CN105168201B - Application of the Vitexin in pain medication after preparing iatrotechnics - Google Patents
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Abstract
The present invention relates to pharmaceutical technology field, and in particular to application of the Vitexin in pain medication after preparing iatrotechnics.The pharmaceutical preparation of the present invention is generally used in intraperitoneal injection mode, naturally it is also possible to use other administering modes：(single) acute after modeling administration consumption is 1~10mg/kg, and chronic (repeated multiple times) administration consumption is 3~10mg/kg.The pharmaceutical preparation acute administration and chronic administration of the present invention can effectively mitigate postoperative pain, without calm side effect and tolerance and additive generation be not observed.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to application of the Vitexin in pain medication after preparing iatrotechnics.
Background technology
Pain is a kind of tissue damage or potential tissue damage related unhappy sensation and emotional experience.It is slow according to onset
It is anxious to be categorized as Acute Pain and chronic ache with course of disease length.Postoperative pain (postoperative pain) belongs to acute pain
Bitterly (course of disease is generally less than 6 weeks), be body to disease in itself and a kind of complicated physiological reaction of tissue damage for causing of operation
(Zhang Chuanhan Clinical Pains treatment guidelines [M] Beijing：China Medical Science Press, 2008：502).Postoperative pain is at present
Clinically a stubborn problem, if Acute postoperative pain processing is not good at, can cause a series of adverse consequences, for example, can cause
The chance of chronic ache, increase infection of incisional wound and respiratory tract and cardiovascular complication, postpones discharge time, reduces minimal invasive treatment
Quality, even results in physical disabilities, the increase incidence of disease and case fatality rate etc. (Argoff CE.Recent management
advances in acute postoperative pain[J].Pain Pract,2014,14(5):477-87.).Although right
The pathomechanism of postoperative pain and treatment deepen continuously research, and new analgesic and technology sequential use are in clinic, various countries
Also a variety of postoperative pain administration guides have all been formulated, but postoperative pain is still within insufficient therapy state at present.It is beautiful
The national survey of state shows, about 80% patient experience Post operation Acute Pain, and 39% has severe to extreme pain
(Apfelbaum JL,Chen C,Mehta SSet al.Postoperative pain experience:results from
a national survey suggest postoperative pain continues to be undermanaged[J]
.Anesth Analg,2003,97(2):534-40.).Currently used for treatment postoperative pain common drug mainly have opiates,
NSAIDs (NSAIDs), antianxiety and the adjuvant such as anticonvulsion, and local anesthetic etc..But these medicines usually by
Limited there are effect or security to make its clinical value discount in its.Such as opioid drug is currently clinically
Maximally effective analgesic, but the side effect such as its respiration inhibition, nausea and vomiting, constipation and tolerance and additive face it
Bed application is restricted.NSAIDs only has moderate analgesic effect, and can produce peptic ulcer, heart function and renal function
Side effect (the Argoff CE.Recent management advances in acute postoperative pain such as infringement
[J].Pain Pract,2014,14(5):477-87.).Therefore also need to further to find new good effect, Small side effects and
Medicine without tolerance with addicted treatment postoperative pain.
Vitexin (vitexin, No. CAS：3681-93-4, chemical entitled 8- β-D-glucopyranosyl-5,7-
Dihydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one), also known as Vitexina, it is a kind of natural plant
Thing flavone c-glycosides, are extraction in rosaceous plant hawthorn (Crateagus pinnatifida) dry mature fruit
One of the principle active component of general flavone, be also widely present in other plant, such as Vitex negundo var cannabifolia, pigeonpea, mung bean, the leaf of bamboo, lily feet
Flower, passionflower etc..Its chemical name is 8- β-D- glucopyanosyls -4', 7- dihydroxy isoflavones, and molecular formula is C21H20O10, phase
To molecular mass 432.4, molecular structure See Figure.Modern pharmacology research proves that Vitexin has anti-infarction, drop blood
The multiple pharmacological effect such as pressure, anti-inflammatory analgesic, antibacterial, antiviral, anti-oxidant, antitumor, antithyroid, spasmolysis.(Gu Chengbo, Cai
It is graceful, the plant resources and Advance on Pharmacological Activities [J] CHINA JOURNAL OF CHINESE MATERIA MEDICAs of the Vitexinas such as Yuan Xiaohan, 2015 (03):382-
89.)
