CN110772516A - Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy - Google Patents
Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy Download PDFInfo
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- CN110772516A CN110772516A CN201911213972.8A CN201911213972A CN110772516A CN 110772516 A CN110772516 A CN 110772516A CN 201911213972 A CN201911213972 A CN 201911213972A CN 110772516 A CN110772516 A CN 110772516A
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- uric acid
- isocorydine
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- QELDJEKNFOQJOY-ZDUSSCGKSA-N Isocorydine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=CC=C(OC)C(O)=C13 QELDJEKNFOQJOY-ZDUSSCGKSA-N 0.000 title claims abstract description 32
- DRVVGOFZCWCCSA-UHFFFAOYSA-N isocorydine Natural products COc1cc2CCN(C)C3Cc4cccc(C)c4c(c1O)c23 DRVVGOFZCWCCSA-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 29
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims abstract description 22
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229940116269 uric acid Drugs 0.000 title claims abstract description 21
- 210000004369 blood Anatomy 0.000 title claims abstract description 16
- 239000008280 blood Substances 0.000 title claims abstract description 16
- 150000003839 salts Chemical class 0.000 title claims abstract description 16
- 206010046337 Urate nephropathy Diseases 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 230000017074 necrotic cell death Effects 0.000 claims abstract description 8
- 201000002793 renal fibrosis Diseases 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 16
- 229940109239 creatinine Drugs 0.000 claims description 8
- 210000004969 inflammatory cell Anatomy 0.000 claims description 4
- 230000010339 dilation Effects 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 201000001431 Hyperuricemia Diseases 0.000 abstract description 18
- 208000017169 kidney disease Diseases 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 7
- 241001465754 Metazoa Species 0.000 abstract description 6
- 241000699670 Mus sp. Species 0.000 abstract description 5
- 239000002585 base Substances 0.000 abstract description 3
- 239000002547 new drug Substances 0.000 abstract description 3
- 210000005239 tubule Anatomy 0.000 abstract description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 238000010186 staining Methods 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 7
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 5
- 229960003459 allopurinol Drugs 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000005084 renal tissue Anatomy 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 208000006750 hematuria Diseases 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- IAPCTXZQXAVYNG-UHFFFAOYSA-M Potassium 2,6-dihydroxytriazinecarboxylate Chemical compound [K+].[O-]C(=O)C1=NC(=O)NC(=O)N1 IAPCTXZQXAVYNG-UHFFFAOYSA-M 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229950000193 oteracil Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Images
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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
- A61K31/395—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
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- 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
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to application of isocorydine or salts thereof in preparing medicines for reducing the level of uric acid and preventing and treating uric acid nephropathy, belonging to the field of medicines. In one aspect, the invention provides the use of isocorydine base or a salt thereof in the preparation of a medicament or health care product for reducing the level of uric acid in blood. In another aspect, the invention also provides the use of isocorydine alkali or salt thereof in the preparation of a medicament for preventing and/or treating uric acid nephropathy. Animal experiments prove that the isocorydine can greatly reduce the blood uric acid level and improve the degree of dilatation, necrosis and renal fibrosis of the renal tubules of the mice with the hyperuricemia. The application of the invention can provide a new drug selection for clinical treatment of hyperuricemia and hyperuricemia nephropathy caused by the hyperuricemia.
Description
Technical Field
The invention relates to application of isocorydine or salts thereof in preparing medicines for reducing the level of uric acid and preventing and treating uric acid nephropathy, belonging to the field of medicines.
Background
Hyperuricemia refers to non-daily measurement of fasting serum uric acid levels of greater than or equal to 416 μmol/L (7mg/dl) in men and equal to 357 μmol/L (6mg/dl) in women under normal purine diet. In recent years, numerous studies at home and abroad prove that hyperuricemia is closely related to the occurrence and development of gout, cardiovascular diseases, metabolic syndrome, hypertension and kidney diseases. Hyperuricemia is a significant cause of increased prevalence of Chronic Kidney Disease (CKD) and is an independent risk factor for CKD progression. Studies have shown that lowering the level of uric acid in the blood can delay the progression of renal disease. Treating hyperuricemia, preventing and correcting hyperuricemia, lowering blood uric acid level and preventing urate from depositing in kidney.
