CN105030799A - Application of stilbene glycoside to preparing analgesic medicine - Google Patents
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- CN105030799A CN105030799A CN201510408205.8A CN201510408205A CN105030799A CN 105030799 A CN105030799 A CN 105030799A CN 201510408205 A CN201510408205 A CN 201510408205A CN 105030799 A CN105030799 A CN 105030799A
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Abstract
The invention discloses novel application of stilbene glycoside to the field of analgesic medicine, and particularly discloses application of stilbene glycoside to preparing medicine for enhancing analgesic effects of opioid medicine and delaying or relieving opioid tolerance. The application has the advantages that the stilbene glycoside is used with the opioid medicine, or compound preparations are made of the stilbene glycoside and the opioid medicine, so that the analgesic time can be prolonged, the analgesic efficacy can be enhanced, and opioid tolerance during chronic opioid medicine treatment procedures can be delayed or relieved; excessive activation of spinal glial cells induced by the opioid medicine is particularly suppressed by the stilbene glycoside, so that effects can be realized.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the novelty teabag of stilbene glucoside in analgesic field, be specifically related to strengthen opioid drug analgesic effect in preparation, delay or alleviate the purposes in the medicine of opiate tolerance.
Background technology
Pain is a kind of Physiological Psychology activity of complexity, comprise noxious stimulation and act on pain caused by body and feel, and body reacts the pain of noxious stimulation.The pain sensation can be used as the one warning that body comes to harm, and causes the protective reaction of body series of defence, but some acute or long-term having an intense pain, be a kind of insufferable torment to body.Pain is one of modal symptom clinically, is also medical personnel's major issue in the urgent need to address.
Pain, with regard to the course of disease, can be divided into acute pain and chronic pain.Acute pain is recently produce the pain that also persistent period is shorter, usually relevant with damage or disease.Chronic pain for continuing the pain of long period, may be then that acute pain therapeutic effect is bad, or the pain of still sustainable existence after wound healing, and patient often changes with the psychiatric such as anxiety, depression.No matter be acute pain or chronic pain, be far from being met to the demand of Pain management clinically.
Opium kind analgesics mainly comprises morphine, fentanyl, codeine, hydromorphone, oxycodone, methadone, Pethidine and tramadol etc.Opioid has powerful analgesic effect, is widely used in the treatment of pain, such as postoperative acute pain, neuropathic pain and cancer pain etc.Opioid drug plays analgesic activity common mechanism of action, namely mainly through acting on the specific opiate receptor in nervous system, reducing the irritability of pain sensation transmission unit and playing powerful analgesic activity.
Opioid drug is in treatment always, the choice drug of severe acute pain, in acute analgesia process, the use of opioid drug is many along with multiple untoward reaction, as nausea and vomiting, calm drowsiness, respiration inhibition, constipation, acute poisoning, addiction, dependence etc., wherein respiration inhibition is the most dangerous complication that opioid drug uses, and constipation is then the most reluctant a kind of untoward reaction that the patient of nearly all use opium analgesics may run into.These untoward reaction seriously limit opioid drug widely using as excellent analgesic.Mostly these untoward reaction are what opioid analgesics dosage was correlated with, balance, often need to sacrifice analgesia drug effect to alleviate untoward reaction between the reluctant untoward reaction needing the effective dose required for easing pain in ideal and this dosage to bring clinically.Clinical route of administration or the dosage form of also changing, as sublingual lozenge, transdermal patch etc. solve the problems referred to above, but effect unsatisfactory.If a kind of medicine can be had, the acute analgesic effect of opioid drug can be strengthened, extend the analgesia time of opioid drug, can reduce " accumulated dose " that need when opioid drug controls acute analgesia, so this medicine will contribute to the application of opioid drug in acute pain treatment very much.