Vitexin chemical structural formula
The research on Vitexin analgesic activity reports and few that only 2 foreign language literatures clearly indicate that Vitexin at present
There is certain analgesic activity as only monomer compound.(Demir OU, the Can OD.Anti-nociceptive such as Demir
effect of vitexin mediated by the opioid system in mice[J].Pharmacol Biochem
Behav,2013,109:23-30.) research show, Vitexin can mitigate healthy mice be subjected to heat injury, mechanical wounding and
The analgesic effect of physiological reaction during chemical noxious stimulus.Author is caused using hot plate stimulation mouse foot licks sufficient reaction, rat-tail
Piercing swashs whipping reaction caused by mouse tail, and acetic acid intraperitoneal injection causes mouse writhing three kinds of models of reaction male to show
Jing Su has lenitive effect.These three animal models are all normal physiological pain shapes when simulating acute injury sexual stimulus
State, with clear and definite pain transduction mechanism, this is dramatically different with postoperative pain.Postoperative pain pain simulation rest pain shape
State, may relate to the mechanism such as inflammatory reaction, periphery nociceptor sensitization and central sensitization, but specific mechanism is still not
Clearly.Such as dopamine-receptor antagonist haloperole or kappa opioid receptor activator U69593 can be to three of the above models
With anti-pain Injury death, but it is invalid antalgesic but to be confirmed in clinic.So this article can not be confirmed
Under surgical condition, Vitexin can mitigate postoperative pathologic hyperalgia.
(Borghi SM, Carvalho TT, the Staurengo-Ferrari L et al.Vitexin such as other Borghi
inhibits inflammatory pain in mice by targeting TRPV1,oxidative stress,and
cytokines[J].J Nat Prod,2013,76(6):1141-49.) research shows that Vitexin is for capsaicine, formal
The inflammatory pain that woods, carrageenan and complete Freund's adjuvant induce is respectively provided with mitigation.But inflammatory pain belongs to chronic pain
Bitterly, its cause of disease, pain feature and pathogenesis are different from postoperative pain, clinically some medicines such as glucocorticoids
Medicine metacortandracin, dexamethasone etc. are effective for inflammatory pain, but invalid to acute sharp pain, postoperative pain.So also not
It can be shown that Vitexin can treat postoperative pain.Do not find in addition yet and prepare the correlation of analgesic application specially on Vitexin
Profit.Therefore, the available data Vitexin that can not all be unequivocally established can apply to the treatment of postoperative pain as sole active agent.
The content of the invention
In order to solve current postoperative pain still insufficient therapy, the validity of its medicine is low, erious adverse reaction or have
Tolerance and addicted problem, are specifically to ache after iatrotechnics is prepared the invention provides the new clinical application of Vitexin
Application in pain medicine.
A kind of application the invention provides Vitexin as sole active agent in pain medication after preparing iatrotechnics.
Specifically, in mouse metapedes otch postoperative pain model, no matter single-dose or repeated multiple times administration, Vitexin all show
Excellent analgesic activity is shown, and produced without obvious calm side effect and tolerance.
Technical scheme is as follows：
Application of the Vitexin in pain medication after preparing iatrotechnics, wherein Vitexin are that sole active agent is used to prepare
The pharmaceutical preparation of postoperative pain.
Application of the Vitexin of the present invention in pain medication after preparing iatrotechnics, specifically Vitexin can be alleviated
Or mitigate postoperative pain.
Vitexin of the present invention can be obtained by commercially available mode.
" postoperative pain " of the present invention, be body to disease in itself and one kind of tissue damage for causing of operation is complicated
Pathologic-physiological reaction, show as in psychology and behavior a kind of sour experience (Zhang Chuanhan in series reaction and emotion
Clinical Pain treatment guidelines [M] Beijing：China Medical Science Press, 2008：502).
" postoperative pain " of the present invention, including post-surgical incisions pain, primary disease tract pain etc..
