CN109223781B - Medicine for treating kidney injury caused by lithium salt and application thereof - Google Patents
Medicine for treating kidney injury caused by lithium salt and application thereof Download PDFInfo
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- CN109223781B CN109223781B CN201811142569.6A CN201811142569A CN109223781B CN 109223781 B CN109223781 B CN 109223781B CN 201811142569 A CN201811142569 A CN 201811142569A CN 109223781 B CN109223781 B CN 109223781B
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- tabersonine
- lithium salt
- acetylcysteine
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- injury caused
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- 229910003002 lithium salt Inorganic materials 0.000 title claims abstract description 32
- 159000000002 lithium salts Chemical class 0.000 title claims abstract description 32
- 206010061481 Renal injury Diseases 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 208000037806 kidney injury Diseases 0.000 title claims abstract description 19
- 229940079593 drug Drugs 0.000 title abstract description 10
- FNGGIPWAZSFKCN-ACRUOGEOSA-N tabersonine Chemical compound N1C2=CC=CC=C2[C@]2([C@H]34)C1=C(C(=O)OC)C[C@]3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-ACRUOGEOSA-N 0.000 claims abstract description 47
- JSLDLCGKZDUQSH-RTBUJCADSA-N 19-epivindolinine Natural products O=C(OC)[C@H]1[C@@]23[C@H](C)[C@]4([C@@H]5N(CC=C4)CC[C@]25c2c(N3)cccc2)C1 JSLDLCGKZDUQSH-RTBUJCADSA-N 0.000 claims abstract description 45
- KILNDJCLJBOWAN-UHFFFAOYSA-N Tabersonine Natural products CCC12CC(=C3N(C)c4cc(OC)ccc4C35CCN(CC=C1)C25)C(=O)OC KILNDJCLJBOWAN-UHFFFAOYSA-N 0.000 claims abstract description 45
- FNGGIPWAZSFKCN-UHFFFAOYSA-N xi-tabersonine Natural products N1C2=CC=CC=C2C2(C34)C1=C(C(=O)OC)CC3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-UHFFFAOYSA-N 0.000 claims abstract description 45
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical group CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 41
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 35
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 abstract description 15
- 229920002472 Starch Polymers 0.000 abstract description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 abstract description 15
- 239000008108 microcrystalline cellulose Substances 0.000 abstract description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 abstract description 15
- 235000019698 starch Nutrition 0.000 abstract description 15
- 239000008107 starch Substances 0.000 abstract description 15
- 239000011734 sodium Substances 0.000 abstract description 14
- 229910052708 sodium Inorganic materials 0.000 abstract description 14
- 229940083542 sodium Drugs 0.000 abstract description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 abstract description 13
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 abstract description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 abstract description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 abstract description 12
- 239000008101 lactose Substances 0.000 abstract description 12
- 235000019359 magnesium stearate Nutrition 0.000 abstract description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 10
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 229940093429 polyethylene glycol 6000 Drugs 0.000 abstract description 10
- 230000036285 pathological change Effects 0.000 abstract description 9
- 231100000915 pathological change Toxicity 0.000 abstract description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract description 7
- 239000007935 oral tablet Substances 0.000 abstract description 7
- 229940096978 oral tablet Drugs 0.000 abstract description 7
- 229940069328 povidone Drugs 0.000 abstract description 7
- 208000024891 symptom Diseases 0.000 abstract description 7
- 229940057948 magnesium stearate Drugs 0.000 abstract description 5
- 239000003963 antioxidant agent Substances 0.000 abstract description 4
- 230000003078 antioxidant effect Effects 0.000 abstract description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 29
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 13
- 210000003734 kidney Anatomy 0.000 description 13
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 11
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 11
- 229960001375 lactose Drugs 0.000 description 11
- 229920003081 Povidone K 30 Polymers 0.000 description 10
- 239000003826 tablet Substances 0.000 description 9
- 210000002700 urine Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 8
- 208000004880 Polyuria Diseases 0.000 description 8
- 229910052744 lithium Inorganic materials 0.000 description 8
- 230000007170 pathology Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 230000017074 necrotic cell death Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 210000005239 tubule Anatomy 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 206010038540 Renal tubular necrosis Diseases 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000003825 pressing Methods 0.000 description 3
- 239000007779 soft material Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 229920003082 Povidone K 90 Polymers 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940100487 povidone k25 Drugs 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 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
- A61K31/33—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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
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- 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)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to a medicine for treating kidney injury caused by lithium salt and application thereof. The active ingredients of the medicine for treating the kidney injury caused by the lithium salt are tabersonine and a sulfhydryl antioxidant, wherein the sulfhydryl antioxidant is preferably N-acetylcysteine. The medicine is preferably an oral tablet, and the pharmaceutic adjuvant is preferably lactose, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl starch sodium, magnesium stearate, polyethylene glycol 6000 and povidone. The medicine has effect in improving pathological change and specific symptoms of kidney injury caused by lithium salt.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for treating kidney injury caused by lithium salt and application thereof.