Opioid drug is in treatment equally, the choice drug of severe chronic pain, especially chronic cancer pain, in this type pain therapy, except above-mentioned some untoward reaction, a major issue affecting opioid drug clinical practice is also had to be " opiate tolerance ".When opiate tolerance refers to that take opioid drug reaches more than doses (every daily amount is at least oral Morphine 50mg, oxycodone 30mg, hydromorphone 8mg, oxymorphone 25mg, fentanyl patch 25 μ g/h or other equivalent medicines) at least 1 week on time, the analgesic effect of opioid drug lowers, show as analgesic activity after continuing to give opioid drug to weaken gradually and even disappear, need increase opioid dose and could rebuild equal analgesic effect, namely the amount effect curve of medicine moves to right presented clinical picture.Increase the analgesic effect that opium drug dose rebuilds medicine, mean the more unmanageable untoward reaction that client need bears more high dose opium kind analgesics and brings.Equally, not having clinically to eliminate opiate tolerance, is even only the treatment means alleviating or delay opiate tolerance generation, and this is the problem being badly in need of clinically solving, and seriously limits the application of the powerful analgesic activity of opioid drug.
Large quantifier elimination and standard literature display, give morphine, fentanyl, hydrogen examines the multiple opioid drugs such as ketone, while it to be combined with opiate receptor and to play powerful analgesic activity, opioid drug can also cause central nervous system, and especially the microglia of spinal levels significantly activates.Although opioid drug causes the mechanism of microglia to be illustrated not yet completely, but academia has demonstrated the mechanism that at least existence two kinds is different: one is that opioid drug can depend on neuronic mechanism activation microglia by multiple, the nitric oxide synthetase in neuron can be activated as opioid drug, caused the microglial activation closed on by synthesis release nitric oxide; Another is that opioid drug directly by acting on opiate receptor on microglia or TLR receptor, directly can activate microglia.The microglia of activation discharges a large amount of inflammatory factors, as IL-1 β, TNF-α, many active substances such as IL-6, act on receptor or the signal path of its correspondence respectively, stimulate the more glial cell of activation on the one hand, form positive feedback, another one aspect, these active substances of microglia release, can cause neuronal excitability to strengthen by excited pain pathways related Neurons, cause pain sensation sensitization, counteract the analgesic activity of opioid drug greatly and then affect the lasting performance of its analgesic effect, or facilitating the generation of tolerance phenomenon.In this process, MAPK signal path, comprises ERK, and P38, c-JNK, ERK5 may play an important role.Research shows, the MAPK activation of opioid drug induction, shows the selectivity of obvious cell type in spinal cord.The P38 that chronic opioid drug process causes significantly activates and is mainly manifested in spinal cord microglia, and then cause synthesis and the release of multiple proinflammatory factor, weaken the analgesic effect of opioid drug, and the p-ERK activation of opiates induction shows relatively weak cell type selectivity, the activation of p-ERK all can be observed in neuron, microglia, neurogliocyte.In fact, have animal to show in spinal levels in body research, the synthesis of the microglia overactivity that blocking-up opium is induced and the inflammation factor and release, block the generation that overactive p-P38 can delay even to cancel chronic opiate tolerance.But, mostly the result of these intervention studies is to apply the laboratory tool realization without clinical development potentiality, these links can only be pointed out to be critical link to opiate tolerance, with regard to intervention means, not have the potentiality of exploitation or extensive use.
Similar by the drug-induced activation of opium with chronic opiate tolerance No microglial, also have in bibliographical information acute opioid drug analgesia process, also there is opium induction microglia overactivity phenomenon, and the acute analgesic effect having report to show to give in sheath minocycline (a kind of inhibitor of Activated Microglia) opioid drug can be strengthened.
Stilbene glucoside (2,3,5,4 '-tetrahydroxystilbene-2-O-β-D glucosides; Tetrahydroxystilbeneglyeoside, TSG) be primary water-soluble composition in Radix Polygoni Multiflori.Radix Polygoni Multiflori has effect of removing toxic substances, eliminating carbuncle, preventing the attack (or recurrence) of malaria, loosening bowel to relieve constipation; Can be used for treatment carbuncle sore, scrofula, rubella pruritus, chronic malaria body void, dryness of the intestine constipation etc.Pharmacodynamic study result shows, stilbene glucoside (TSG) has antioxidation, effect of scavenging radical, has certain protective effect to the HaCaT cell oxidative damage of mouse experiment colitis and long wave ultraviolet induction.In addition, stilbene glucoside (TSG) also has good antitumor, blood fat reducing, study of anti-atherogenic effect, the liver protecting, vasodilator, defying age and prevents and treats the effects such as alzheimer disease.
