CN114073691A - Medicine for treating gouty nephropathy - Google Patents
Medicine for treating gouty nephropathy Download PDFInfo
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- CN114073691A CN114073691A CN202010813710.1A CN202010813710A CN114073691A CN 114073691 A CN114073691 A CN 114073691A CN 202010813710 A CN202010813710 A CN 202010813710A CN 114073691 A CN114073691 A CN 114073691A
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- Prior art keywords
- levocarnitine
- injection
- pharmaceutically acceptable
- uric acid
- derivative
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- 206010046337 Urate nephropathy Diseases 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title description 8
- 229960001518 levocarnitine Drugs 0.000 claims abstract description 34
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims abstract description 32
- -1 acetyl levocarnitine Chemical compound 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000007924 injection Substances 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims description 14
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
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- 238000011200 topical administration Methods 0.000 claims 1
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- 125000002252 acyl group Chemical group 0.000 description 3
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- 206010058892 Carnitine deficiency Diseases 0.000 description 2
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 2
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- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 1
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- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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- 210000001635 urinary tract Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an application of levocarnitine or a derivative thereof in preparing a medicament for treating gouty nephropathy, wherein the levocarnitine derivative is selected from acetyl levocarnitine, propionyl levocarnitine and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts of levocarnitine, and the medicament is administered in an oral administration form, an injection administration form or a local administration form.
Description
Technical Field
The invention relates to the field of medicine application, in particular to application of levocarnitine and derivatives thereof in preparation of medicines for treating gouty nephropathy.
Background
The gouty nephropathy is characterized in that the urate concentration in blood is increased to reach a supersaturated state, and urate crystals are deposited on the kidney to cause pathological changes. Gout kidneys are characterized histologically by urate crystals in the medulla or papilla of the kidney, with round cells and giant cell responses around them. Patients with gout have higher renal manifestations of gout as described above at autopsy, and are often accompanied by acute and chronic interstitial inflammatory changes, fibrosis, tubular atrophy, glomerulosclerosis, and renal arteriosclerotic events.
In recent years, the incidence of gout is increased by increasing the intake of protein and purine-rich food in the diet of people in China. Gout is often seen in obese, carnivorous and alcoholics, men are obviously higher than women, the average age of attack is 45 years, and gout and nephropathy are more than 10 years old after gout. The gout patients who are seen for a long time in clinic have kidney damage of about 1/3, so the patients to be treated, especially the patients with a long course of disease, need to have consciousness for preventing gout and kidney damage, combine syndrome differentiation and disease differentiation, strengthen the treatment of gout attack interval and chronic period, reduce the blood uric acid level, alkalize urine to reduce the uric acid level, reduce the recurrence of gout and prevent gout and kidney damage.
The treatment of the simple typical uric acid renal disease patients mainly comprises low-purine diet, much drinking water, urine quantity keeping, urine alkalization and application of drugs for inhibiting uric acid generation and promoting uric acid excretion; for example, patients with kidney or ureteral calculus or kidney water accumulation should be treated by surgical operation. Gouty nephropathy progresses to chronic renal insufficiency patients, treated with uremia, and dialyzed (including hemodialysis and peritoneal dialysis) as necessary. Nephropathy can be reduced or stopped, for example, by early diagnosis and appropriate treatment (control of hyperuricemia and protection of kidney function).
The existing uric acid-reducing drugs such as allopurinol have side effects of bone marrow suppression, liver and kidney damage, skin toxicity and the like, and benzbromarone can cause urate crystals to deposit in a urinary tract to cause renal colic and renal function damage; both surgical treatment and renal dialysis are traumatic treatments. Therefore, there is a need to find a drug which can effectively treat hyperuricemia, reduce the damage of hyperuricemia to kidney tissues and has low toxic and side effects.
