CN108434130A - The application of bayluscid and its pharmaceutical composition - Google Patents
The application of bayluscid and its pharmaceutical composition Download PDFInfo
- Publication number
- CN108434130A CN108434130A CN201810170783.6A CN201810170783A CN108434130A CN 108434130 A CN108434130 A CN 108434130A CN 201810170783 A CN201810170783 A CN 201810170783A CN 108434130 A CN108434130 A CN 108434130A
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- pharmaceutical composition
- bayluscid
- application
- nen
- kidney
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- 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
Abstract
The present invention relates to the applications of a kind of bayluscid and its pharmaceutical composition; it can play uncoupling to nephridial tissue mitochondria; reduce the albumen homaluria of nephrosis mouse; improve glomerulosclerosis and renal damage; reduce serum creatinine level; therefore bayluscid and its pharmaceutical composition have certain protective effect to kidney trouble, can be used for preventing and treating kidney trouble.
Description
Technical field
The present invention relates to the technical field of renal drug, more specifically to a kind of bayluscid and its
The application of pharmaceutical composition.
Background technology
Kidney trouble is to threaten the great Chronic Non-Communicable Diseases of one kind of human health, this disease cause of disease is complicated, disease treatment
Difficulty is big, and the state of an illness is touching refractory, and medical expense is huge.Albuminuria, serum creatinine progressive increase, glomerulosclerosis and renal tubule are damaged
Wound is the main clinical characteristics of its early stage.Currently, clinically there is no the effective drug for delaying kidney trouble to be in progress.
Niclosamidum is the molluscacide and anthelmintic that WHO is recommended, bayluscid (Niclosamide
Ethanolamine salt, NEN) it is its derivative, there is preferably water solubility, it is bright that research in recent years shows that such drug has
Aobvious antitumor and hypoglycemic effect.
Invention content
The purpose of the present invention is to provide the application of a kind of bayluscid and its pharmaceutical composition, solve existing
There is the problem of there is no the effective drug for delaying kidney trouble to be in progress in technology.
The technical proposal for solving the technical problem of the invention is：Bayluscid and its pharmaceutical composition point
Application not in preparing the drug for treating and preventing kidney trouble.
Bayluscid and its pharmaceutical composition are being prepared for playing uncoupling to kidney mitochondria respectively
Application in drug.
Bayluscid and its pharmaceutical composition are preparing the albuminuria excretion rate for reducing kidney respectively
Application in drug.
Bayluscid and its pharmaceutical composition are being prepared for mitigating in the drug that Pathological damages respectively
Application.
Bayluscid and its pharmaceutical composition respectively the level for lowering kidney trouble serum creatinine for preparing,
Delay the application in the drug of kidney failure.
In the present invention applies, described pharmaceutical composition be include effective active composition bayluscid and medicinal
Oral administration preparation, injecting and administering preparations, mucosa delivery preparation or the percutaneous drug administration preparation of auxiliary material.
In an application of the invention, described pharmaceutical composition is oral administration preparation, the oral administration preparation be tablet,
Capsule, granule or oral solution；Or described pharmaceutical composition is mucosa delivery preparation, the mucosa delivery preparation is patch
Or gelling agent；Or described pharmaceutical composition is percutaneous drug administration preparation, the percutaneous drug administration preparation is patch or gelling agent.
Implement the bayluscid of the present invention and its application of pharmaceutical composition, has the advantages that：This
Invention bayluscid and its pharmaceutical composition can play nephridial tissue mitochondria uncoupling, reduce nephrosis mouse
Albumen homaluria, improve glomerulosclerosis and renal damage, reduce serum creatinine level, therefore bayluscid
And its pharmaceutical composition has certain protective effect to kidney trouble, can be used for preventing and treating kidney trouble.
Description of the drawings
Fig. 1 is the curve of influences of the NEN to kidney mitochondria oxygen consumption in the case of oligomycin (Oligomycin) is not present
Figure；
Fig. 2 is the curve graph of influences of the NEN to kidney mitochondria oxygen consumption in the case of oligomycin exists；
Fig. 3 is comparison diagrams of the NEN to the influence result of mRNA IN ADRIAMYCIN NEPHROPATHY murine protein homaluria；
Fig. 4 is the influence comparative result figure that NEN hardens mRNA IN ADRIAMYCIN NEPHROPATHY murine glomerular；
Fig. 5 is that NEN schemes the stained slice photo comparison that mRNA IN ADRIAMYCIN NEPHROPATHY murine glomerular hardens；
Fig. 6 is influence comparative result figures of the NEN to mRNA IN ADRIAMYCIN NEPHROPATHY mouse renal damage；
Fig. 7 is that NEN schemes the stained slice photo comparison of mRNA IN ADRIAMYCIN NEPHROPATHY mouse renal damage；
Fig. 8 is influence comparative result figures of the NEN to mRNA IN ADRIAMYCIN NEPHROPATHY mouse serum creatinine.