Not yet there is the report about being used for by stilbene glucoside strengthening in the medicine of opioid drug analgesic effect in currently available technology, also not having and delaying or alleviate the report in the medicine of opiate tolerance about being used for by stilbene glucoside.The Activated Microglia that can stilbene glucoside suppress opioid drug to be induced equally thus play the analgesia of its opium and strengthen and to delay or to alleviate opiate tolerance effect still unknown.
Summary of the invention
The object of this invention is to provide the novelty teabag of stilbene glucoside in analgesic field: by stilbene glucoside for the preparation of strengthening opioid drug analgesic effect, delaying or alleviate in the medicine of opiate tolerance phenomenon of opioid drug.
Inventor has carried out large quantifier elimination to stilbene glucoside to pathological pain analgesic activity and mechanism, find the expression of the COX-2 albumen that stilbene glucoside can suppress LPS to induce significantly and mRNA, and COX-1 is not affected, and stilbene glucoside can directly suppress COX-2 enzymatic activity, show that THSG suppresses the rising of the PGE2 of LPS induction may be relevant with suppression COX-2 gene expression, also may with directly suppress COX-2 enzymatic activity relevant.Mtt assay detects TSG does not have obvious effect to cell survival rate 100 μMs time, and cell survival rate is greater than 90%, shows that TSG does not have toxicity to cell, is very safe.Stilbene glucoside can suppress the inflammatory reaction caused by dimethylbenzene, carrageenin etc. simultaneously, and has certain analgesic activity.
Inventor reaches a conclusion: the acute or chronic process of opioid drug can induce Activated Microglia, this plays crucial effect in the acute analgesic effect of opioid drug and chronic tolerance course, and stilbene glucoside plays the analgesia of acute the opium effect strengthened and the generation alleviating opiate tolerance phenomenon by blocking above-mentioned link.Simultaneously, inventor is by a large amount of experimental datas, research draws: stilbene glucoside has under the dosage not affecting the intact animal threshold of pain, can the analgesia time of significant prolongation opioid drug, strengthen its analgesic activity, and can the generation of opiate tolerance phenomenon that causes of delaying chronic opioid drug.
Therefore, he of the invention proposes stilbene glucoside in the application prepared in analgesic and provides the dosage form that can realize.Described analgesic is opioid drug.Described opioid drug comprises: morphine, codeine, dihydrocodeine, hydromorphone, oxycodone. methadone, fentanyl, Pethidine tramadol etc., and preparation.
The present invention embodies mainly through following technical scheme:
First aspect, the present invention relates to stilbene glucoside for the preparation of strengthening in the medicine of opioid drug analgesic effect.
Second reverse side, the present invention relates to stilbene glucoside for delaying or alleviating in the medicine of opiate tolerance phenomenon of opioid drug.
Concrete, the present invention can be that active component makes the use of preparation cooperation opioid drug with stilbene glucoside.Or make compound preparation with opioid drug to use.Described preparation, compound preparation are selected from the one in injection, subdermal implants, tablet, powder, granule, capsule, oral liquid, slow releasing agent respectively.
The third aspect, the present invention relates to a kind of preparation: be active component with stilbene glucoside, adds the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
Also relate to a kind of compound preparation: with stilbene glucoside, opioid drug for active component, add the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
Described adjuvant or complementary composition comprise the diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant etc. of pharmaceutical field.
Beneficial effect: stilbene glucoside, as a kind of abundance, has the Chinese medicine active component of good safety, the present invention makes public for the first time the analgesic activity can used it for and strengthen opioid drug, delays or alleviate the generation of opiate tolerance.The present invention can strengthen the application space of opioid drug in moderate and severe pain treatment field: stilbene glucoside can reduce the using dosage in acute opium analgesia process, alleviate the generation of untoward reaction, the tolerance phenomenon being difficult in chronic opium application process overcome can be resisted, give full play to the analgesic activity that opioid drug is powerful, for pain therapy provides more selection.
Accompanying drawing explanation
Fig. 1 stilbene glucoside is to the schematic diagram of Acute Morphine analgesic effect effect.
Fig. 2 stilbene glucoside alleviates the schematic diagram of the opiate tolerance phenomenon that chronic morphine process causes.
