CN107050025A - Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis - Google Patents
Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis Download PDFInfo
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- CN107050025A CN107050025A CN201710321976.2A CN201710321976A CN107050025A CN 107050025 A CN107050025 A CN 107050025A CN 201710321976 A CN201710321976 A CN 201710321976A CN 107050025 A CN107050025 A CN 107050025A
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- anisodine
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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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The invention belongs to field of medicaments, and in particular to application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis.Technical problem solved by the invention is to provide the new application of anisodine, particularly application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis.Specifically, its effect, which is embodied in anisodine, can reduce α SMA in the level of Scr, BUN in serum, reduction nephridial tissue; the level of TGF β albumen; promote or improve proliferation of fibrous tissue in renal interstitial, illustrate that anisodine kidney region fibrosis has protective effect, improve kidney region fibrosis.Inventive compound anisodine is preferred to use Anisodine.Be experimentally confirmed, Anisodine have prevent or treatment kidney fibrosis effect, a kind of new selection can be provided by suppressing the Proliferative Activated so as to improve kidney fibrosis of myofibroblast in nephridial tissue for clinical prevention, treatment kidney fibrosis.
Description
Technical field
The invention belongs to field of medicaments, and in particular to anisodine answering in the medicine for preparing prevention or treatment kidney fibrosis
With.
Background technology
Kidney fibrosis is the final co-channel and pathology that various chronic renal diseases (CKD) are developed to end stage renal failure
Basis, is to seriously endanger one of important diseases of human life and health.Kidney region fibrosis is characterized in substantial amounts of extracellular base
Matter (ECM) composition is progressively deposited in renal tubule and peritubular capillary gap, destroy normal renal tubule and
Renal interstitial structure, ultimately results in kidney and completely loses organ function.The pathogenesis of kidney region fibrosis is sufficiently complex, is related to thin
The processes such as born of the same parents' Phenotypic change, oxidative stress, inflammatory reaction, cytokine profiles and cell-cell interaction, are prevented even inverse
The progress for turning kidney region fibrosis is of great significance for CKD treatment.
The medicine of kidney region fibrosis can effectively be treated by clinically still lacking at present, and existing remedy measures essentially consist in control
Primary disease processed and its degradation factors, such as：Hypoglycemic, hypotensive, infection control, the microcirculation for adjusting fat and improvement kidney part
Deng.But these modes are only capable of slowing down advancing of disease very limitedly, when advancing to the kidney fibrosis irreversible stage or occur tight
During the renal dysfunction of weight, patient can only be sustained life by haemodialysis, peritoneal dialysis, kidney transplant, this to patient and its
Family and society all bring white elephant.Clinically existing anti-fibrosis medicine has that toxicity is big, security is low asks
, there is great limitation in topic, therefore in actual applications, and the potential anti-fibrosis medicine of high-efficiency low-toxicity is found from natural products
Thing is significant.
Anisodine (anisodine), chemical formula is C17H21NO5, relative molecular weight is 319.35, and chemical constitution is as follows：
It is, by a kind of China scientist new anticholinergic agents isolated from Anisodus tanguticus root first, to face
Its hydrobromate is mainly used on bed.Anisodine is white crystals, soluble in water, insoluble in chloroform, ether,
Odorless, bitter with releasing smooth muscle spasm, suppresses the anticholinergic effects such as salivary secretion, mydriasis.The current camphor tree willow in clinic
Alkali can be used for treatment vascular headache, retinal angiospasm, centrality PVR, ischemic optic neuropathy, acute
Paralysis, shaking plasy, bronchial astehma, motion sickness, organophosphorus poisoning etc..
The application of the final drug or compound preparation of Anisodine, such as Chinese patent have been related at present
97120175 disclose a kind of compound anisodine injection, pass through anisodine and procaine, vitamin B12, hyaluronic acid etc.
Combination, overcome it is alone it is bad to eye ischemic curative effect, the drawbacks of adverse reaction is more, the effective percentage of eye ischemic has been reached 90% with
On.A kind of oral liquid of compound anisodine is disclosed in Chinese patent 200410098938, use it is more convenient compared with parenteral solution,
The pain of patient is alleviated, can voluntarily be taken whenever and wherever possible, the compliance of patient is substantially increased.Chinese patent
The compound preparation of a kind of anisodine and procaine is disclosed in 200510132127, interstitial pneumonia and lung can be effectively treated
The diseases such as fibrosis, cerebral infarction, ischemic angiocardiopathy and cerebrovascular disease, ischemic eye disease.Disclosed in Chinese patent 200810006924
Anisodine is used to prepare the purposes in the medicine for the treatment of amblyopia, and obtained medicine can be injection, eye drops,
Can also be the oral formulations such as tablet, capsule, oral liquid, dripping pill.Hydrobromic acid is disclosed in Chinese patent 201210274372
The purposes that anisodine is used in medicament for treatment of depression, it lacks for excitement, pleasant sensation disappears, excitement degree is reduced, body weight increases
The depressive symptoms such as dosage reduction have good therapeutic effect.But in the prior art, do not record anisodine and can be used for treatment
The document report of kidney fibrosis.
