CN101829126B - Application of 3-carbethoxy phenyl-beta-D-glucoside in treating chronic neuropathic pains - Google Patents
Application of 3-carbethoxy phenyl-beta-D-glucoside in treating chronic neuropathic pains Download PDFInfo
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Abstract
The invention relates to 3-carbethoxy phenyl-beta-D-glucoside, or a pharmaceutically acceptable salt, ester or solvate thereof and application in preparing medicaments for treating neuropathic pains, wherein a glycosyl part is arbitrary pyranose or furanose; and a representative compound is 3-carbethoxy phenyl-beta-D-acylated xyloside the structural formula of which is disclosed in the specification. On a classical sciatic nerve chronic compression injury (CCI) model, through single intragastric administration and continuous intragastric administration for 7 days, the compound shows definite treatment effect on resisting nervous pains. At a dose point appointed by an experiment, the compound can obviously improve the mechanical stimulus pain threshold, the nervous pain resistant efficacy is equivalent to that of Gabapentin which is a contrast medicament, and the duration is superior to that of the Gabapentin. Proved by research results, the compound can be used for treating the chronic neuropathic pains.
Description
Technical field
The present invention relates to the medical compounds of medical and health and chemical field, be specifically related to the purposes that 3-carbethoxy phenyl-β-D-acidylate glycoside compounds and officinal salt, ester and solvate thereof are used to treat chronic neuropathic pains.
Background technology
According to durante dolors length, clinical pain is categorized as two kinds of acute pain and chronic pains, these two kinds of pain have essential distinction on genesis mechanism.Acute pain is called nociceptive pain, the pain that promptly causes by tissue injury, and along with the reparation of tissue injury, pain stops naturally, between period of disease, can use analgesic, comes alleviating pain like narcotic analgesics and the agent of nonsteroidal antipyretic-antalgic; Chronic pain is main with neuropathic pain then, and its pathogeny is complicated, and is difficult to radical cure, is the basis of pain medical science and the frontier of clinical research and medicament research and development.The external rise about 30 years has the research of 15-20 historical in China approximately.
One, neuropathic pain basic conception
Neuropathic pain is to cause the chronic pain due to nerve injury or the pathological changes by wound, inflammation or other diseases.Its exemplary comprises: the chronic pain that spine disorders compressing spinal cord or neural lumbago and backache, maincenter and the peripheral damage that causes cause, phantom limb pain behind the polyneuritis property pain of postherpetic neuralgia, diabetes, the apoplexy after pain syndrome, the amputation and intractable cancer pain etc.Neuropathic pain is considered to progressive nervous system disease, is the persistent state of the pain sensation, the adaptive change of neural plasticity and the biochemical reaction of secondary etc. with the difference of acute pain.
Neuropathic pain pathophysiology characteristics are pain sensation high responses, mainly show as: hyperpathia (hyperalgesia), to noxious stimulation increased response or sensitization; Allodynia (allodynia) produces the noxious stimulation reaction to non-noxious stimulation; Spontaneous pain (spontaneous pain) pain occurs under non-stimulated condition.
Since its complicated and diversified pathogeny with lack effective specific aim medicine (classical analgesic drug product such as opiates and nonsteroidal antipyretic analgesic are to such pain poor effect), neuropathic pain becomes on the clinical treatment comparatively stubborn problem.
Two, neuropathic pain pathogeny
The pain sensation high response of neuropathic pain shows as pain sensation threshold value and descends on animal experimental model, ectopic discharge etc. appears in the electroactive enhancing of Primary Sensory Neuron.Over nearly 5 years, the research of the mechanism of these phenomenons is obtained remarkable break-throughs.At present, the pathogenesis of proposition had both related to the neural approach of periphery property, also related to the neural approach of central.The neuralgia mechanism of main flow mainly contains following several kinds at present, in detail can be with reference to Long-Sun Ro, and Kuo-Hsuan Chang Neuropathic pain:Mechanisms andTreatments [J] .Chang Gung Med J28 (9): 597-604, that is:
1. the pain sensation is conducted neural quiet fiber activation and hyperpathia;
2. ion channel hypothesis (Na
+, Ca
2+): think in the tip aixs cylinder of injury nerve, to have several ion channels, these ion channels are specific pain transmitter.Gabapentin is considered to Ca
2+Ionic ion channel blocking agent;
3. neural factor hypothesis;
4. it is ultra quick to stimulating that nervus centralis enhanced sensitivity and plasticity change the nervus centralis that causes, and repairs unusual;
5. the maincenter conduction suppresses deficiency disease.
Three, neuropathic pain medicine
At present, the treatment neuropathic pain does not have specific medicine targetedly, and opiates and nonsteroidal antipyretic analgesic are to this type pain poor effect; Main medicine all belongs to old medicine and newly uses.These medicines are broadly divided into four types: Anti-epileptics, antidepressant, local anesthetic and other.
1. antuepileptic
Nineteen forty-two, Bergonignan reported first phenytoin Sodium can effectively be treated trigeminal neuralgia; Blom in 1962 reports carbamazepine first and also can effectively treat trigeminal neuralgia.But until eighties of last century eighties, relevant clinical research just system launches.Clinical research at present is verified: carbamazepine and gabapentin (gabapetin) can effectively suppress neuralgia.Research shows, carbamazepine block N a
+Passage suppresses Na
+Stride the film conduction, stop action potential to form, weaken the entad conduction of pessimal stimulation, suppress ectopic discharge; And suppress the rabbit trigeminal neuralgia that Kallidin I causes.U.S. FDA approved carbamazepine is used for prosopalgic treatment.Gabapentin analgesic mechanism research report shows that this medicine is to Na
+Do not have influence, maybe with blocking-up Ca
2+Passage is relevant because it can with N type Ca
2+The α of passage and δ
2Subunit combines.Other embody positive findings on animal model, but also need the medicine of further clinical experiment checking that phenobarbital, clonazepam, valproic acid, topiramate (Topiramate), helicide, Pregabalin and Tiagabine etc. are arranged.