Fig. 3 stilbene glucoside is to the mrna expression schematic diagram of the microglia TNF-α that Acute Morphine process is induced.
Fig. 4 stilbene glucoside is to the mrna expression schematic diagram of the microglia IL-1 β that Acute Morphine process is induced.
Detailed description of the invention:
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, some distortion and improvement can also be made.These all belong to protection scope of the present invention.Test method described in following embodiment, if no special instructions, is conventional method; Described test kit material, if no special instructions, all can obtain from commercial channels.
Morphine is the representative drugs the most widely applied in opium kind analgesics, other opioid drug and morphine have similar mechanism of action, as by while being combined with opiate receptor and playing powerful analgesic effect, can inducing neural Activated Microglia, and the performance of this neural its analgesic effect of microglia inflammatory effect and promote the generation of tolerance phenomenon.Therefore, the present embodiment is the most classical open opioid drug---the result of study of-morphine mainly, and morphine has representative widely, and professional field technical staff can reappear similar result of study in other opioid drug.
Embodiment 1 (acute analgesic effect Enhancement test)
A) experimental animal: healthy adult Female ICR mice, cleaning grade, body weight 18-22g.Experimental animal feeding is in the 12h-12h freestanding environment that day alternates with night, and room temperature maintains 24 ± 2 DEG C, freely drinks water and ingests, and tests after conforming 1 week.All process of animal are all followed to the requirement of Ethics Committee of IASP.
B) test drug and reagent:
Medicine stilbene glucoside, purity 98%, commercially available.Morphine hydrochloride, purchased from Shenyang No. 1 Pharmaceutical Factory.
C) test method:
Stilbene glucoside and morphine administration dosage and method: stilbene glucoside physiological saline solution, dosage is 60mg/kg, and administering mode is gavage (i.g.).Injection of morphia dosage is respectively 10mg/kg, and administering mode is subcutaneous injection (s.c.).
ICR mice is divided into three groups at random: morphine model group (10mg/kg), stilbene glucoside 60mg/kg concomitant dosing group and blank group.Treatment group mice gives stilbene glucoside 60mg/kg starting to measure front 15min, and model group and treatment group are starting to measure front 30min subcutaneous injection morphine, and the behavioristics carrying out pain subsequently measures.
Mice Determination of Pain Threshold: before test and after last administration, mouse tail 1.5-3.0cm immerses in water bath with thermostatic control (52 ± 0.5 DEG C) by 0.5h, with stopwatch record Mus tail from being immersed in the water the time occurring whipping action, as (tailflicklatency incubation period of whipping reaction, TFL), for preventing tissue injury, if the non-whipping of mice 10s, then TFL is designated as 10s.TFL ceiling effect percent MPE value represents: MPE (%)=(after administration before TFL-administration TFL)/(before 10-administration TFL) × 100%.
D) result of the test describes:
As shown in Figure 1, wherein A is that whole body gives the analgesic effect schematic diagram of stilbene glucoside 60mg/kg to subcutaneous morphine 10mg/kg, water-bath tail-flick method measures the display of mice Basic Pain Threshold result, and stilbene glucoside can significantly improve whipping response latency (TFL) (Fig. 1) to mice.Above result shows: stilbene glucoside can the analgesia time of significant prolongation morphine, promotes morphine analgesia effect.
Embodiment 2 (opiate tolerance phenomenon alleviates experiment)
A) experimental animal:
Female ICR mice, cleaning grade, body weight 18 ~ 22g.Experimental animal feeding is in 12h ~ 12h freestanding environment that day alternates with night, and room temperature maintains 24 ± 2 DEG C, freely drinks water and ingests, and tests after conforming 1 week.All process of animal are all followed to the requirement of Ethics Committee of IASP.
B) test drug and reagent:
Medicine stilbene glucoside, purity 98%, commercially available.Morphine hydrochloride, purchased from Shenyang No. 1 Pharmaceutical Factory.
C) test method:
Stilbene glucoside dosage and method: stilbene glucoside physiological saline solution, dosage is 60mg/kg, and administering mode is gavage.
ICR mice is divided into four groups at random: morphine model group, morphine stilbene glucoside administration group, blank group, treatment group mice gives stilbene glucoside 60mg/kg starting to measure front 15min, model group and treatment group are starting to measure front 30min subcutaneous injection morphine 10mg/kg, the behavioristics carrying out pain subsequently measures, every day repeats with upper type, continuous 7 days.