Mouse metapedes otch postoperative pain animal model of the present invention is generally received to be representational in the world
Model (Pogatzki EM, Raja the SN.A mouse model of incisional pain [J] of postoperative pain
.Anesthesiology,2003,99(4):1023-27.)。
The present invention also uses the compound close with Vitexin structure, and such as isovitexin etc carries out same experiment,
Experimental result finds that it does not have postoperative analgesia.
Pharmaceutical preparation of the present invention is to be prepared into medical science pharmacy to commonly use agent using this area customary preparation methods
Type.
Described pharmaceutical preparation is decoction, granule, tablet, pill or liquid preparation etc., and one in the present invention is excellent
Select in embodiment, be its liquid preparation such as injection, mixed suspension preparation etc..
Pharmaceutically acceptable carrier is also added into described pharmaceutical preparation.
The pharmaceutical preparation of the present invention is generally used in intraperitoneal injection mode, naturally it is also possible to use other administering modes：Make
(single) acute after mould administration consumption is 1~10mg/kg (preferably 1,3,5.5,10mg/kg), chronic administration (repeated multiple times), medicine
Consumption is 3~10mg/kg of administration (preferably 3,5.5,10mg/kg) every time, is administered once a day.
The pharmaceutical preparation acute administration and chronic administration of the present invention can effectively mitigate postoperative pain, no calm secondary work
With and be not observed tolerance and additive generation.
Brief description of the drawings
Under the premise of Fig. 1 is the foundation of mouse incision pain model, non-administration, incision pain model (Model) mouse and just
The often change of control (Control) mouse postoperative pain threshold value；
Fig. 2 is the experiment of Vitexin calming effects, calming effects of the Vitexin (3~20mg/kg) to normal mouse；
Fig. 3 is influence of 1~10mg/kg of Vitexin single-doses to incision pain model mice mechanical pain threshold, male
The change of incision pain model mice mechanical pain threshold after Jing Su (1~10mg/kg) acute (single) administrations；
Fig. 4 is shadow of Vitexin (3~10mg/kg) the repeated multiple times administration to incision pain model mice mechanical pain threshold
Ring；The change of incision pain model mice mechanical pain threshold after chronic (repeated multiple times) administration of Vitexin (3~10mg/kg)；
Embodiment
The implementation of the present invention is elaborated with reference to embodiments of the invention and accompanying drawing, following examples be with
It is lower premised on technical solution of the present invention to be implemented, detailed embodiment is given, but protection scope of the present invention is not limited to
Following embodiments.
Vitexin used in following examples, is detected through HPLC, purity>98%, purchased from Aladdin company.
The foundation of the mouse incision pain model of embodiment 1
Assay method：
The method for building up of mouse incision pain model is with reference to (Pogatzki EM, Raja SN.A mouse model of
incisional pain[J].Anesthesiology,2003,99(4):1023-27.Sahbaie P,Sun Y,Liang DY
et al.Curcumin treatment attenuates pain and enhances functional recovery
after incision[J].Anesth Analg,2014,118(6):1336-44.), specific method for building up：Using Anesthesia machine,
Mouse puts on anaesthetic mask with after 3% isoflurane induced anesthesia, maintains to anaesthetize with 1.5% isoflurane, fixation of lying on the back, mouse is right
Metapedes is carried out after aseptic process using 75% alcohol, to direction of toe of last, is drawn from close at heel 0.2cm with No. 11 knife blades
Skin is opened, makees the longitudinal cut of 0.5cm length, manadesma is chosen, and is scratched in manadesma center longitudinal direction.After light pressure hemostasis, with single 6
Number nylon wire sutures a pin at otch midpoint position, then puts back to animal in cage, treats that its is revived.Control group mice receives anesthesia
With aseptic process, but incision surgery is not done, carry out mechanical pain threshold measure together with model group after reviving.Mechanical pain threshold is surveyed
Method is determined with reference to (Pogatzki EM, Raja SN.A mouse model of incisional pain [J]
.Anesthesiology,2003,99(4):1023-27.) be specially：Measured and be set with using Von-Frey filaments