Background
Metal salt drugs have been widely used in the treatment of human diseases, such as iron salts, calcium salts, lithium salts, and the like. The lithium salt such as lithium carbonate is approved for treating mania, has good therapeutic and preventive effects on bipolar affective psychosis with alternate onset of mania and depression, has preventive effect on recurrent depression, and can be used for treating schizo-affective psychosis.
For the treatment of mental disorders, drugs are often used for a long period of time to maintain the control effect on mental activities. However, long-term use of the drug often damages the organs. As early as 1876, humans have noted the effects of lithium on the kidneys, and subsequently there are increasing reports of lithium causing acute renal injuries such as renal failure. Reports of lithium preparations causing chronic kidney damage were first reported in 1977.
Lithium salt-induced kidney injury is also medically known as lithium nephropathy (lithium nephropathies), and its manifestations include polyuria, tubular cell degeneration, and necrosis. It is statistically estimated that about 50% of patients who take lithium preparations for a long period of time suffer from urine concentration dysfunction, about 20% of patients suffer from polyuria, and even suffer from impaired glomerular filtration rate.
Acute lithium poisoning may be treated urgently by emetic, hemodialysis, etc. The acute kidney injury caused by lithium salt can recover automatically after stopping taking the medicine, but no specific therapeutic medicine is available for chronic injury such as kidney injury caused by long-term taking of lithium preparation. Most drugs are only able to alleviate some of the pathological changes or clinical symptoms of damage caused by lithium preparations. For example, for renal injury caused by lithium salt, N-acetylcysteine can improve the indices such as creatinine, urea nitrogen, glomerular filtration rate and other pathological changes such as tubular necrosis, but lacks therapeutic effects on polyuria accompanied by renal injury caused by lithium salt. Acetazolamide was shown to improve polyuria associated with lithium salt-induced renal injury, but had no effect on urinary concentration.
For the above reasons, there is still a need for a renal protection drug against lithium salt-induced renal injury in order to improve the medication safety of patients.
Disclosure of Invention
In view of the above prior art, it is an object of the present invention to provide a medicament for treating lithium salt-induced renal injury.
In order to achieve the purpose, the invention adopts the technical scheme that:
a medicine for treating renal injury caused by lithium salt is prepared from tabersonine, a sulfhydryl antioxidant and pharmaceutically acceptable medicinal adjuvants.
Preferably, the mercapto antioxidant is N-acetylcysteine.
Preferably, the preparation dosage form of the medicament for treating the kidney injury caused by the lithium salt is an oral tablet.
Preferably, the weight ratio of the tabersonine to the N-acetylcysteine in the medicine for treating the kidney injury caused by the lithium salt is 1 weight part of the tabersonine and 10-20 weight parts of the N-acetylcysteine.
Preferably, the weight ratio of the tabersonine to the N-acetylcysteine in the medicament for treating the kidney injury caused by the lithium salt is 1 weight part of tabersonine and 10 weight parts of N-acetylcysteine.
