CN108992458A - Vitamin B12 is used to prepare prevention and/or treats the application of Postoperative Cognitive Dysfunction drug - Google Patents
Vitamin B12 is used to prepare prevention and/or treats the application of Postoperative Cognitive Dysfunction drug Download PDFInfo
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- CN108992458A CN108992458A CN201810600765.7A CN201810600765A CN108992458A CN 108992458 A CN108992458 A CN 108992458A CN 201810600765 A CN201810600765 A CN 201810600765A CN 108992458 A CN108992458 A CN 108992458A
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- vitamin
- folic acid
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- drug
- pocd
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The present invention relates to the applications that vitamin B12, folic acid are used to prepare prevention and treatment Postoperative Cognitive Dysfunction drug.Using vitamin B12, folic acid mixture as when prevention POCD drug, it can prevent and mitigate the Cognitive function damage symptom in patient's early postoperation and long term, POCD patient's postoperative cognitive is accelerated to restore.
Description
Technical field
The present invention relates to vitamin B12s and its derivative (Vitamin B12, VB12) to be used to prepare prevention or/and treatment
The application of Postoperative Cognitive Dysfunction drug.
Background technique
Postoperative Cognitive Dysfunction (Postoperative cognitive dysfunction, POCD), is patient in hand
One of serious long-term complications of postoperative appearance are mainly shown as the obstacles such as memory, abstract thinking, while living with society
The decline of kinetic force.Receiving high risk patient with operation, in especially old, orthopaedics or Patients Received Heart Surgery group,
The disease incidence of POCD may be up to 53%, and small number of patients (about 1%) symptom can extend to postoperative 1-2.Meanwhile POCD can also cause
The incidence of other types complication increases, and 1 year death rate is also higher after operation.Especially current China existing 2.3 hundred million
Elderly population, Aging Problem increasingly sharpen, and old POCD has become clinical problem urgently to be resolved.
Summary of the invention
Inventor studies discovery vitamin B12 and participates in a variety of metabolic responses that such as methylate in vivo, further has been surprisingly found that
The mutually collaboration of both vitamin B12 folic acid mixture participates in a variety of metabolic responses that such as methylate in vivo, in vascular dementia etc.
Pivot nervous system and cognition class disease have specific protective effect, especially have the effect for preventing and treating POCD to old group
Fruit.
Based on above-mentioned discovery the present invention provides:
(1) vitamin B12 is used to prepare prevention and/or treats the application of Postoperative Cognitive Dysfunction drug.
The vitamin B12 is replaced by vitamin B12 derivative or vitamin B12 pharmaceutically acceptable salt.
The dosage of conventional normalised diet replenishing vitamins of the day dosage of the vitamin B12 greater than 5 times.
(2) vitamin B12 folic acid mixture is used to prevent or/and treat the application of Postoperative Cognitive Dysfunction drug.
Conventional normalised supplement dietary vitamins of the day dosage of the vitamin B12 greater than 5 times supplement dosage, excellent
12 μ g~2mg are selected, conventional normalised supplement dietary vitamins of the day dosage greater than 5 times of the folic acid supplement dosage, excellent
Select 2mg~10mg.
The vitamin B12 is replaced by vitamin B12 derivative or vitamin B12 pharmaceutically acceptable salt.
The folic acid is replaced by folic acid pharmaceutically acceptable salt.
(3) a kind of drug for treating POCD, which is characterized in that the drug is made of vitamin B12 and folic acid.
The pharmaceutical dosage form collapses dosage form, effervescent tablet, ointment, gel or transdermal including injection, tablet, capsule, dispersing agent, speed
Sustained release agent dosage form etc..
The vitamin B12 is replaced by vitamin B12 derivative or vitamin B12 pharmaceutically acceptable salt.
The folic acid is replaced by folic acid pharmaceutically acceptable salt.
When using the solution of the present invention, especially vitamin B12 folic acid mixture as the drug for preventing POCD, it can prevent
And mitigate the Cognitive function damage symptom of patient's early postoperation and long term, accelerate POCD patient's postoperative cognitive to restore.