Specific implementation mode
With reference to the accompanying drawings and examples, the pharmaceutical composition to the calcium-sensing receptor correlation peptides of the present invention and its application
It is described further：
For kidney trouble mainly due to caused by urinary protein excretion increase caused by kidney injury, albuminuria can also aggravate kidney damage
Evil, leads to glomerulosclerosis and renal damage, and then detection of glomeruli filtration function is caused to decline, and serum creatinine progressive increases, most
Renal failure is moved towards eventually, this disease cause of disease is complicated, and pathogenesis is not completely clear, and treatment difficulty is big.
The present invention provides with bayluscid (NEN) and containing bayluscid (NEN) medicine
Application of the compositions in preparing the drug for treating and preventing kidney trouble.Wherein, bayluscid (NEN)
For the structural compounds of CAS NO 1420-04-8 number, structural formula is as follows：
Wherein, pharmaceutical composition is to include the oral medication of effective active composition bayluscid and pharmaceutic adjuvant
Preparation, injecting and administering preparations, mucosa delivery preparation or percutaneous drug administration preparation.Such as tablet, capsule, granule, oral solution, patch
Or gelling agent etc..The above-mentioned dosage form of bayluscid is the prior art, is equally no longer described in detail here.
Pharmaceutical composition to bayluscid (NEN) and containing bayluscid (NEN) below
Application be described in detail.
One, experimental method
1, animal model：Male BALB/c mouse (weight 20-25g) purchase is moved in Guangdong Medical Lab Animal Center
Object experiment is carried out in strict accordance with animal welfare correlation criterion and regulations, is raised in Shenzhen Graduate School of Peking University's animal center.
Experimental animal is controlled under conditions of 23 ± 1 DEG C of constant room temperature, illumination in 12 hours and 12 hours dark cycles, while freely ingesting
And drinking-water.18 mouse are randomly divided into Normal group (control groups, n=6 in illustrating), mRNA IN ADRIAMYCIN NEPHROPATHY group
(adriamycin nephropathy, AN, n=6) and mRNA IN ADRIAMYCIN NEPHROPATHY+NEN treatment groups (AN+NEN, n=6).Adriamycin kidney
Sick mouse model is induced by disposable tail vein injection 10.4mg/kg adriamycins (sigma, the U.S.), and Normal group gives
The disposable tail vein injection of normal saline.Modeling proceeds by intervention after 2 weeks, wherein Normal group and AN group mouse is fed
Conventional food is supported, AN+NEN groups feed the food of addition NEN, amount to and feed 4 weeks.NEN purchases contain day perseverance creation object section in Hubei
Skill Co., Ltd (China) is added to 2g/kg standard proportional mixings in the food of mouse.
2, kidney mitochondrial function measures：After extracting normal male BALB/c mouse kidney mitochondria, oxygen electrode is used
(Hansatech Instrument, Britain) is respectively in the oxygen consumption for detecting mitochondria without oligomycin and under the conditions of containing oligomycin
Amount.A concentration of 1mg/ml of mitochondria, each concentration of substrate：Glutamate/malate (Glutamate/malate), 2.5mM/
2.5mM；Adenosine diphosphate (ADP) (ADP), 200 μM；oligomycin,5μg/ml；NEN,10μM.
3, it respectively 4 weeks and 6 weeks before modeling, after modeling, is left and taken using mouse metabolism cage (Tecniplast, Italy) each
The urine for 24 hours of group mouse urinates total egg for 24 hours using Bradford protein determination kits (Bio-Rad, the U.S.) detection each group mouse
It is white quantitative.
4, tissue prepares：After modeling 6 weeks, after that is to say that NEN intervenes 4 weeks, after putting to death each group mouse, serum sample is left and taken,
Kidney is taken out, a certain amount of renal tissue is cut along vertical section and is fixed with 10% formalin, carry out dehydration paraffin embedding later, is remained
Remaining renal tissue freezes in liquid nitrogen and is stored in -80 DEG C for subsequent experimental research immediately.Serum creatinine uses full-automatic
Biochemical Analyzer (Roche, Switzerland) measures.
