description 24
- 231100000753 hepatic injury Toxicity 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 14
- 229940079593 drug Drugs 0.000 title abstract description 10
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 5
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- 229930040373 Paraformaldehyde Natural products 0.000 description 2
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- 125000002619 bicyclic group Chemical group 0.000 description 2
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- 150000001875 compounds Chemical class 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
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- RDAGYWUMBWNXIC-UHFFFAOYSA-N 1,2-bis(2-ethylhexyl)benzene Chemical compound CCCCC(CC)CC1=CC=CC=C1CC(CC)CCCC RDAGYWUMBWNXIC-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- HJUFTIJOISQSKQ-UHFFFAOYSA-N fenoxycarb Chemical compound C1=CC(OCCNC(=O)OCC)=CC=C1OC1=CC=CC=C1 HJUFTIJOISQSKQ-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
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- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052752 metalloid Inorganic materials 0.000 description 1
- KXMTXZACPVCDMH-UHFFFAOYSA-N methyl 4-[5-(hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1CO KXMTXZACPVCDMH-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- 231100000417 nephrotoxicity Toxicity 0.000 description 1
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Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
Abstract
The invention relates to an application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparing liver injury drugs. The team of the invention adopts NaAsO2Constructing an in-vivo liver injury model mouse, performing gastric lavage intervention on the mouse by using bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester separated from mentha plants, and observing the control effect on the liver injury mouse. The animal in vivo experiment results prove that the extract has prevention and treatment effects on liver injury caused by sodium arsenite, and the prevention effect is superior to the treatment effect.
Description
Technical Field
The invention relates to the field of medicine application, in particular to application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparing liver injury medicines.
Background
Arsenic is a metalloid element with strong toxicity and is widely distributed in soil, water, air, plants and microorganisms in nature in both inorganic and organic forms. Arsenic is thus easily incorporated into humans and animals through food, water and occupational contamination. Arsenic exposure can cause damage to the liver, causing multiple organ diseases such as dermatitis, renal toxicity, neurotoxicity, diabetes, atherosclerosis, hypertension, cardiovascular disease, skin cancer, bladder cancer, and lung cancer. There is evidence that liver, which is the main metabolism and detoxication organ of arsenic, can be retained in high concentration during its metabolism, thus causing liver lesions such as liver dysfunction, hepatomegaly, liver fibrosis, liver cirrhosis and even cancerous liver diseases of different degrees, which become one of the main causes of arsenic death. The research finds that oxidative stress and lipid peroxidation are causative factors of liver injury caused by arsenic, and arsenic can generate a large amount of free radicals and non-free radical products in liver metabolism to cause lipid peroxidation of liver cell membranes, so that cell membrane and organelle structures are damaged, and the membrane fluidity is abnormal; a large amount of intracellular enzymes (ALT, AST) are released into the blood, and free radical scavenging enzymes (SOD, GPx) are exhausted, so that the damage to the liver cells is further aggravated, the activity level of Glutathione (GSH) is reduced, and the level of Malondialdehyde (MDA) is increased, thereby causing abnormal liver function and fat metabolism disorder. The antioxidant can restore an unbalanced oxidation-reduction system, protect the morphology and activity of cells, reduce the generation of active oxygen in the cells, and restore the normal liver function, and is a key for preventing and treating the generation and development of arsenic-induced liver injury.
at least 25 ten thousand natural product derivatives identified as plant kingdom, only 10% of which are used in pharmacological studies, exist in flowers, stems, leaves, bark and roots, have various pharmacological actions in the human system, and are antioxidant, antispasmodic, analgesic, antiemetic, antibacterial, antitumor, etc. Whether the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester has a protective effect on liver injury or not has not been reported in related researches at home and abroad. The team of the invention adopts NaAsO2Constructing an in-vivo liver injury model mouse, performing gastric lavage intervention on the mouse by using bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester separated from mentha plants, and observing the control effect on the liver injury mouse. The animal in vivo experiment results prove that the extract has prevention and treatment effects on liver injury caused by sodium arsenite, and the prevention effect is superior to the treatment effect.
Disclosure of Invention
The invention provides an application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparing liver injury drugs.
Preferably, the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester is applied to the preparation of medicines for preventing and treating liver injury.
Preferably, the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester is applied to the preparation of medicines for preventing and treating liver injury caused by sodium arsenite.
Preferably, the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester is used for preparing a pharmaceutical preparation for preventing and treating liver injury.