Test chronic tolerance: injection of morphia every day (10mg/kg, subcutaneous), continuous 7 days, after per injection 30min, measure analgesic effect (water-bath tail-flick method).Before test and after last administration, mouse tail 1.5-3.0cm immerses in water bath with thermostatic control (52 ± 0.5 DEG C) by 0.5h, with stopwatch record Mus tail from being immersed in the water the time occurring whipping action, as (tailflicklatency incubation period of whipping reaction, TFL), for preventing tissue injury, if the non-whipping of mice 10s, then TFL is designated as 10s.TFL ceiling effect percent MPE value represents: MPE (%)=(after administration before TFL-administration TFL)/(before 10-administration TFL) × 100%.
D) result of the test describes:
As shown in Figure 2, for whole body gives maximum analgesia percentage rate-time dynamic schematic diagram that stilbene glucoside delaying chronic gives the analgesia tolerance that morphine causes.As shown in Figure 2, within 7 days, chronic morphine subcutaneous injection makes morphine in mice analgesic effect occur tolerance, and the MPE value of stilbene glucoside treatment group (60mg/kg) is significantly higher than model group.Above result shows: stilbene glucoside can alleviate and chronicly gives the opiate tolerance phenomenon that opioid drug causes.
Embodiment 3 (inflammation-inhibiting factor mRNA raises experiment)
A) cell is tested:
BV2 microglia cultivates the DMEM culture medium containing 10% hyclone, 5%CO2, and 37 DEG C of constant temperature incubators are cultivated.Can go down to posterity when covering culture bottle bottom surface 80%.Test first 24 hours, culture medium is changed into 0.5% hyclone DMEM in high glucose.
B) test drug and reagent:
Hyclone is purchased from Hyclone; DMEM, Trizol are purchased from Invitrogen; TaKaRaPrimeScript test kit is purchased from the precious biological engineering company limited in Dalian.
C) test method:
Real-time quantitative PCR: the extracting of application Trizol method respectively organizes cell RNA.The SYBRGreenAssay of reverse transcription reaction application TaKaRaPrimeScript test kit, reaction system is: 5 × PrimeScriptBuffer2 μ l, PrimeScriptRTEnzyme0.5 μ l, OligodTPrimer0.5 μ l, Random6mers0.5 μ l, TotalRNA is quantitatively to 500ng, RNaseFreeddH
20, end-body is 10 μ l.Reverse transcription reaction condition is as follows: 37 DEG C of 15min (reverse transcription reaction); 85 DEG C of 5sec (inactivation reaction of reverse transcription).Real-timePCR application 7300Real-timePCR system (AppliedBiosystems, Warrington, UK).CDNA sample adopts three-step approach pcr amplification standardization program.Reaction system is: cDNA template 4 μ l, forward primer 1 μ l, downstream primer 1 μ l, ddH
2o, ROX10 μ l, end-body is 20 μ l.
Primer sequence is as follows:
PCR reaction condition is as follows: 95 DEG C of 10min, 40 circulations: 60 DEG C of 60s, 95 DEG C of 15s, and solubility curve 60 DEG C-90 DEG C ensures that amplification is for single product.Carry out interpretation of result with Ct value, adopt relative measurement to compare with internal reference GAPDH.Computing formula is: 2
-Δ CT, Δ Ct=Ctgene-Ctcontrol.
D) result of the test describes:
BV2 cell is divided into matched group, morphine model group, morphine stilbene glucoside treatment group and stilbene glucoside group at random.After morphine stilbene glucoside treatment group and stilbene glucoside group stilbene glucoside (10 μMs/L) pre-administration 5min, morphine model group and morphine stilbene glucoside treatment group give 200 μMs, morphine, hatch 6 hours altogether.