Preferably, the weight ratio of the tabersonine to the N-acetylcysteine in the medicament for treating the kidney injury caused by the lithium salt is 1 weight part of the tabersonine and 15 weight parts of the N-acetylcysteine.
Preferably, the weight ratio of the tabersonine to the N-acetylcysteine in the medicament for treating the kidney injury caused by the lithium salt is 1 weight part of tabersonine and 20 weight parts of N-acetylcysteine.
Preferably, the pharmaceutically acceptable pharmaceutical excipients of the oral tablet comprise lactose, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, polyethylene glycol 6000 and povidone.
Preferably, the dosage of the lactose in the oral tablet is 28 times of the weight of the tabersonine, the dosage of the microcrystalline cellulose is 16 times of the weight of the tabersonine, the dosage of the hydroxypropyl cellulose is 4 times of the weight of the tabersonine, the dosage of the carboxymethyl starch sodium is 2.4 times of the tabersonine, the dosage of the magnesium stearate is 3.6 times of the tabersonine, and the dosage of the polyethylene glycol 6000 is 3.2 times of the tabersonine.
In another aspect of the invention, the application of the medicine for treating lithium salt-induced kidney injury in preparing a medicine for treating lithium salt-induced kidney injury is also provided.
In the technical scheme of the invention, "Tabersonine", also called Tabersonine, has the English name of Tabersonine and the CAS number of 4429-63-4; in the technical scheme of the invention, the N-acetylcysteine is adopted; i.e., N-acetyl-L-cysteine, CAS number 616-91-1; in the technical scheme of the invention, "carboxymethyl starch sodium" is also called carboxymethyl starch sodium, starch sodium glycolate and the like, and is commonly used as a disintegrating agent, a binding agent and the like in a tablet; in the technical scheme of the invention, "polyethylene glycol 6000" is commonly used as a binding agent in the tablet; in the technical scheme of the invention, "povidone" is also called polyvinylpyrrolidone, usually povidone K30, povidone K32, povidone K25 and povidone K90 are used in tablets, and can be used as a binder in the tablets, and the tablets are generally prepared into 3-5% aqueous solution (W/W) and then used for tablet preparation.
Experimental research shows that tabersonine has certain improvement effect on kidney injury caused by lithium salt, including remarkable improvement on polyuria symptoms and improvement on pathological changes of kidney. N-acetylcysteine can improve kidney pathological change caused by lithium salt, and has effect in treating polyuria symptom deficiency. The two are combined to have obvious improvement effect on the explicit symptoms and microscopic pathological changes of the kidney injury caused by lithium salt. . For patients with renal injury caused by lithium salt, the recommended human oral dosage is 2.5mg of tabersonine each time, 1-2 times per day, 25-50 mg of N-acetylcysteine each time, and 1-2 times per day.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the following examples are only for illustrating the present invention, and are not intended to limit the scope of the present invention.
EXAMPLE 1 oral tablet for treatment of lithium salt-induced renal injury
The formula is as follows:
tabersonine 25g
N-acetylcysteine 250g
Lactose 700g
Microcrystalline cellulose 400g
Hydroxypropyl cellulose 100g
Carboxymethyl starch sodium 60g
Magnesium stearate 90g
Polyethylene glycol 600080 g
Povidone K3061 g
Respectively crushing tabersonine, N-acetylcysteine, lactose, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, polyethylene glycol 6000 and povidone K30 according to the formula and sieving with a 80-mesh sieve;
taking povidone K30 with the prescription amount and adding water to prepare aqueous solution with the concentration of 5 percent;
uniformly mixing tabersonine, N-acetylcysteine, lactose, hydroxypropyl cellulose, polyethylene glycol 6000 and 200g of microcrystalline cellulose according to the formula, preparing a soft material by using povidone K30 aqueous solution, sieving with a 40-mesh sieve, granulating, drying at 60 ℃, mixing with 200g of microcrystalline cellulose, carboxymethyl starch sodium according to the formula and magnesium stearate according to the formula, and pressing into 10000 tablets.