Isocorydine base, (+) -isocorynolene, CAS number 475-67-2, having the formula shown below:
isocorydine is an antispasmodic analgesic approved by the State administration of drug administration, and has antimalarial, vasodilating and antiarrhythmic effects. However, reports on the effects of reducing uric acid and preventing and treating uric acid nephropathy of isocorydine are not found at present.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention aims to provide the application of isocorydine alkali or salt thereof in preparing medicines or health care products for reducing the level of hematuria acid. Another object of the present invention is to provide the use of isocorydine base or a salt thereof for the preparation of a medicament for the prevention and/or treatment of uric acid nephropathy.
The invention provides application of isocorydine or salt thereof in preparing a medicine or health-care product for reducing the level of hematuria acid.
The invention provides application of isocorydine or salt thereof in preparing a medicine for preventing and/or treating uric acid nephropathy.
Further, the pharmaceutical product reduces blood creatinine levels.
Further, the drug lowers blood uric acid levels.
Further, the drug lowers the urinary protein creatinine ratio.
Further, the drug improves tubular dilation and/or necrosis.
Further, the medicament reduces the number of renal inflammatory cells.
Further, the medicine improves renal fibrosis.
Furthermore, the medicine or health care product is a preparation prepared by taking isocorydine or salt thereof as an active ingredient and adding acceptable auxiliary materials or auxiliary ingredients.
Further, the preparation is an oral preparation or an injection preparation.
The invention provides application of isocorydine or salt thereof in preparing a medicine for reducing the level of uric acid and preventing and treating uric acid nephropathy. Animal experiments prove that the isocorydine can greatly reduce the blood uric acid level and improve the degree of dilatation, necrosis and renal fibrosis of the renal tubules of the mice with the hyperuricemia. The application of the invention can provide a new drug selection for clinical treatment of hyperuricemia and hyperuricemia nephropathy caused by the hyperuricemia.
The invention provides application of isocorydine or salt thereof in preparing a medicine for reducing the level of uric acid and preventing and treating uric acid nephropathy. Animal experiments prove that the isocorydine can greatly reduce the blood uric acid level and improve the degree of dilatation, necrosis and renal fibrosis of the renal tubules of the mice with the hyperuricemia. The application of the invention can provide a new drug selection for clinical treatment of hyperuricemia and hyperuricemia nephropathy caused by the hyperuricemia.
Drawings
FIG. 1 is a graph showing the results of measurement of the blood uric acid level of a mouse in example 1;
FIG. 2 is a graph showing the results of measurement of the serum creatinine level of the mouse in example 1;
FIG. 3 is a graph showing the results of measurement of the ratio of mouse urine protein to creatinine in example 1;
FIG. 4 is a PAS staining pattern of mouse kidney tissue in example 1;
FIG. 5 is a graph of MASSON staining of mouse kidney in example 1.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1 animal experiments with isocorydine to lower serum uric acid levels and prevent uric acid nephropathy
Experimental animals: SPF grade male C57BL/6J mice. The standard experiment daily ration is raised in a constant temperature environment for at least 1 week before the experiment, and drinking water is not limited.
Animal grouping: mice were divided into 5 groups of 60: 12 normal control groups, 12 hyperuricemic nephropathy model groups, 12 isocorydine low dose treatment groups (100mg/kg/d), 12 isocorydine high dose treatment groups (200mg/kg/d), and 12 positive control allopurinol (5 mg/kg/d).
The molding method comprises the following steps: mixing adenine of 100mg/kg and oteracil potassium of 1500mg/kg according to the mass of the mouse body, preparing suspension with the final concentration of 80g/L by using distilled water, performing intragastric administration on the model group in the morning and evening every day, and continuously performing for 3 weeks to establish a hyperuricemia renal injury animal model. The normal control group animals were gavaged with distilled water twice a day in the morning and at night at equal doses. Mice were sacrificed 3 weeks later, abdominal aorta was bled and kidney tissue was retained.