Preferably, the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester is applied to the preparation of medicines for preventing and treating liver injury caused by sodium arsenite.
The preparation is prepared by adding pharmaceutically acceptable auxiliary materials.
The pharmaceutically acceptable preparation is a solid preparation or a liquid preparation.
The solid preparation is tablets, granules, capsules, pills, powder and powder injection.
the liquid preparation is injection and oral liquid.
the auxiliary materials are not limited, and can be accepted in pharmacy.
The beneficial effects are that:
Compared with the prior art, the invention has the following beneficial effects:
Whether the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester has a protective effect on liver injury or not has not been reported in related researches at home and abroad. The team of the invention adopts NaAsO2Constructing an in-vivo liver injury model mouse, performing gastric lavage intervention on the mouse by using bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester separated from mentha plants, and observing the control effect on the liver injury mouse. The animal in vivo experiment results prove that the extract has prevention and treatment effects on liver injury caused by sodium arsenite, and the prevention effect is superior to the treatment effect.
Drawings
FIG. 1 microscopic image of the pathological changes in liver tissue of mice of the prophylaxis group (HE staining, X400)
a. Blank group; b. a model group; c. a bicyclic alcohol group; d. a glutathione group; e. low dose group; f. medium dose group; g. high dose group.
FIG. 2 microscopic image of the pathological changes in liver tissue of mice of the treatment group (HE staining, ×400)
a. blank group; b. a model group; c. a bicyclic alcohol group; d. a glutathione group; e. low dose group; f. medium dose group; g. high dose group
Detailed Description
The technical scheme of the invention is further specifically described by the following specific examples.
Example 1
1 Material
1.1 Compounds
Bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester: in the technical scheme of the invention, bis (2-ethylhexyl) benzene
-1, 2-dicarboxylic acid esters, which are compounds of the structure
1.2 major instrumentation
The instrument used included an ME204E analytical balance (Mettler-Toledo, switzerland); chemray 800 type full-automatic biochemical analyzer (Shenzhen society of life technologies); MCR-88-8 bench top micro-cryocentrifuge (singapore ESCO); allegraX-15R frozen bench type general purpose centrifuge (Beckman Co., U.S.A.); DW-HL340 ultra-low temperature refrigerator (Mitsubishi low temperature technology Co., ltd.); KZ-LLL-FP high-speed low-temperature tissue grinder (WUKaville Biotechnology Co., ltd.); SYNERGY-H4 multifunctional microplate reader (Bio-Tek Co., U.S.A.); ECLIPSE TS100-F inverted biological microscope; DMI8 type fluorescence inverted microscope (Leica Germany)
1.3 reagents and pharmaceutical products
Sodium arsenite (lot number SLCB4632, 100g, purity > 90%) is purchased from America Sigma company alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) assay kits, lot numbers (20200124, 20201027) are respectively purchased from Lei Du life sciences Co., ltd; total Bilirubin (TBIL) assay kit lot number (20200001) was purchased from Changchun Hui Biotechnology Co., ltd; the Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH) detection kit with batch numbers (20200729, 20200627 and 20200823) are purchased from Nanjing to build bioengineering institute; hematoxylin-eosin (HE) dye liquor lot numbers (JX 200301, CR 2011065) were purchased from the wuhanseville biotechnology company, inc; 4% paraformaldehyde (batch No. 0830A 21) Beijing Lei Gen Biotechnology Co., ltd.
1.4 laboratory animals
The experimental animals are SPF-grade male Kunming mice, 140 animals are 8-10 weeks old, and have a weight of 25-30 g, and are provided by Liaoning province's experimental animal resource center (agency is Chongqing Tengxin Bel experimental animal sales Co., ltd.), and animal license number (qualification number: SCXK 2020-0001). The temperature of the raising environment is (22+/-2) DEG C, the humidity is (50+/-10)%, the normal light and dark circulation is maintained, and food and water are freely taken.