Detailed description of the invention
Fig. 1 receives behaviouristics and serology variation before and after POCD modeling for Aged Mice and young mouse.It compares first
Blueness Aged Mice Serum Vitamin B12 and folate content difference (Figure 1A, 1B) under physiological status, as the result is shown Aged Mice serum
Vitamin B12 content is substantially less than young mouse, serum folic acid content difference with insignificance.Then comparison youth and Aged Mice art
14 days new object identifications (Fig. 1 C) afterwards, scene fear memory (Fig. 1 D), spatial memory (Fig. 1 E), Aged Mice is postoperative as the result is shown
POCD symptom is obvious, and young mouse is postoperative to be not susceptible to POCD.All data in serology histogram using mean ±
P < 0.05 SEM, *；All data in behaviouristics histogram use mean ± SD, P < 0.05 *.
Fig. 2 is the influence of vitamin B12 and folic acid to Aged Mice POCD；It looks first at preoperative 2 weeks and starts until postoperative
The Serum Vitamin B12 and folate content of Aged Mice change (Fig. 2A, 2B) after 5 multiple dose vitamin of oral supplementation, as a result show
Show that postoperative 4 days mice serum vitamin B12s and folate content are remarkably decreased, after be gradually recovered, and preoperative replenishing vitamins B12
Although there is same variation tendency with folic acid group mouse, but the Serum Vitamin B12 level of entire peri-operation period is aobvious after supplement
It writes and is higher than control sets of numbers, and both serum folate levels do not have notable difference.Then observation Aged Mice continues using dimension life
Plain B12 folic acid mixture supplement mouse grain or the cognitive function behaviouristics performance for implementing operation after control mouse grain 2 weeks, are respectively as follows: postoperative
The new object identification action trail figure of 14 days mouse and performance statistics (Fig. 2 C)；Scene fear memory stimulate the reaction and memory capability
(Fig. 2 D)；The learning ability and memory capability (Fig. 2 E) of georeferencing, P < 0.05 *；P < 0.01 *, all data in histogram
Using mean ± SEM.Fig. 2A, Fig. 2 B and Fig. 2 C show that starting within preoperative 2 weeks lasting replenishing vitamins B12 and folic acid can effectively change
Kind Aged Mice POCD symptom.
Fig. 3 is the influence of vitamin B12 and folic acid to Aged Mice cognitive function；Vitamin B12 and folic acid mixture are compared,
With independent replenishing vitamins B12 or folic acid to the difference of Aged Mice POCD prevention effect, intervene 2 using different replenishment strategies
Zhou Hou, the postoperative new object identification of comparison Aged Mice, scene fear, spatial memory cognitive behavior show difference；Fig. 3 A, Fig. 3 B,
Fig. 3 C respectively indicates the new object identification ability of postoperative 14 days different disposals group Aged Mice, scene fear memory ability, space ginseng
Examine three kinds of cognitive function performance (control control groups of ability of learning and memory；The independent folic acid supplementation group of FA；The independent vitamin of VB12
B12 supplementation group；The compound replenishing vitamins B12 of FA+VB12 and folic acid group).Independent replenishing vitamins B12 or folic acid as the result is shown
When, only there is improvement to Barnes maze spatial memory capability, and supplementing mixture can also be to fear memory and new object identification
The ability effect of being significantly improved.
Specific embodiment
" the conventional normalised supplement dietary vitamins of vitamin B12 supplement dosage " of the present invention can be according to relevant criterion
Or dietary recommendation determines.Standard supplement metering common at present is: 14 years old or more adult: daily 2.4 microgram, pregnant woman 2.6 are micro-
Gram, 2.8 microgram of lactation, therapeutic dose be 500 micrograms, [1] on the 3/th." conventional normalised supplement diet folic acid of the present invention
Supplement dosage " it can be determined according to relevant criterion or dietary recommendation.Standard supplement metering common at present is daily 14 years old or more
Adult, 400 micrograms, 600 microgram of pregnant woman, 500 microgram of lactation.
Vitamin B12 of the invention refers to vitamin B12, vitamin B12 also known as cobalamin used in clinical and food,
There are many active forms in vivo, and vitamin B12 derivative of the invention includes Mecobalamin, cyanocobalamin, cobamamide, hydroxycobalamin
Deng.