The levocarnitine and the derivative thereof have wide application range, are mainly clinically used for carnitine deficiency caused by long-term hemodialysis, and also have application in the aspects of ischemic cardiomyopathy and oligospermia. The applicant previously disclosed the use of levocarnitine or a derivative thereof in the preparation of a medicament for the treatment of hyperuricemia, a disease related to hyperuricemia, said hyperuricemia being primary or secondary hyperuricemia, and a disease related to hyperuricemia being gout (publication No. CN 101278928A).
Disclosure of Invention
The invention utilizes the new pharmacological action of the levocarnitine and the derivative thereof, adds new medicinal application, and is used for preventing and assisting in treating the gouty nephropathy. Overcomes the defects of the existing uric acid reducing medicines, reduces the blood uric acid and protects the kidney tissue at the same time, and achieves the effects of preventing and treating the gouty nephropathy.
The levocarnitine derivative is selected from acetyl levocarnitine, propionyl levocarnitine, pharmaceutically acceptable salts thereof and pharmaceutically acceptable salts of levocarnitine. Preference is given to levocarnitine, acetyl levocarnitine and their pharmaceutically acceptable salts. Particularly preferred are levocarnitine and pharmaceutically acceptable salts thereof.
The pharmaceutically acceptable salts described in the present invention include: hydrochloride, hydrobromide, iodohydrite, sulphate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulphonate, p-toluenesulphonate.
The main content of the invention is to utilize the action mechanisms of levocarnitine and derivatives thereof for regulating and controlling glycolipid metabolism, reducing oxygen free radicals and stabilizing cell membranes, and the invention is applied to gouty nephropathy and can improve, alleviate or delay nephropathy.
Levocarnitine and derivatives thereof are known compounds and have been clinically applied to the treatment of carnitine deficiency caused by various reasons. Is a generally accepted safe substance by the FDA in the United states, and the levocarnitine is also listed as food and medicine in the national standard in China. The oral dosage is 1-3 g/day; the injection dosage is 50-300mg/kg, and the safety is better.
The researchers of the present invention unexpectedly found through animal experiments that: the levocarnitine and the derivative thereof have good curative effect on treating the gouty nephropathy. And the compounds are recognized safe substances, have the characteristics of safety and effectiveness in clinical application, and open up new medicinal application of the compounds.
We fed yeast feed and added potassium oxonate, a uricase inhibitor, and then induced the formation of a model of gouty nephropathy in rats by intragastric administration for 60 days, and then administered levocarnitine to observe the new pharmacological effect of the levocarnitine (see example 1 for details).
The test result shows that: the levocarnitine can reduce the levels of uric acid, creatinine and urea nitrogen of a rat with gouty nephropathy, reduce the content of urine protein for 24 hours, reduce urinary crystallization of kidney tissues and protect the kidney function. The kidney pathological examination result also shows that the kidney tissue inflammatory reaction of the model control group is heavier, a large amount of uric acid crystals exist in the renal tubular cavities, compared with the model control group, the kidney tissue pathological change of the treatment group is obviously reduced, the uric acid crystals are reduced, and particularly, the lesion degree is correspondingly reduced along with the increase of the medicament dose of the levocarnitine treatment group.
Gouty nephropathy is caused by elevated blood uric acid due to decreased uric acid excretion caused by purine metabolic disorders and/or impaired renal function. The kidney is known as the main organ for uric acid excretion, and studies prove that the rise of blood uric acid is an independent risk factor for the occurrence and the progression of renal diseases. From the mechanism of action of uric acid, uric acid in normal level in human body can remove about 2/3 free radicals in blood plasma, and has antioxidant effect. However, when the concentration of uric acid is too high, uric acid is switched from oxidation resistance to oxidation promotion, and the over-high uric acid can aggravate the oxidative stress reaction of the organism, promote the inflammatory reaction and destroy the stability of cell membranes, thereby causing damage to organs and tissues of the organism.