2 Experimental methods
2.1 grouping, modeling and administration treatments of mice
The male Kunming mice of SPF grade were randomly aliquoted into two large groups, a prophylaxis experimental group and a treatment experimental group, after 1 week of adaptive feeding prior to the formal experiment, and the specific grouping and the gastric lavage modes are shown in Table 1 and Table 2. Wherein the model group is administered with reference to the 5mg/kg dose; the positive control group was administered with reference to the pharmacological test methodology at dosages of 11.375mg/kg of bicyclol and 182mg/kg of glutathione, respectively[22]The study selects the two clinical liver protection medicines to evaluate the low, medium and high dosages of the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester so as to compare the curative effects; referring to the results of the study of Wei Huailing et al, low, medium and high doses of SGP-25 were set at doses of 25, 50 and 100mg/kg, respectively, with the preventive group drugs being in intragastric NaAsO2Administered for the first 30 min. After the last administration, all mice are fasted, not forbidden for 8 hours, the weights of the mice are weighed and recorded, an eyeball method is taken to collect blood samples of the mice, the mice are kept stand for half an hour at room temperature, and the supernatant is collected by centrifugation at 3000r/min for 15min and frozen in a refrigerator at-80 ℃ for subsequent experiments. After blood collection, mice were sacrificed by cervical dislocation, whole livers were removed, quickly rinsed with pre-chilled Phosphate Buffered Saline (PBS), blotted dry on filter paper, and the liver weight was weighed. Part of liver tissue is fixed in 4% paraformaldehyde solution for preservation for pathological examination; the rest liver tissue is rapidly placed in liquid nitrogen and then frozen in a refrigerator at-80 ℃ for subsequent experiments.
Table 1 preventive experimental group and gastric lavage mode thereof
Table 2 treatment experiment group and its lavage mode
3 experimental results:
the experimental results are shown in tables 3,4, 5, 6, 7, 8.
TABLE 3 prevention of the changes in the body weight, liver weight and liver coefficients of the mice of the experimental groupn＝10)
Note [ ]. In comparison with the blank set of the cells,**P <0.01; in comparison with the set of models,##P<0.01
TABLE 4 variation of liver weight and liver coefficient in mice of treatment groupn＝10)
Note [ ]. In comparison with the blank set of the cells,**P <0.01; in comparison with the set of models,##P<0.01
Liver weight, significant increase in liver coefficient (P < 0.01), no significant difference between positive control group and SGP-25 dose group (P > 0.05); compared with the model group, the body weight of the mice in the positive control group and the SGP-25 dosing group is obviously increased (P < 0.01), and the liver coefficient is obviously reduced (P < 0.01); there was no significant difference (P > 0.05) between each dose group of SGP-25 compared to the above index for the positive control group. In the treatment group (see Table 4), the trend of the change of the body weight, liver weight and liver coefficient of the mice was consistent with that of the prophylaxis group, and all showed dose dependency, i.e. as the SGP-25 dose was increased, the body weight of the mice was increased, and the liver weight and liver coefficient were decreased.
TABLE 5 prevention of ALT, AST, TBIL Activity changes in mice serum from experimental groupsn＝10)
The notes are compared with the normal group,**P is less than 0.01; in comparison with the set of models,##P＜0.01
TABLE 6 variation of ALT, AST, TBIL Activity in mice serum of treatment groupn＝10)
The notes are compared with the normal group,**P is less than 0.01; in comparison with the set of models,##P＜0.01
In the prophylaxis group (see Table 5), the activity of mice ALT, AST, TBIL in the model group was significantly increased (P < 0.01) compared to the blank group, and there was no significant difference (P > 0.05) between the positive control group and each of the SGP-25 dose groups, whereas the activity of mice ALT, AST, TBIL in the positive control group and each of the SGP-25 dose groups was decreased (P < 0.01) compared to the model group, and there was no significant difference (P > 0.05) between each of the SGP-25 dose groups and the positive control group compared to the above index. In the treated group (see Table 6), the trend of change in the activity of mouse serum ALT, AST, TBIL was consistent with that of the prophylactic group and was dose dependent, i.e., the activity decreased with increasing SGP-25 dose.