(Stoelting Co., Ltds, the U.S.), measurement operation side (right side) rear solid end is under a series of stimulation of Von-Frey filaments
Paw withdrawal threshold value (Paw withdrawal threshold, PWT) be used as its mechanical pain threshold, when observation each group mouse is different
Between put mechanical allodynia change.Mouse is individually placed in the lucite grid on metallic sieve, adapts to environment
It is continuous to adapt to 3 days to quiet, and operation consent determines the preoperative basic PWT of each group mouse for 1 day 3 times, based on averaging
Value.And 2h and then every 24h an art side mouse PWT is determined after surgery, until its recovery is to operation consent basic value water
It is flat, then stop measurement.It is measured using the Von-Frey filaments of 7 kinds of intensity, bending dynamics (etc. is increased according to about logarithmic
Imitate in 0.07,0.16,0.4,0.6,1.0,1.4,2.0g), during measurement, mouse is individually placed in organic glass on metallic sieve
In glass grid, environment is adapted at least 15 minutes, Von-Frey filaments are vertical to stimulate the pawl bottom of mouse right hind since 0.07g
(using the slightly bent standard as complete stress of Von-Frey filaments), the duration≤4s, observes the reaction of mouse, if contracting
Pawl, pawl is got rid of, the phenomenons such as pawl is licked and is considered as positive reaction, being otherwise feminine gender.The equal METHOD FOR CONTINUOUS DETERMINATION of fiber filaments of each intensity 3 times, 3 times
In be considered as PWT if having the reaction of 2 times or more than 2 times.With adjacent big first order force if occurring without the positive reaction of at least 2 times
Degree is stimulated.Maximum dynamics is 2g, and 2g is still designated as during more than this value.Minimum dynamics is designated as 0.07g, the lower explanation machinery pains of PWT
It is quick more serious.
Animal packet：Male ICR mouse 24, control group (Control) 12, model group (Model) 12.
Performed the operation according to foregoing " assay method ", then carry out mechanical pain threshold and determine.As a result such as Fig. 1.Operation consent is (i.e.
Shown in Pre in figure), between control mice group and model group rear solid end mechanical pain threshold (PWT) without notable difference (1.42 ±
0.06g vs 1.28±0.09g,P>0.05).The PWT of Post operation 2h model group mouse is substantially reduced, and is then gradually recovered,
Return to preoperative level within 5th day.With dual factors duplicate measurements variance analysis, intraoperative factors (F [1,22]=79.49, P<
0.0001), time factor (F [6,132]=14.62, P<0.0001) and the time × operation interaction (F [6,132]=
26.09,P<0.0001) there is conspicuousness statistical significance.Compare between group using Bonferroni post hoc analyses, model
2h to the 4 days period after surgery is organized, the PWT of mouse is compared with control group has significant difference (with control group Control phases
Than * P<0.05).During experiment, blank control group is measured with von Frey filaments repeatedly, but the pain threshold of mouse claw
It is held at foundation level (Fig. 1 is represented with gray filled circle).This explanation incision model mouse 2h to 4 days time after surgery
Mechanical pain threshold is decreased obviously in section, is indicated significant mechanical hyperalgesia, is then recovered to preoperative foundation level.
The Vitexin calming effects of embodiment 2 are tested
Autonomic activities method of testing is with reference to (Zhu Q, Sun, YH；Yun XD et al.Antinociceptive
effects of curcumin in a rat model of postoperative pain,Scientific Reports,
2014,4:4932), it is specially：Using big mouse autonomic activities tester (YLS-1B, Jinan Yan Yi Science and Technology Ltd.s, in
State), instrument includes a control unit and 4 cylindrical black plastic camera bellows (diameter 30cm, height 30cm), and mouse is put into
Black plastic is secretly interior, and optical sensor is located at the centre of case lid, for recording mouse autonomic activities number of times.Record in 60min
Mouse autonomic activities number of times.
Animal packet：Male ICR mouse 48；It is divided into 4 groups, i.e. Normal group and Vitexin 3mg/kg, 10mg/kg,
Tri- dosage groups of 20mg/kg, every group 12.Normal group gives physiological saline, and Vitexin is injected intraperitoneally in remaining group respectively
After 3mg/kg, 10mg/kg, 20mg/kg (using normal saline, administration volume is 10ml/kg), seen according to foregoing assay method
Examine autonomic activities in its 1h.