Result as shown in Figure 3, Figure 4, wherein Fig. 3 is the mrna expression schematic diagram of stilbene glucoside to the microglia TNF-α that Acute Morphine process is induced, and Fig. 4 is the mrna expression schematic diagram of stilbene glucoside to the microglia IL-1 β that Acute Morphine process is induced.From in figure, morphine process makes BV-2 cell proinflammatory factor L-1 β, TNF-α and IL-6mRNA express to be increased, and stilbene glucoside treatment group significantly suppress the high expressed of Pro-inflammatory mediator mRNA level in-site, and stilbene glucoside basic administration is on all no impacts of BV-2 cell.Above result shows: stilbene glucoside can suppress the rise of morphine induction microglia inflammation factor mRNA.
Embodiment 4 (compound preparation)
A) prescription: stilbene glucoside 0.2g, morphine 0.6g, sodium hydroxide 4.3g, hydrochloric acid is appropriate, injects water to 2L, makes 100.
B) preparation technology: get sodium hydroxide, adds the water for injection of 50% consumption, is stirred to and dissolves completely, be heated to 90 DEG C, add stilbene glucoside and morphine, stir and make it dissolve completely, add to the full amount of water for injection, with salt acid for adjusting pH value to 6.4 ~ 7.0 of 1mol/L, add active carbon, 60 ~ 70 DEG C are stirred 30min, be cooled to room temperature, filter successively with 0.45 μm, 0.22 μm microporous filter membrane, lid is rolled in fill, 121 DEG C of sterilizing 15min.
Above specific embodiments of the invention are described.It is to be appreciated that the present invention is not limited to above-mentioned particular implementation, those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (9)
1. stilbene glucoside is preparing the application in analgesic.
2., as right wants the application as described in 1, it is characterized in that described analgesic is opioid drug.
3. applying as claimed in claim 2, it is characterized in that described stilbene glucoside is for the preparation of strengthening in the medicine of opioid drug analgesic effect.
4. apply as claimed in claim 2, it is characterized in that described stilbene glucoside is for delaying or alleviating in the medicine of opiate tolerance phenomenon of opioid drug.
5. the application as described in claim 3 or 4, is characterized in that being that active component is made preparation and coordinated opioid drug use or make compound preparation with opioid drug and use with stilbene glucoside.
6. apply as claimed in claim 5, it is characterized in that described preparation, compound preparation are selected from the one in injection, subdermal implants, tablet, powder, granule, capsule, oral liquid, slow releasing agent respectively.
7. apply as claimed in claim 2, it is characterized in that described opioid drug comprises: morphine, codeine, dihydrocodeine, hydromorphone, oxycodone. methadone, fentanyl, Pethidine or tramadol and preparation thereof.
8. a preparation, is characterized in that with stilbene glucoside being active component, adds the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
9. a compound preparation, to is characterized in that with stilbene glucoside, opioid drug, for active component, adding the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
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| CN110917190A (en) * | 2019-11-29 | 2020-03-27 | 中国人民解放军军事科学院军事医学研究院 | Preparation for inhibiting adverse reaction of opioid analgesic and application thereof |
| CN115381729A (en) * | 2022-09-02 | 2022-11-25 | 广州捷创生物科技有限公司 | Toothpaste with effects of whitening skin, removing stains and relieving gingival inflammation and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110467522A (en) * | 2019-08-30 | 2019-11-19 | 山东省分析测试中心 | There are active diphenylethylene compounds of anti-enteritis and preparation method thereof, application in a kind of indigo naturalis |
| CN110467522B (en) * | 2019-08-30 | 2022-04-19 | 山东省分析测试中心 | Toluylene compound with anti-enteritis activity in natural indigo, and preparation method and application thereof |
| CN110917190A (en) * | 2019-11-29 | 2020-03-27 | 中国人民解放军军事科学院军事医学研究院 | Preparation for inhibiting adverse reaction of opioid analgesic and application thereof |
| CN110917190B (en) * | 2019-11-29 | 2022-12-23 | 中国人民解放军军事科学院军事医学研究院 | Preparation for inhibiting adverse reaction of opioid analgesic and application thereof |
| CN115381729A (en) * | 2022-09-02 | 2022-11-25 | 广州捷创生物科技有限公司 | Toothpaste with effects of whitening skin, removing stains and relieving gingival inflammation and preparation method thereof |
| CN115381729B (en) * | 2022-09-02 | 2023-10-10 | 广东领康日用品有限公司 | Toothpaste with effects of whitening, removing stains and reducing gingivitis and preparation method thereof |
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Application publication date: 20151111 |