Vitamin B12 folic acid mixture of the invention refers to vitamin B12 and folic acid mixture.
Postoperative Cognitive Dysfunction of the present invention includes postoperative discrimination, directive force, implementation capacity, attention, language
Ability and learning and memory function.
Following present invention specific embodiment materials and methods:
1. animal used in is purchased from this experimental animal Co., Ltd of Changzhou Cavan, is the grade C57BL/6 of health SPF
(C57) male mice.Aged Mice is 20~22 months, and weight is between 35~40g.
2.ELISA detects Serum Vitamin B12, folate content
Arterial blood serum sample use collected after 4 days, 8 days, 15 days, 29 days after the operation implementation of Aged Mice abdominal exploration
Elisa method carries out the assay of vitamin B12, folic acid.
Vitamin B12 detection: reacting on ELISA Plate, and the vitamin B12 in standard items and sample and PNPP substrate work
Liquid colour developing finally plus terminate liquid surveys OD value 450nm at, and Vitamin B12 concentration is directly proportional to OD value, can pass through drafting mark
Directrix curve finds out Vitamin B12 concentration in sample.
The detection of folic acid: double-antibody sandwich ABC-ELISA method is used.It is coated on ELISA Plate with anti-mouse folic acid monoclonal antibody,
Biotinylated anti-mouse folic acid is added in conjunction with monoclonal antibody in folic acid in standard items and sample, forms immune complex and is connected to
On plate, the aobvious blue of substrate working solution is added in conjunction with biotin in the Streptavidin of horseradish peroxidase-labeled, finally plus
Terminate liquid sulfuric acid surveys OD value at 450nm, and folic acid concentration is directly proportional to OD value, can be found out in sample by drawing standard curve
Folic acid concentration.Above-mentioned all reagents are purchased from Shanghai Xi Tang Biotechnology Co., Ltd.
3.POCD model
Operation mouse 2% (oxygen flow 1L/min) Isoflurane sucking induced anesthesia is given to be placed in after righting reflex loss
In heating plate, and fixing limbs.It is 1.2-1.4% (oxygen flow 1L/min) that isoflurane anesthesia, which maintains concentration,.Skin of abdomen is cleaned,
Disinfection prolongs the layering of abdomen median line and makees longitudinal direction 1.5-2cm notch, separates left and right rectus aabdominis, the small intestinal segment of exposure.With the sterile yarn of wetting
Cloth protects notch, and the small intestine of the same mesenteric artery loop blood supply range of 5cm is dissociated to outside abdominal incision, and with the nothing soaked
Bacterium gauze covers exposure intestinal segment.Every gauze afterturn intestinal segment 10min.After rubbing, intestinal segment is also received, layering suture abdominal incision,
Disinfection.4% Ropivacaine of notch locally injecting 0.1ml, and smear lidocaine ointment.Whole-process control perform the operation in 25-30min.
Smear lidocaine ointment analgesia in postoperative three days at abdominal incision daily.
4. behaviouristics detection method:
4.1 new object identifications:
1) adaptation process: experiment mice is put into empty behavior case, adapts it to 10min, trains afterwards for 24 hours；2) training
Process: being put into two identical objects in behavior case, mouse be put into, it is allowed to explore 10min in the case, records mouse to every
The exploration time of a object；3) test process: after 2h is completed in mouse training, one of object in behavior case is changed into new object
Body allows mouse to explore 5min, exploration time of the record mouse to new object and past heritage body in the case.
4.2 scene fear memories:
1) training process: mouse was placed in frightened case in first day and adapts it to environment.Mouse was put into second day identical
Frightened case tests its foundation motion state 120s, records the Freezing time, then (non-to one foot shock stimulation of mouse
Conditional stimulus continues 2s, 0.7mA) frightened scene training is carried out, totally 5 recycle；2) test process: in frightened environmental training
After for 24 hours, mouse is put into identical frightened case, its time for occurring Freezing behavior within a certain period of time, number is recorded, calculates
Freezing percentage.