TABLE 7 prevention of MDA content, GSH content and SOD Activity changes in liver tissue of mice of experimental groupn＝10)
The notes are compared with the normal group,**P is less than 0.01; in comparison with the set of models,##P＜0.01
TABLE 8 variation of MDA content, GSH content and SOD Activity in liver tissue of mice of treatment groupn＝10)
The notes are compared with the normal group,**P is less than 0.01; in comparison with the set of models,##P＜0.01
In the preventive group (see Table 7), the MDA content of each dose group of SGP-25 and the positive control group is remarkably reduced (P < 0.01), and GSH content and SOD activity are remarkably increased (P < 0.01) compared with the model group; compared with a blank group, the MDA content of a model group mouse is obviously increased (P < 0.01), the GSH content and SOD activity are obviously reduced (P < 0.01), and the dose groups of SGP-25 and a positive control group have no obvious difference (P > 0.05); the comparison of the above indexes is carried out between each dosage group of SGP-25 and the positive control group, and no obvious difference exists (P is more than 0.05). In the treatment group (table 8), the positive control group showed significantly decreased MDA content (P < 0.01) and significantly increased GSH content and SOD activity (P < 0.01) compared to the model group; SGP-25 dosed mice showed a significant decrease in MDA content (P < 0.01) and a significant increase in GSH content and SOD activity (P < 0.01); compared with a blank group, the MDA content of a model group mouse is obviously increased (P < 0.01), the SOD activity and GSH content are obviously reduced (P < 0.01), and the positive control group and the SC dose group have no obvious difference (P > 0.05); the comparison of the above indexes is carried out between each dose group of SGP-25 and the positive control group, and the difference is obvious (P > 0.05).
Through observation under a HE (human embryonic stem) staining microscope of liver tissues of mice, in a prevention group, model groups have hepatomegaly, loose cell structures, glass-like degeneration is visible, liver lobule structures are unclear, a large number of inflammatory cells infiltrate into a cell interstitium, liver blood sinuses expand, a large number of erythrocytes and partial circular vacuoles are visible, and the model groups are suspected to be fat-variable. The liver cells of the normal group are orderly arranged, the structure is full, inflammatory cell exudation does not exist, the liver lobular structure is clear, the chromosome is rich, the central vein outline of liver tissue is clear, and the hepatic chordae are radially arranged along the central vein. The hepatic cells of the bicyclo-ethanol group have loose structure, inflammatory cell infiltration is visible in the interstitial space, and a small amount of congestion exists in the hepatic sinus. The glutathione-group liver cells can be seen as glass-like degeneration, and the tissues can be seen as small inflammatory cell infiltration. The SGP-25 low dose group liver cells can see glass-like degeneration, liver sinuses can see little congestion, and obvious inflammatory cell infiltration is not seen. The hepatic sinus gap was significantly increased in the SGP-25 dose group. The liver tissue of the SGP-25 high-dose group has normal integral structure and no obvious pathological change. In conclusion, the SGP-25 high-dose liver tissue structure has lighter damage, clearer liver lobule structure, tidy liver cable arrangement, slightly expanded liver blood sinus, less inflammatory cell infiltration and improvement of NaAsO2Resulting in pathological damage to the liver (see figures 1, 2).
Conclusion of the experiment
the animal in vivo experiment results prove that the extract has prevention and treatment effects on liver injury caused by sodium arsenite, and the prevention effect is superior to the treatment effect.
Example 2
Taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 1/10 of medicinal dextrin or starch, and granulating to obtain granules.
Example 3
Taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 1/13 of medicinal dextrin or starch, uniformly mixing, and filling into capsules to obtain capsules.
Example 4
Taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 1/12 of medicinal dextrin or starch, uniformly mixing, drying, and preparing into pills.
Example 5
Taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 1/10 of medicinal starch, granulating, tabletting and preparing into tablets.
Example 6
taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 10 times of water for injection, soaking for 1 hour, filtering, and sterilizing to obtain the injection.
Example 7
taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 10 times of water for injection, soaking for 1 hour, filtering, and freeze-drying to obtain freeze-dried powder.
Example 8
Taking bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester as a raw material medicine, adding 5 times of purified water, uniformly mixing, soaking for 2 hours, filtering, and sterilizing to obtain the oral liquid.
While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (5)
1. The application of bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester in preparing medicaments for preventing and treating liver injury caused by sodium arsenite.
2. The use according to claim 1, wherein the bis (2-ethylhexyl) benzene-1, 2-dicarboxylic acid ester is formulated into a pharmaceutically acceptable formulation by adding pharmaceutically acceptable excipients.
3. The use according to claim 2, wherein the pharmaceutically acceptable formulation is a solid formulation or a liquid formulation.
4. The use according to claim 3, wherein the solid preparation is a tablet, granule, capsule, pill, powder injection.
5. The use according to claim 3, wherein the liquid preparation is an injection preparation or an oral liquid.
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| Impact of the Di(2-Ethylhexyl) Phthalate Administration on Trace Element and Mineral Levels in Relation of Kidney and Liver Damage in Rats;Duygu Aydemir等;《Biological Trace Element Reaearch》;第186卷;第474-488页 * |
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