The content of the invention
Technical problem solved by the invention is to provide the new application of anisodine, particularly anisodine prepare prevention or
Treat the application in the medicine of kidney fibrosis.
Inventive compound anisodine is preferred to use Anisodine.Its effect is embodied in Anisodine can be with
The level of Scr, BUN in serum are reduced, suppresses α-SMA, the expression of TGF-β albumen, it was confirmed that Anisodine in nephridial tissue
Effect with anti-kidney fibrosis.
Using when prevent or treatment kidney fibrosis medicine in can contain 0.1-99.9wt% anisodine as activity
Composition, can also carry out compounding with other drugs and compound medicine is made；According to pharmacy conventional method, add pharmaceutically acceptable
Carrier is prepared into suitable pharmaceutical dosage form, and oral formulations or injection can be specifically made, by oral, intramuscular injection,
The mode such as vein input or intraperitoneal injection is administered.Such as soft capsule, tablet, freeze dried powder or injection.
It is experimentally confirmed, Anisodine has the effect for preventing or treating kidney fibrosis, can be by suppressing kidney group
The Proliferative Activated so as to improve kidney fibrosis of middle myofibroblast is knitted, one kind is provided for clinical prevention, treatment kidney fibrosis
New selection.
Embodiment
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright, illustrate but do not limit the present invention.
Embodiment：Therapeutic action of the Anisodine to kidney fibrosis rat model
First, experimental program
1st, material and method
1.1 experimental animal：6~8 week old cleaning grades health male SD rat 40, purchase is limited from the magnificent Fukang science and technology in Beijing
Company.Experimental animal feeding is followed entirely in biological therapy National Key Laboratory of Sichuan University animal center constant temperature, constant humidity and air
In ring filtering environment.
1.2 material：Anisodine (99% is pure), is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute, rabbit-anti rat α-flat
Sliding flesh actin antibodies, rabbit-anti rat anti-TGF-β are biological purchased from Hangzhou Huaan.
1.3 method：
The foundation of 1.31 animal models：Rat is with sleeping on the right side of being taken after 2% yellow Jackets (50mg/kg) intraperitoneal injection of anesthesia
Position is fixed, operative region preserved skin, sterilization.Below the costolumbar point of left side, a stringer otch is made in left side by backbone, separates ureter,
5-0 silk threads ligation ureter two ends, cut ureter, layer-by-layer suture makes UUO models in the middle of 2 ligation points.Sham-operation group
Abdomen rear left side Ureter dissection is only opened, bundle is not connect and cuts.
1.32 experiment packet：Rat is randomly divided into sham-operation group (10), UUO model groups (10), UUO models+hydrogen
Bromic acid anisodine 2.5mg/kg treatment groups (anisodine low dose group, 10), UUO models+Anisodine 5mg/kg treatments
Group (anisodine high dose group, 10).Started administration in the postoperative same day, be administered once a day.
1.33 detection project：Blood specimen was collected in postoperative 14th day, separation serum carries out serum creatinine (Scr) and urea nitrogen
(BUN) detect, put to death animal, take operation side kidney, 1/3 is stored in 4% paraformaldehyde fixer in case follow-up HE, MASSON
And immunohistochemical staining is used, remaining 2/3 is equally divided into 10 pieces, is transferred to -80 DEG C of Low-temperature Ices after quick freeze in liquid nitrogen
Preserved in case, for subsequently carrying out α-SMA, SABC and Western the blot detection of TGF-β.
1.4 data processing：Measurement data withRepresent, analyzed with the software statistics of SPSS 22.0.Multisample mean
Between compare with one-way analysis of variance (One-way ANOVA), compare two-by-two between group and examined with LSD-t, used during heterogeneity of variance
Dunnett, s T3 are examined.
2nd, result
2.1 rat Scr and BUN situation of change, is shown in Table 1.
Table 1 each group rat BUN, Scr level (mmol/L, umol/L)
Note：Compared with sham-operation group：#P ＜ 0.05；Compared * P ＜ 0.05 with model group
The result of table 1 is shown：Compared with sham-operation group, the significantly raised (P of Scr, BUN level in remaining each group rat blood serum
＜ 0.05)；Compared with model group, there is different degrees of drop in Scr, BUN level in serum after being treated through Anisodine
It is low, become apparent (P ＜ 0.05) with anisodine high dose group effect.
2.2 renal tissues of rats pathological observations
1. visually observe：Sham-operation group kidney is in kermesinus, and surface is smooth, both sides kidney contrast no significant difference, remaining
Each group Kidney Volume is significantly increased, and color is pale, and cortex is thinning.2. light microscopic is detected：Sham-operation renal tissue structure is normal, interstitial
It is interior without cell infiltration, visible a small amount of collagen Lan Ran areas at MASSON dyeing only glomerulus and renal tubular basement membrane.Model group
Renal cells atrophy, vacuole sample becomes, and substantially, visible protein cast in the tube chamber of part, part renal tubule is bad for lumen distention
Extremely, the visible proliferation of fibrous tissue of necrotic zone, a large amount of cell infiltrations of renal interstitial, the collagen that MASSON dyes visible large area is blue
Proliferation of fibrous tissue is compared with sham-operation group showed increased in dye area, renal interstitial.Two treatment group's lesions have different degrees of compared with model group
Improve, especially become apparent with anisodine high dose group, difference is statistically significant compared with model group, is shown in Table 2.