4.3 Barnes labyrinths:
1) mouse: being placed in 3.5L glass beaker by training process on the 1st day, is placed in Barnes labyrinth center, opens white light
And white noise, so that mouse is adapted to environment 30s.Slowly mouse is directed in target hole with beaker, makes mouse only from target hole
It is escaped in cage from getting into.Mouse was placed in lighttight cylinder cover in 2nd day, buzzer is opened after 15s and removes cylinder simultaneously
Cover, allows exploration 3min of the mouse in labyrinth.Period puts it again in escaping cage to 1min if mouse, which reaches, escapes cage
Enter to store cage；If mouse does not reach and escapes cage, it is channeled to and is escaped in cage using first day method.The every wheel of every mouse
Training 5-7min amounts to 15 wheels (taking turns within the 1st day 3, the 2-4 days daily 4 wheels)；2) test process:, will be small after training terminates for 24 hours
Mouse is placed in lighttight cylinder cover, is placed in Barnes labyrinth center, opens buzzer, removes cylinder cover, allow mouse from
2min is explored in labyrinth by ground, records mouse time of residence time and its exploration hole in each quadrant.Use view
Frequency tracking software (Anymaze 5.0, the U.S., Stoeling company) records mouse heuristic process, and record mouse finds target hole
Time, number and time, number etc. for entering wrong hole.
Embodiment 1:
The embodiment vitamin B12 folic acid mixture compensation process:
Mouse grain: AIN93G standardizes mouse grain and (is purchased from OpenSource DietsTM, common quantity covers usual vitamin packet
Vitamin Mix10037, including vitamin B12 25 μ g/kg, folic acid 2mg/kg), vitamin B12 folic acid mixture supplements mouse grain
(it is purchased from OpenSource DietsTM, uses 5 multiple dose replenishing vitamins B12 and folic acid vitamin nutrition packet, including vitamin
B12 125 μ g/kg, folic acid 10mg/kg).
Control group (control) persistently feeds AIN93G standardization mouse grain and clean water, vitamin B12 folic acid mixture supplement
Group (Vitamin group) persistently feeds vitamin B12 folic acid mixture supplement mouse grain and clean water, implements POCD after supplement 14 days and makes
Mould.
Inventor detects old age and the young mice serum vitamin B12, folic acid of feeding standardization mouse grain with ELISA method
Content, the more young mouse of comparison display Aged Mice Serum Vitamin B12 content decline about 30% (Figure 1A), and folate content is constant
(Figure 1B) compares postoperative 14 days new object identifications, scene fear memories, spatial reference memory ability, Aged Mice cognitive behavior
The more young mouse of ability is impaired significant (Fig. 1 C, 1D and 1E).
Embodiment 2:
The embodiment is containing the effect after vitamin B12 and folic acid supplement and the influence to Aged Mice postoperative cognitive.
The entire perioperative serum vitamin B12 level of the Aged Mice of replenishing vitamins B12 and folic acid is significantly higher than control
Group (Fig. 2A), two groups of folate levels do not have notable difference (Fig. 2 B).
Aged Mice continuous supplementation vitamin B12 and folic acid two weeks, implement POCD modeling, and postoperative 14 days cognitive abilities are relatively marked
Standardization diet group significantly improves, such as new object identification ability (Fig. 2 C), scene fear memory ability (Fig. 2 D), georeferencing note
Recall ability (Fig. 2 E) performance to significantly improve.
The above results are shown by using vitamin B12 and folic acid mixture, and it is susceptible can be effectively improved old group POCD
State prevents POCD, and postoperative cognitive is accelerated to restore.
Embodiment 3:
Method: the embodiment prepares the mouse grain or normal control mouse grain that VB12 is individually supplemented containing 125 μ g/kg dosage, feeds
Row is performed the operation after eating 2 weeks, postoperative to continue to take different diet, until detection cognitive behavior, compares and individually supplements VB12, folic acid, or
Difference on effect of the compound supplement VB12+ folic acid Different Strategies supplement VB12 to prevention and treatment POCD.As a result as shown in figure 3, showing art
2 weeks 5 times of physiological dose vitamin B12s of preceding independent supplement or the individually mouse of 5 times of physiological dose folic acid of supplement, postoperative 14 days new
Barnes maze spatial memory capability (Fig. 2 C) significantly improves, but to scene fear memory (Fig. 2 B) and new object identification ability
(Fig. 2A) does not have improvement result.