Statistical method, which is used, to be compared between one-way analysis of variance, group using Student-Newman-Keuls post hoc
Analysis, display 20mg/kg groups ambulatory activity count compared with Normal group is substantially reduced, with significant difference (with compareing
Group Control is compared, * P<0.05), with certain calming effects.And 3mg/kg, 10mg/kg dosage group and Normal group phase
Than no notable difference, illustrate there is no sedation (such as Fig. 2) under the two dosage.
Because 20mg/kg has obvious calming effects, so we are selected under 1,3,5.5,10mg/kg tetra- dosage progress
Face acute administration analgesic experiment.
Influence of 1~10mg/kg of the Vitexin acute administrations of embodiment 3 to incision pain model mice mechanical pain threshold
Animal packet：ICR mouse 60, are divided into 5 groups；That is excipient group (CMC-Na for giving 0.5%) 12；Vitexin
1,3,5.5,10mg/kg tetra- dosage group, every group 12 (notes：Using intraperitoneal injection, Vitexin by 0.5% CMC-Na
Configuration).
Each group mouse all carries out incision surgeries, and operation method is with foregoing, and postoperative 24h first tests each group PWT baseline value
(now not yet be administered), treats that basic threshold test terminates, pain threshold such as occur substantially reduces, then intraperitoneal injection immediately, and
In testing a PWT at interval of 30min after administration, until pain threshold recovers postoperative baseline value.Determine pain threshold method same
It is foregoing.As a result as shown in figure 3, Post operation 24h, determines mechanicalness threshold of pain baseline value (being represented with 0min), then before administration
Respectively at 30 after administration, 60,90,120,150,180,210,240min determine its mechanical pain threshold (PWT).As a result find,
The Vitexin of 3-10mg/kg dosage can dose-dependently increase the pain threshold of Post operation mouse.Excipient group (Post operation abdomen
The CMC-Na of chamber injection 0.5%) in the 4h during testing, the pain threshold of duplicate measurements is held at floor level (in Fig. 3
Gray circles).And Vitexin administration group mouse PWT gradually rises over time upon administration, maximum is reached in 90min,
Then gradually reduce, pain threshold returns to preoperative level after administration 4h.With dual factors duplicate measurements variance analysis, medicine
Factor (F [4,55]=3.31, P<0.05), time factor (F [8,440]=28.54) and medicine × when interphase interaction (F
[32,440]=2.66, P<0.0001) there is conspicuousness statistical significance.Compare between group using Bonferroni post hoc
Analysis, the pain threshold of postoperative mouse can substantially be increased when 90min is administered by learning the Vitexin of 3mg/kg and 5.5mg/kg dosage
Value, and 10mg/kg Vitexin upon administration 60 to 150min have significantly act on (P<0.05).1mg/kg Vitexins are to mould
Type mouse does not have pain of alleviation effect.It is all to be represented with the data point of filled black in Fig. 3, have compared with excipient group
Statistical significance (P<0.05).This shows that acute administration Vitex negundo var cannabifolia extract for treating can dose-dependently improve the machinery in this model
Property hyperalgia.