5, glomerulosclerosis Index Assessment method：Every group randomly selects 4 samples, and under PAS stained slices, every slice exists
20-30, region of random shooting Renal Cortex glomerulus under 40 × object lens, glomerulosclerosis be mainly shown as extracellular matrix expansion,
Capillary occlusion, hyaline degeneration and adhosion.0 point is accumulated if glomerulus normal (or lesion ＜ 5%), if lesion
It is then 1 point long-pending to accumulate 5~25% region of glomerulus, 25~50% 2 points of products, 50~75% 3 points of products, 75~100% 4 points of products, so
The average value of every slice is calculated afterwards.
6, renal damage Index Assessment method：Every group randomly selects 4 samples, and under PAS stained slices, every slice exists
10-20, random shooting Renal Cortex portion renal tubule region under 20 × object lens, renal damage are mainly shown as tubule cast, wither
Contracting, expansion and inflammatory cell infiltration.0 point is accumulated if renal tubule normal (or lesion ＜ 5%), if lesion accumulates renal tubule
5~25% regions then accumulate 1 point, then 25~50% 2 points of products, 50~100% 3 points of products calculate the average value of every slice.
7, statistical analysis
Measurement data is indicated using mean+SD.Statistical discrepancy between two groups of samples uses independent samples t test
It is analyzed, the comparison between multigroup sample uses one-way analysis of variance, and statistical analysis is using at 16.0 statistical softwares of SPSS
Reason.P<Being considered as statistically difference when 0.05 has conspicuousness.
Two, result
1, bayluscid (NEN) has BALB/c mouse kidney mitochondria (mitochondria) apparent
Uncoupling.
As shown in Figure 1, NEN can there is no situations to increase kidney mitochondria oxygen consumption in oligomycin (Oligomycin)；Such as
Shown in Fig. 2, NEN can exist in oligomycin increases kidney mitochondria oxygen consumption.A concentration of 1mg/ml of mitochondria.Each substrate
Concentration：Glutamate/malate (Glutamate/malate), 2.5mM/2.5mM；Adenosine diphosphate (ADP) (ADP), 200 μM；
oligomycin,5μg/ml；NEN,10μM.
2, bayluscid (NEN) can obviously reduce the excretion of mRNA IN ADRIAMYCIN NEPHROPATHY murine protein urine.
As shown in figure 3, being influence results (n=6) of the NEN to mRNA IN ADRIAMYCIN NEPHROPATHY murine protein homaluria.With normal group ratio
Compared with,*P<0.05,***P<0.001；Compared with AN groups,#P<0.05,##P<0.01。
When adriamycin modeling originates (at 0 week), control groups, Urinary Albumin Excretion is without bright between AN groups and AN+NEN groups
Significant difference is different.(it that is to say that NEN is treated 2 weeks) 4 weeks after modeling, compared with control groups, AN group Urine proteins obviously increase, through NEN
After treating 2 weeks, AN+NEN groups Urine proteins are decreased obviously compared with AN groups.(it that is to say that NEN is treated 4 weeks) 6 weeks after modeling, AN group Urine proteins
Declined when 4 weeks before relatively, but still be significantly higher than control groups, AN+NEN groups Urine proteins are still significantly low after NEN is treated 4 weeks
In AN groups.
3, bayluscid (NEN) can substantially reduced mRNA IN ADRIAMYCIN NEPHROPATHY murine glomerular hardening.
As shown in Figures 4 and 5, the influence result (n=4) mRNA IN ADRIAMYCIN NEPHROPATHY murine glomerular hardened for NEN.With normal group
Compare,***P<0.001；Compared with AN groups,#P<0.05.After modeling 6 weeks (NEN is treated 4 weeks), the hardening of AN group murine glomerulars refers to
Number dramatically increases, and compared with AN groups, AN+NEN group glomerulosclerosis indexes are substantially reduced.
4, bayluscid (NEN) can substantially reduced mRNA IN ADRIAMYCIN NEPHROPATHY mouse renal damage.
As shown in Figures 6 and 7, it is influence results (n=4) of the NEN to mRNA IN ADRIAMYCIN NEPHROPATHY mouse renal damage.With normal group
Compare,***P<0.001；Compared with AN groups,##P<0.01.After modeling 6 weeks (NEN is treated 4 weeks), AN group mouse renal damages refer to
Number dramatically increases, and compared with AN groups, AN+NEN group renal damage indexes are substantially reduced.
5, it is horizontal to can obviously reduce mRNA IN ADRIAMYCIN NEPHROPATHY mouse serum creatinine for bayluscid (NEN).
As shown in figure 8, being influence results (n=6) of the NEN to mRNA IN ADRIAMYCIN NEPHROPATHY mouse serum creatinine.Compared with normal group,**P
<0.01；Compared with AN groups,#P<0.05.After modeling 6 weeks (NEN is treated 4 weeks), AN group mice serum creatinines obviously increase, with AN
Group is compared, and AN+NEN group serum creatinines are substantially reduced.