EXAMPLE 2 oral tablet for treatment of lithium salt-induced renal injury
The formula is as follows:
tabersonine 25g
375g of N-acetylcysteine
Lactose 700g
Microcrystalline cellulose 400g
Hydroxypropyl cellulose 100g
Carboxymethyl starch sodium 60g
Magnesium stearate 90g
Polyethylene glycol 600080 g
Povidone K3061 g
Respectively crushing tabersonine, N-acetylcysteine, lactose, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, polyethylene glycol 6000 and povidone K30 according to the formula and sieving with a 80-mesh sieve;
taking povidone K30 with the prescription amount and adding water to prepare aqueous solution with the concentration of 5 percent;
uniformly mixing tabersonine, N-acetylcysteine, lactose, hydroxypropyl cellulose, polyethylene glycol 6000 and 200g of microcrystalline cellulose according to the formula, preparing a soft material by using povidone K30 aqueous solution, sieving with a 40-mesh sieve, granulating, drying at 60 ℃, mixing with 200g of microcrystalline cellulose, carboxymethyl starch sodium according to the formula and magnesium stearate according to the formula, and pressing into 10000 tablets.
EXAMPLE 3 oral tablet for treatment of lithium salt-induced renal injury
The formula is as follows:
tabersonine 25g
N-acetylcysteine 500g
Lactose 700g
Microcrystalline cellulose 400g
Hydroxypropyl cellulose 100g
Carboxymethyl starch sodium 60g
Magnesium stearate 90g
Polyethylene glycol 600080 g
Povidone K3061 g
Respectively crushing tabersonine, N-acetylcysteine, lactose, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, polyethylene glycol 6000 and povidone K30 according to the formula and sieving with a 80-mesh sieve;
taking povidone K30 with the prescription amount and adding water to prepare aqueous solution with the concentration of 5 percent;
uniformly mixing tabersonine, N-acetylcysteine, lactose, hydroxypropyl cellulose, polyethylene glycol 6000 and 200g of microcrystalline cellulose according to the formula, preparing a soft material by using povidone K30 aqueous solution, sieving with a 40-mesh sieve, granulating, drying at 60 ℃, mixing with 200g of microcrystalline cellulose, carboxymethyl starch sodium according to the formula and magnesium stearate according to the formula, and pressing into 10000 tablets.
Example 4 Effect on improvement of lithium salt-induced renal injury
First, modeling, grouping and administration
Sprague Dawley rats, body weight 200 g-250 g, male. Rats were housed in cages and fed for 7 days on week 1 by changing the drinking water to 15% LiCl aqueous solution (W/W) daily, 15mL LiCl aqueous solution per rat daily, and changing to distilled water after LiCl aqueous solution was consumed. In the 2 nd week, distilled water is adopted as rat drinking water, and the rat is normally fed for 7 days; on week 3, the drinking water was changed to a 7% aqueous solution of LiCl (W/W) daily, each rat was given 15mL of aqueous solution of LiCl daily, and after the aqueous solution of LiCl was consumed, it was changed to distilled water, and the rats were fed for 7 days.
Surviving rats were randomized into 5 groups starting at week 4, 6 per group:
group 1 is a model group, and the rats are administered 1mL of physiological saline by gavage twice a day (6 am and 18 am);
group 2 is tabersonine group, 1mL of tabersonine physiological saline suspension is administered by intragastric administration to each rat twice a day (6 am and 18 am), and 0.05mg of tabersonine is administered to each rat.
Group 3 was N-acetylcysteine group, and N-acetylcysteine physiological saline solution was administered by gavage, 1mL each time, twice daily (6 am, 18 am) each time, and 2mg of N-acetylcysteine was administered each time to each rat.