Influence of 3~10mg/kg of the Vitexin chronic administrations of embodiment 4 to incision pain model mice mechanical pain threshold
Because 1mg/kg Vitexin does not have obvious analgesic effect, we are in research Vitexin repeat administration to small
In the experiment of mouse incision pain effect, three dosage in selection 3-10mg/kg are tested.Animal packet：ICR mouse 48,
It is divided into 4 groups；That is excipient group (CMC-Na for giving 0.5%) 12；Vitexin 3,5.5, tri- dosage groups of 10mg/kg, every group
12 (notes：Using intraperitoneal injection, Vitexin is configured by 0.5% CMC-Na).Each group mouse all carries out incision surgery,
Operation method is with foregoing.Pain threshold is determined in postoperative 2h, is then administered, is administered once a day, successive administration 6 in postoperative 24h
My god.Pain threshold is determined in 90min after daily administration, pain threshold method is determined the same.As a result as shown in figure 4, giving daily
Vitexin can dose-dependently improve mechanical hyperalgesia caused by incision surgery.With dual factors duplicate measurements variance analysis,
Drug factors (F [3,36]=3.56, P<0.05), time factor (F [6,216]=39.94, P<0.0001) and medicine × when
Interphase interaction (F [18,216]=2.20, P<0.01) there is conspicuousness statistical significance.Compare between group and use Bonferroni
Post hoc are analyzed, and 3mg/kg or 5.5mg/kg Vitexin can significantly improve the pain threshold of claw in first day after surgery,
And the Vitexin of 10mg/kg dosage can significantly reduce the mechanical hyperalgesia (P of mouse in 1-3 days after surgery<0.05).Figure
It is all to be represented with the data point of filled black in 4, with statistical significance (P compared with excipient group<0.05).This shows
Daily administration Vitex negundo var cannabifolia extract for treating can dose-dependently alleviate the mechanical hyperalgesia in this model, and not produce tolerance
Property.
Unexpected drug withdrawal is carried out after long term administration experiment is finished, does not observe that mouse has any abnormal drug withdrawal for three days on end
Reaction, illustrates it without additive.
Above-described embodiment is not limited for the present invention preferably embodiment, but embodiments of the present invention by above-described embodiment
System.The deformation made under other any spirit and principle for not departing from the present invention, is considered as protection scope of the present invention.
Claims (7)
1. application of the Vitexin in pain medication after preparing iatrotechnics, described postoperative pain is post-surgical incisions pain.
2. application of the Vitexin according to claim 1 in pain medication after preparing iatrotechnics, it is characterised in that described
Medicine be that sole active agent is used as using Vitexin.
3. application of the Vitexin according to claim 1 or 2 in pain medication after preparing iatrotechnics, it is characterised in that
Described medicine is common drug preparation in medical science pharmacy.
4. application of the Vitexin according to claim 3 in pain medication after preparing iatrotechnics, it is characterised in that described
Pharmaceutical preparation be decoction, granule, tablet, pill, injection or mixed suspension preparation.
5. application of the Vitexin according to claim 3 in pain medication after preparing iatrotechnics, it is characterised in that described
Pharmaceutical preparation in be also added into pharmaceutically acceptable carrier.
6. application of the Vitexin according to claim 3 in pain medication after preparing iatrotechnics, it is characterised in that described
The administering mode of pharmaceutical preparation be：Acute single-dose consumption is 1~10mg/kg after modeling；Or it is chronic repeatedly many after modeling
Secondary administration, survival dose is 3~10mg/kg of administration every time, is administered once a day.
7. application of the Vitexin according to claim 3 in pain medication after preparing iatrotechnics, it is characterised in that described
The administering mode of pharmaceutical preparation be：Acute single-dose consumption is 1,3,5.5 or 10mg/kg after modeling；Or it is chronic after modeling
Repeated multiple times administration, survival dose is 3,5.5 or 10mg/kg of administration every time, is administered once a day.
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Citations (2)
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|---|---|---|---|---|
| CN102743373A (en) * | 2011-04-22 | 2012-10-24 | 中国人民解放军第二军医大学 | Application of Casticin in medicine preparation for analgesia |
| CN103415286A (en) * | 2010-11-11 | 2013-11-27 | 阿克伦分子有限公司 | Compounds and methods for treating pain |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103415286A (en) * | 2010-11-11 | 2013-11-27 | 阿克伦分子有限公司 | Compounds and methods for treating pain |
| CN102743373A (en) * | 2011-04-22 | 2012-10-24 | 中国人民解放军第二军医大学 | Application of Casticin in medicine preparation for analgesia |
Non-Patent Citations (2)
| Title |
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| anti-nociceptive effect of vitexin mediated by the opioid system in mice;Umide Demir Ozkay等;《Pharmacology, Biochemistry and Behavior》;20130430;第109卷;23-30 * |
| Vitexin inhibits inflammatroy pain in mice by targeting trpv1, oxidative stress, and cytokines;Borghi SM等;《Journal of natural products》;20130630;第76卷(第6期);1141-1149 * |
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