It is above-mentioned the experimental results showed that, bayluscid (NEN) in the prior art is as a kind of anthelmintic and anti-
Tumour medicine can play uncoupling to kidney mitochondria, reduce the albumen homaluria of kidney trouble, improve glomerulosclerosis
And renal damage, serum creatinine level is reduced, and then delay kidney trouble to kidney failure process.Therefore, containing chlorine nitre willow
The pharmaceutical composition of amine ethanolamine salt (NEN) equally can play uncoupling to kidney mitochondria, reduce the egg of kidney trouble
Albiduria is drained, and glomerulosclerosis and renal damage are improved, and reduces serum creatinine level, and then delay kidney trouble to renal failure
Exhaust process.
It should be understood that for those of ordinary skills, it can be modified or changed according to the above description,
Within all these improvement or transformation should all belong to the protection domain of appended claims of the present invention.
Claims (7)
1. bayluscid and its pharmaceutical composition are respectively in preparing the drug for treating and preventing kidney trouble
Application.
2. bayluscid and its pharmaceutical composition are preparing the medicine for playing uncoupling to kidney mitochondria respectively
Application in object.
3. bayluscid and its pharmaceutical composition are respectively in the medicine for preparing the albuminuria excretion rate for reducing kidney
Application in object.
4. bayluscid and its pharmaceutical composition are respectively in preparing the drug for mitigating Pathological damage
Using.
5. bayluscid and its pharmaceutical composition are being prepared for lowering the level of kidney trouble serum creatinine, prolonging respectively
Application in the drug of slow kidney failure.
6. according to the application described in any one of claim 1-5 claims, which is characterized in that described pharmaceutical composition is to include
The oral administration preparation of effective active composition bayluscid and pharmaceutic adjuvant, injecting and administering preparations, mucosa delivery system
Agent or percutaneous drug administration preparation.
7. application according to claim 6, which is characterized in that described pharmaceutical composition is oral administration preparation, the mouth
It is tablet, capsule, granule or oral solution to take drug-delivery preparation；Or described pharmaceutical composition is mucosa delivery preparation, it is described
Mucosa delivery preparation is patch or gelling agent；Or described pharmaceutical composition is percutaneous drug administration preparation, the percutaneous drug administration preparation
It is patch or gelling agent.
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| CN201810170783.6A CN108434130A (en) | 2018-03-01 | 2018-03-01 | The application of bayluscid and its pharmaceutical composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111032030A (en) * | 2019-04-28 | 2020-04-17 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparation of medicines for treating systemic lupus erythematosus and complications thereof |
| CN112316150A (en) * | 2020-12-04 | 2021-02-05 | 深圳市中医院 | A pharmaceutical composition for preventing or treating metabolism or injury related diseases |
| CN112426531A (en) * | 2020-12-04 | 2021-03-02 | 深圳市中医院 | Application of pharmaceutical composition in preparation of drugs for preventing or treating kidney diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103415287A (en) * | 2010-11-16 | 2013-11-27 | 新泽西医科和牙科大学 | Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers |
| CN106420684A (en) * | 2016-09-23 | 2017-02-22 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparing diabetes type 1 treating medicines |
-
2018
- 2018-03-01 CN CN201810170783.6A patent/CN108434130A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103415287A (en) * | 2010-11-16 | 2013-11-27 | 新泽西医科和牙科大学 | Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers |
| CN106420684A (en) * | 2016-09-23 | 2017-02-22 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparing diabetes type 1 treating medicines |
Non-Patent Citations (1)
| Title |
|---|
| XIAOYAN CHANG ET AL.: "The antihelmenthic phosphate niclosamide impedes renal fibrosis by inhibiting homeodomain-interacting protein kinase 2 expression", 《KIDNEY INTERNATIONAL》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111032030A (en) * | 2019-04-28 | 2020-04-17 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparation of medicines for treating systemic lupus erythematosus and complications thereof |
| WO2020220170A1 (en) * | 2019-04-28 | 2020-11-05 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparation of medicament for treating systemic lupus erythematosus and complications thereof |
| CN111032030B (en) * | 2019-04-28 | 2023-02-17 | 深圳市中医院 | Application of niclosamide ethanolamine salt in preparing medicine for treating systemic lupus erythematosus and complications thereof |
| CN112316150A (en) * | 2020-12-04 | 2021-02-05 | 深圳市中医院 | A pharmaceutical composition for preventing or treating metabolism or injury related diseases |
| CN112426531A (en) * | 2020-12-04 | 2021-03-02 | 深圳市中医院 | Application of pharmaceutical composition in preparation of drugs for preventing or treating kidney diseases |
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