Group 4 is tabersonine + N-acetylcysteine group (1: 10), 1mL of a normal saline suspension containing tabersonine and N-acetylcysteine is administered to each rat every time, twice a day (6 am and 18 am), 0.05mg of tabersonine and 0.5mg of N-acetylcysteine are administered to each rat every time.
Group 5 is tabersonine + N-acetylcysteine group (1: 20), 1mL of aqueous saline suspension containing tabersonine and N-acetylcysteine was gavaged per rat, twice a day (6 am and 18 am), 0.05mg of tabersonine and 1mg of N-acetylcysteine were administered per rat.
On week 5, the drinking water was changed to 5% aqueous LiCl (W/W) daily, each rat was given 15mLLiCl daily, and after the aqueous LiCl solution was consumed, it was changed to distilled water, and then fed for 7 days. Then, the rats in each group were individually housed.
The rats in each group were dosed continuously for 4 weeks, starting at week 4 and 2 times daily until week 7 for 28 days.
Second, index and observation and measurement method
1. Measuring urine volume
On day 1 of week 8, i.e., the next day after the last dose, rats were fasted for 24 hours with no water; on day 2 of week 8 rats were free to ingest water intake and 24 hour urine was collected from the rats and the average urine volume (mL) over 24 hours was calculated for each group of rats.
2. Evaluation of renal pathological changes
On day 3 of week 8, each group of rats was sacrificed, kidneys were removed, paraffin sections were routinely prepared by pathologists, stained with hematoxylin-eosin, and pathological changes in the kidneys of each group of rats were observed under light microscopy. One field was randomly selected at 400 times field and scored as the percentage of the area of tubular necrosis to the total area of the tubular. 0 minute: : tubular necrosis area < 5%; 1 minute: the necrosis area of the renal tubule is less than 20 percent but more than or equal to 5 percent; and 2, dividing: the necrosis area of the renal tubule is less than 40% but more than or equal to 20%; and 3, dividing: the necrosis area of the renal tubule is less than 60 percent but more than or equal to 40 percent; and 4, dividing: the necrosis area of the renal tubule is less than 80 percent but more than or equal to 60 percent; and 5, dividing: the necrosis area of the renal tubule is more than or equal to 80 percent. The kidney pathology score of each group of rats is expressed as the mean of the kidney pathology scores of each rat in the group.
The comparison between the group of rats urine volume and kidney pathology score was performed using a t-test, with P <0.05 considered as statistically significant.
Fourth, experimental results
The urine volume and kidney pathology score statistics for each group of rats are shown in the following table.
In the table, a represents p <0.05 as compared with group 1, and b represents p <0.01 as compared with group 1.
As can be seen from the above table: from the urine volume analysis, the urine volume of the group 3, i.e., the N-acetylcysteine group, was not significantly different from that of the model group (p > 0.05), and the urine volume of each of the other groups was significantly lower than that of the group 1, i.e., the model group (p < 0.01). The N-acetylcysteine has no obvious improvement effect on the polyuria symptom of the chronic kidney injury caused by the lithium chloride, but the tabersonine and the composition of the tabersonine and the N-acetylcysteine can obviously reduce the polyuria symptom of a model rat. From the analysis of the kidney pathology scores, the kidney pathology scores of the groups 2 and 3, namely the group where tabersonine and N-acetylcysteine are independently administered are obviously lower than that of the group 1 (p is less than 0.05), and the pathology scores of the groups 4 and 5 are lower, which shows that the pathological changes of the kidney caused by lithium chloride can be reduced by independently or jointly administering tabersonine and N-acetylcysteine, and the effect of the combination of the tabersonine and the N-acetylcysteine is better.
Claims (1)
1. The application of the composition in preparing the medicine for treating the kidney injury caused by the lithium salt is characterized in that the composition is prepared from 1 part by weight of tabersonine and 10-20 parts by weight of N-acetylcysteine by using 1 part by weight of tabersonine and 10-20 parts by weight of pharmaceutically acceptable pharmaceutic adjuvants.
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