The each group tubulointerstitial fibrosis in rats damage index of table 2, renal interstitial collagen relative area scoring (N=10)
Note：Compared with sham-operation group：#P ＜ 0.05,；Compared * P ＜ 0.05 with model group
2.3 α-SMA, the expression of TGF-β albumen
Hardly express alpha-SMA in rats in sham-operated group renal interstitial, remaining each group is in renal interstitial and part renal tubular epithelial
Intracellular visible different degrees of positive expression；Compared with model group, anisodine high and low dose group expression quantity substantially reduces (P
＜ 0.05)；Anisodine high dose group no significant difference (P ＞ 0.05) compared with low dose group, is shown in Table 3.
TGF-β is only expressed in renal tubule, the endochylema of interstitial cell on a small quantity in sham-operation group；In model group nephridial tissue
The expression quantity of TGF-β substantially increases (P ＜ 0.05), mainly based on renal cells, renal interstitial region.Controlled through anisodine
The expression quantity of TGF-β is substantially reduced (P ＜ 0.05) compared with model group after treatment, anisodine high dose compared with low dose group difference without system
Meter learns meaning (P ＞ 0.05), is shown in Table 3.
The each group renal tissues of rats α-SMA of table 3, the expression of TGF-β albumen
Note：Compared with sham-operation group：#P ＜ 0.05,；Compared * P ＜ 0.05 with model group
3 conclusions
Compared with model group, Scr, BUN level of rat will substantially reduce (P ＜ after being treated through Anisodine
0.05), kidney region fibrosis degree substantially mitigates α-SMA, the expression quantity of TGF-β in (P ＜ 0.05), nephridial tissue and substantially reduced,
Prompting Anisodine has protective effect to renal interstitial fibrosis rat caused by UUO, and its mechanism may be by suppressing kidney
It is intrinsic fibroblastic Proliferative Activated in the expression of interior TGF-β, reduction renal interstitial, so as to improve kidney region fibrosis.
Claims (9)
1. application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis.
2. application according to claim 1, it is characterised in that：Prevention or the treatment kidney fibrosis is by reducing in serum
Scr, BUN level are realized.
3. application according to claim 1, it is characterised in that：Prevention or the treatment kidney fibrosis is by reducing nephridial tissue
Middle α-SMA, the level of TGF-β albumen is realized.
4. application according to claim 1, it is characterised in that：The prevention or treatment kidney fibrosis are by promoting or improving
Proliferation of fibrous tissue is realized in renal interstitial.
5. application according to claim 1, it is characterised in that：The medicine using 0.1-99.9wt% anisodine are used as work
Property composition, according to pharmacy conventional method, add pharmaceutically acceptable carrier and be prepared into pharmaceutical dosage form.
6. application according to claim 1, it is characterised in that：The medicine using 0.1-99.9wt% anisodine are used as master
Active component is wanted, carrying out compounding with other drugs is made compound medicine, according to pharmacy conventional method, adds pharmaceutically acceptable
Carrier is prepared into pharmaceutical dosage form.
7. the application according to claim 5 or 6, it is characterised in that：The pharmaceutical dosage form is oral formulations, ejection preparation.
8. the application according to claim 5 or 6, it is characterised in that：The pharmaceutical dosage form is soft capsule, tablet, freezed
Pulvis or injection.
9. application according to claim 1, it is characterised in that：The anisodine is Anisodine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710321976.2A CN107050025A (en) | 2017-05-09 | 2017-05-09 | Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710321976.2A CN107050025A (en) | 2017-05-09 | 2017-05-09 | Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis |
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| CN107050025A true CN107050025A (en) | 2017-08-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710321976.2A Pending CN107050025A (en) | 2017-05-09 | 2017-05-09 | Application of the anisodine in the medicine for preparing prevention or treatment kidney fibrosis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115634196A (en) * | 2022-12-15 | 2023-01-24 | 成都第一制药有限公司 | Stable-quality anisodine hydrobromide injection and preparation method thereof |
-
2017
- 2017-05-09 CN CN201710321976.2A patent/CN107050025A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| 刘文娟主编: "《药物化学》", 31 January 2010, 中国医药科技出版社 * |
| 唐云海等: "山莨菪碱对梗阻性肾病大鼠间质纤维化的抑制", 《贵阳医学院学报》 * |
| 虞文嫣等: "TGF-β1在COPD气道重塑中的作用及抗胆碱能药物干预效应实验研究", 《医学研究杂志》 * |
| 赵雪谦等: "肾纤维化相关生长因子研究新进展", 《临床肾脏病杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115634196A (en) * | 2022-12-15 | 2023-01-24 | 成都第一制药有限公司 | Stable-quality anisodine hydrobromide injection and preparation method thereof |
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Application publication date: 20170818 |