Claims (12)
1. vitamin B12 is used to prepare prevention and/or treats the application of Postoperative Cognitive Dysfunction drug.
2. application as described in claim 1, which is characterized in that the vitamin B12 is by vitamin B12 derivative or vitamin
The replacement of B12 pharmaceutically acceptable salt.
3. application as described in claim 1, which is characterized in that the day dosage of the vitamin B12 is greater than 5 times of routine
Standardize the dosage of diet replenishing vitamins.
4. the application that vitamin B12 folic acid mixture is used to prevent or/and treat Postoperative Cognitive Dysfunction drug.
5. application as claimed in claim 4, which is characterized in that the day dosage of the vitamin B12 is greater than 5 times of routine
Standardization supplement dietary vitamins supplement dosage, and the day dosage of the folic acid is greater than 5 times of conventional normalised supplement diet
Folic acid supplement amount.
6. application as claimed in claim 4, which is characterized in that the day dosage of the vitamin B12 is 12 μ g~2mg,
The day dosage of the folic acid is 2mg~20mg.
7. application as claimed in claim 4, which is characterized in that the vitamin B12 is by vitamin B12 derivative or vitamin
The replacement of B12 pharmaceutically acceptable salt.
8. application as claimed in claim 4, which is characterized in that the folic acid is replaced by folic acid pharmaceutically acceptable salt.
9. a kind of drug for treating POCD, which is characterized in that the drug is made of vitamin B12 and folic acid.
10. as claimed in claim 9 treatment POCD drug, which is characterized in that the pharmaceutical dosage form be injection, tablet,
Capsule, dispersing agent, speed collapse dosage form, effervescent tablet preparation formulation, ointment dosage form, gel preparations or transdermal slow-release agent dosage form.
11. the drug for the treatment of POCD as claimed in claim 9, which is characterized in that the vitamin B12 is spread out by vitamin B12
Biology or the replacement of vitamin B12 pharmaceutically acceptable salt.
12. the drug for the treatment of POCD as claimed in claim 9, which is characterized in that the folic acid is pharmaceutically acceptable by folic acid
Salt replacement.
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| CN201810600765.7A CN108992458A (en) | 2018-06-12 | 2018-06-12 | Vitamin B12 is used to prepare prevention and/or treats the application of Postoperative Cognitive Dysfunction drug |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590040A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The composition and use thereof that contains indopamide and vitamin B group |
| CN103118743A (en) * | 2010-07-01 | 2013-05-22 | Isis创新有限公司 | Treatment of cognitive disorders |
| CN105476997A (en) * | 2009-07-10 | 2016-04-13 | 林齐·O·斯科特三世 | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
| CN110339204A (en) * | 2018-04-04 | 2019-10-18 | 北京斯利安药业有限公司 | A kind of composition containing folic acid and its preparing the application in cerebral apoplexy drug |
-
2018
- 2018-06-12 CN CN201810600765.7A patent/CN108992458A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590040A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The composition and use thereof that contains indopamide and vitamin B group |
| CN105476997A (en) * | 2009-07-10 | 2016-04-13 | 林齐·O·斯科特三世 | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
| CN103118743A (en) * | 2010-07-01 | 2013-05-22 | Isis创新有限公司 | Treatment of cognitive disorders |
| CN110339204A (en) * | 2018-04-04 | 2019-10-18 | 北京斯利安药业有限公司 | A kind of composition containing folic acid and its preparing the application in cerebral apoplexy drug |
Non-Patent Citations (4)
| Title |
|---|
| ELVIRA BISBE ET AL: "Prevalence of preoperative anemia and hematinic deficiencies in patients scheduled for elective major orthopedic surgery", 《TRANSFUSION ALTERNATIVES IN TRANSFUSION MEDICINE》 * |
| 张春英: "甲基维生素B12对反复前脑缺血再灌注大鼠学习、记忆功能的影响", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 石伟发等: "快速康复外科下全髋关节置换术围术期血液管理研究进展", 《中国当代医药》 * |
| 黄国伟等: "叶酸、维生素B6、B12对脑缺血大鼠学习记忆的影响", 《中华预防医学杂志》 * |
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Application publication date: 20181214 |