The invention (see example 1) finds that the levocarnitine and the derivative thereof can improve the capability of tissues for clearing oxygen free radicals, reduce the generation of the oxygen free radicals and reduce the structural and functional abnormality of kidney cells caused by lipid peroxidation, thereby increasing the excretion of uric acid. Meanwhile, levocarnitine probably reduces blood uric acid by correcting metabolic disorder, and is consistent with the disclosure of CN 101278928A.
In fact, with the pharmacological and biochemical knowledge we have already known, hyperuricemia is secondary to metabolic disorders of the body and is a risk factor for causing damage to important organs of the body. The heart muscle and kidney are mainly supplied with energy by oxidation of fatty acid. When the metabolism is disturbed, the level of circulating fatty acid of the organism is increased, the glucose transporters are reduced, the insulin receptors are down-regulated, the energy metabolism of important organs such as cardiac muscle, kidney and the like is disturbed, and a large amount of endogenous carnitine is consumed by the organism for regulating balance. Supplementing exogenous L-carnitine, promoting fatty acid oxidation, regulating the ratio of acyl in mitochondria, discharging excessive or irrational acyl groups in vivo, and eliminating metabolic toxicity of organism caused by acyl accumulation; promote the oxidation of the acetoacetic acid, play a role in the elimination and utilization of ketone bodies; preventing toxicity caused by excessive ammonia in the animal body; scavenging free radicals, maintaining stability of membrane, improving animal immunity and disease and stress resistance, and preventing and treating gouty nephropathy.
The levocarnitine or the derivative thereof provided by the invention comprises granules, tablets, capsules, solutions, injections and other pharmaceutically acceptable forms.
Detailed Description
Example 1:
after the rats are fed with yeast feed and are subjected to a 60-day molding period by adding uricase inhibitor potassium oxonate, the rats with serum uric acid stabilized above 300umol/L are checked to be qualified animals of the model, unqualified animals are eliminated, the rats with uric acid level meeting the requirement are randomly grouped into 6 groups, the 6 groups are respectively a solvent control group (normal saline 2ml/kg), a model control group (potassium oxonate 1.5g/kg), a positive control group (allopurinol 40 mg/kg), a levocarnitine low dose group (150 mg/kg), a levocarnitine medium dose group (300 mg/kg) and a levocarnitine high dose group (600 mg/kg), and the number of animals in each group is 12. The administration was continued for 4 weeks. Urine was collected in a metabolic cage for 24 hours the last day and urine protein content was measured. Detecting serum uric acid UA, creatinine, urea nitrogen BUN, reactive oxygen species ROS and malondialdehyde MDA of the rat after the last administration. The kidney was taken and HE stained to observe the pathological changes of the nephron, and special staining was used to show the uric acid crystal in the nephron, and the changes of the uric acid amount in the glomerulus and the renal tubule of each group tested were known.
As a result: the rat blood uric acid, creatinine, urea nitrogen and 24h urine protein of the model control group are quantified, the active oxygen ROS and malondialdehyde MDA are obviously higher than those of the normal control group, and the kidney pathological examination also proves that the inflammatory reaction of kidney tissues is heavier, a large amount of uric acid crystals exist in glomerulus and renal tubules, and the pathological characteristics of the gouty nephropathy are met.
After 28 days of treatment, the levels of uric acid, creatinine, urea nitrogen and 24-hour urinary protein in the treatment group are obviously reduced, and the contents of ROS and MDA are also obviously reduced. The kidney pathological examination result also shows that compared with the model control group, the pathological change of the kidney tissue of the treatment group is obviously reduced, the crystallization of uric acid is reduced, and particularly, the pathological change degree of the levocarnitine treatment group is correspondingly reduced along with the increase of the medicament dosage.
TABLE 1 Effect of Levocarnitine on uric acid and renal function in gouty nephropathy rats( n=10；x±s )
Pathological results of the kidney of the gouty nephropathy rat show that:
model group: the glomerulus is heavily congested, has obvious leaf division and is infiltrated by a large amount of lymphocytes. Severe congestion of renal interstitium, infiltration of a large number of inflammatory cells. Necrosis of tubular foci, nephric tubular epithelial cell swelling, and vacuolar degeneration. A large number of needle-like urate crystals are visible in the lumen of the renal tubule.