The experimental method comprises the following steps: the treatment group of isocorydine and allopurinol is administered by an oral administration mode on the 1 st day after the model building and continuously for 21 days; after the model is assembled, normal saline with the same dosage is fed at the same time; the blank control group was fed with the same dose of physiological saline at the same time.
Centrifuging the blood sample of the mouse at the room temperature of 3000r/min for 15min, and then taking serum to measure biochemical indexes; centrifuging the mouse urine specimen at room temperature of 800g/min for 10min, and taking the upper layer urine to determine biochemical indexes. The experimental results are shown in FIGS. 1 to 3. PAS staining was performed on mouse kidney tissue, and the kidney structure was observed, and the experimental results are shown in FIG. 4. The kidney fibrosis was observed by MASSON staining and the results are shown in fig. 5.
As can be seen from FIG. 1, isocorydine can greatly reduce the blood uric acid level, and the effect achieved by the high-dose treatment group is better than that achieved by the first-line clinical uric acid reducing allopurinol (P <0.05, # # P <0.01, and # # P <0.001, compared with the model group).
As can be seen from FIG. 2, isocorydine reduced serum creatinine levels with superior efficacy over allopurinol and excellent renal function protection (# P <0.001, and # P <0.0001 compared to model group).
As can be seen from FIG. 3, isocorydine reduced the urinary creatinine ratio, had an effect superior to that of allopurinol, and had the effect of improving renal function (in comparison with the model group, # P <0.05, # P <0.001, # and # P < 0.0001).
As can be seen from fig. 4, PAS staining pictures of the kidney of the normal control group had intact kidney structure. Significant tubular degeneration, necrosis, tubular atrophy, and inflammatory cell infiltration were seen on day 21 in the hyperuricemic renal disease model group. After 21 days of treatment with high doses of isocorydine, the composition can significantly improve tubular dilation and necrosis and reduce the invasion of inflammatory cells of the kidney.
As can be seen in fig. 5, the images of MASSON staining of the normal control group kidneys had intact renal structures. Obvious renal tubular degeneration, necrosis, tubular atrophy and fibrosis can be seen on the 21 st day in the hyperuricemic kidney disease model group; MASSON staining was evident in blue areas (blue areas indicate the extent of fibrotic lesions). After 21 days of treatment with high doses of isocorydine, the blue areas of MASSON staining were significantly less than in the hyperuricemic renal disease model group, indicating that it ameliorates hyperuricemic renal fibrosis.
Claims (10)
1. Use of isocorydine or its salt in preparing medicine or health product for reducing blood uric acid level.
2. Use of isocorydine or its salt in the preparation of a medicament for the prevention and/or treatment of uric acid nephropathy.
3. Use according to claim 2, characterized in that: the drug reduces blood creatinine levels.
4. Use according to claim 2, characterized in that: the medicine reduces the blood uric acid level.
5. Use according to claim 2, characterized in that: the medicine reduces the urinary protein creatinine ratio.
6. Use according to claim 2, characterized in that: the medicament improves tubular dilation and/or necrosis.
7. Use according to claim 2, characterized in that: the medicament reduces the number of renal inflammatory cells.
8. Use according to claim 2, characterized in that: the medicine can improve renal fibrosis.
9. Use according to any one of claims 1 to 8, characterized in that: the medicine or health care product is a preparation prepared by taking isocorydine alkali or salt thereof as an active ingredient and adding acceptable auxiliary materials or auxiliary ingredients.
10. Use according to claim 9, characterized in that: the preparation is an oral preparation or an injection preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911213972.8A CN110772516B (en) | 2019-12-02 | 2019-12-02 | Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911213972.8A CN110772516B (en) | 2019-12-02 | 2019-12-02 | Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy |
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| CN110772516A true CN110772516A (en) | 2020-02-11 |
| CN110772516B CN110772516B (en) | 2022-10-04 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113040093A (en) * | 2021-03-11 | 2021-06-29 | 四川大学华西医院 | Application of oteracil potassium and adenine in inducing rat hyperuricemia renal injury model |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113040093A (en) * | 2021-03-11 | 2021-06-29 | 四川大学华西医院 | Application of oteracil potassium and adenine in inducing rat hyperuricemia renal injury model |
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