Allopurinol group: the glomeruli were moderately congested, with obvious lobular division and mild atrophy of the glomeruli. The renal interstitium is slightly congested, and a small amount of inflammatory cells infiltrate. Partial nephric tubular epithelial cell nephelosis and degeneration necrosis. A small amount of needle-like urate crystals are visible in the lumen of the renal tubule.
Low dose group: the glomerulus is slightly congested, the lobe is obvious, and the glomerulus is slightly atrophied. The renal interstitium is slightly congested and a large amount of inflammatory cells infiltrate. Necrosis is localized in the tubular foci, and a part of the tubular epithelial cells are vacuolized and denatured. The renal tubules are slightly dilated, and a large number of acicular urate crystals are visible in the lumen.
The medium dose group: the glomeruli were slightly congested with visible lobular branches. The renal interstitium is slightly congested and a large amount of inflammatory cells infiltrate. Small renal tubular epithelial cell turbidimetry and necrosis. A small amount of needle-like urate crystals are visible in the lumen of the renal tubule.
High dose group: the glomeruli were slightly congested with visible lobular branches. The renal interstitium is slightly congested, and a small amount of inflammatory cells infiltrate. Partial nephric tubular epithelial cell nephelosis and degeneration necrosis. A small amount of needle-like urate crystals are visible in the lumen of the renal tubule.
The results reported above clearly demonstrate the unexpected therapeutic effect of the drug of the invention in the treatment of gouty nephropathy.
Claims (5)
1. Use of levocarnitine or a derivative thereof in the preparation of a medicament for the treatment of gouty nephropathy.
2. The use of claim 1 wherein the levocarnitine derivative is selected from the group consisting of acetyl levocarnitine, propionyl levocarnitine, and their pharmaceutically acceptable salts and pharmaceutically acceptable salts of levocarnitine.
3. The use of claim 2, wherein the pharmaceutically acceptable salt comprises hydrochloride, hydrobromide, iodohydrite, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, pantothenate, methanesulfonate, p-toluenesulfonate.
4. Use according to claim 1, wherein the pharmaceutical composition is administered orally, by injection or topically.
5. Use according to claim 4, characterized in that the oral administration forms comprise tablets, granules, capsules, oral solutions, syrups, inhalants, sprays; the injection administration forms comprise freeze-dried powder injection, suspension for injection, emulsion for injection and solution injection; the topical administration forms comprise aerosol, ointment, lotion, suppository, patch, liniment, eye drop, and vaginal effervescent tablet.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101278928A (en) * | 2007-04-06 | 2008-10-08 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Medicament composition containing levocarnitine or its derivatives and use thereof |
| US20130172414A1 (en) * | 2010-06-29 | 2013-07-04 | Tianjin Nankai Share Pharmaceutical Science & Technology Co., Ltd. | Pharmaceutical composition comprising levocarnitine and dobesilate |
| CN111281865A (en) * | 2018-12-06 | 2020-06-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Application of levocarnitine and derivative thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101278928A (en) * | 2007-04-06 | 2008-10-08 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Medicament composition containing levocarnitine or its derivatives and use thereof |
| US20130172414A1 (en) * | 2010-06-29 | 2013-07-04 | Tianjin Nankai Share Pharmaceutical Science & Technology Co., Ltd. | Pharmaceutical composition comprising levocarnitine and dobesilate |
| CN111281865A (en) * | 2018-12-06 | 2020-06-16 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Application of levocarnitine and derivative thereof |
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| Title |
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| 刘德培总主编: "《中华医学百科全书 中医药学 中医内科学》", 31 July 2019, 中国协和医科大学出版社, pages: 464 * |
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