2. antidepressant
Clinical research confirms that tricyclic antidepressants has analgesic activity to neuropathic pains such as postherpetic neuralgia, chronic low back pain, chronic tension headache, diabetic and non-diabetic polyneuritis pains.
But generally speaking, the untoward reaction of tricyclic antidepressants is more, and clinical use is restricted.
At present, external research to this compounds mainly concentrates on the analgesia research to the less second filial generation third generation antidepressant of untoward reaction.Type mainly contains the dual absorption inhibitor of 5-HT reuptake inhibitor, norepinephrine and 5-HT [like Paroxetine (Paroxetine), cedilanid (citaloprane), venlafaxine (venlafaxine) etc.
3. local anesthetic
Local anesthetic is used maximum in this field be lignocaine.This chemical compound is typical C a
2+Channel blocker.Nineteen eighty-two, reports such as Boas can be alleviated maincenter and peripheral neuralgia with the lignocaine venous perfusion.Administering mode mainly concentrates on vein, subcutaneous perfusion and Taper Pipe perfusion at present.The end of the nineties in last century, drugs approved by FDA lidocaine patch, be mainly used in the neuropathic pain of local application treatment herpes zoster.
Four, the neuralgic correlational study of micromolecule phenol property glucoside for curing
The chemical compound 3-carbethoxy phenyl-β that relates among the present invention-D-acidylate glucosides is to be the analog of parent with micromolecule phenol property glucosides gastrodine and helicide.
Rhizoma Gastrodiae is the dry tuber of orchid Rhizoma Gastrodiae (Gastrodia elata); " the Chinese pharmacopoeia record, Rhizoma Gastrodiae is hidden sweet, slightly warm in nature, goes into Liver Channel; Have the relieving convulsion effect of suppressing the hyperactive liver to relieve the wind syndrome, cure mainly dizzy, the numb limbs and tense tendons of headache, infantile convulsion, epilepsy, hypertension and aural vertigo etc.
The main effective ingredient of Rhizoma Gastrodiae is micromolecule phenol property glucosides gastrodine (gastrodin; GAS); In recent years big quantity research has been carried out in the pharmacological action of Rhizoma Gastrodiae and composition thereof; In treatment is to have obtained new progress aspect the main multiple disease with the nervous system, finds that gastrodine has following effect: cerebral protection, improve cerebral circulation, convulsion, vertigo, anxiety, Fructus Alpiniae Oxyphyllae, slow down aging.Particularly, experiment shows that acegastrodine has analgesic activity; Compound tall gastrodia tuber preparation can comparatively fast improve the basic threshold of pain, the local skin temperature of reduction inflammation, the swelling degree that alleviates ankle joint, the reduction pain rank of pain model rat.Its mechanism maybe be with the transmission that reduces the pain material, reduce neural impulse import, activate that the analgesia system discharges analgesic matter and inhibition of pain gene expression is relevant into, and at present relevant with gastrodine analgesia research mainly concentrates on anti-acute pain aspect.
Bean curd is the Proteaceae plant for mountain Euphoria (Helicia Lour.) really, has the effect of convergence detoxifcation, blood circulation promoting and blood stasis dispelling, is used to treat enteritis, alimentary toxicosis, rheumatism disease such as swell and ache.By its clinical use of product Helicid sheet of processing for many years.
(helicid, chemical constitution HEL) is similar to Gastrodine to main effective ingredient helicide in the bean curd fruit.Clinical, pharmacological research shows that helicide is similar with Gastrodine to central nervous system's effect, but its calmness, analgesic effect are strong than Gastrodine, and the therapeutical effect produce effects of the headache that neurosis is caused, giddy, sleep disorder is fast.The document Liu Gui that sees reference is gorgeous, Wang Gangli, Ma Shuancheng, the mountain Euphoria active components in medicinal plant research overview [J] of Lin Ruichao. Chinese medicine, 2004,35 (5): 593-595.Have and discover that helicide has the effect of antagonism inflammatory pain and neuropathic pain.Its analgesia characteristics are that onset is slow, the analgesic dose is little, long action time, no obvious toxic-side effects under the analgesic dose.
Give Mus tail heat injury sexual stimulus with the resistance wire heat radiator, observe the influence of helicide, helicide (2%, 1.5 * 10 rat whipping pain response time threshold value
-2ML/g, ip.), threshold value obviously raises and more than the lasting 30min; Bestow acusector and helicide (2%, 715 * 10 simultaneously
-3ML/g; Ip.) after, threshold value significantly raises and can continue until and stops 50min behind the pin, shows that helicide has analgesia and prolongs the effect of needle anaesthesia effect; Document Chen Z X sees reference; Lou ZC.A preliminary study of theanalgesic action of D-fornyl-phenyl-β-D allosupranoside [J] .A cad J First Med Coll.PLA (No.1 Military Medical Univ.'s journal), 1985,5 (3): 186-187.
Oral tablet by helicide is processed proves that with " writhing method " and " hot plate method " these article have analgesic activity, and document sees reference: Sha J M, Mao H K.Helicid [J] .Chin Pharm Bull (pharmacy circular), 1987,22 (1): 27.Zhao Nan has the effect that resists neuropathic pain, Chinese pharmacology communication, 2005,22:38～39 in reported first helicide in 2005.This research is thought; (6.25～50mg/kg) can improve CCI injury in rats batter palm pressure pain threshold value by dose dependent to oral helicide; The onset in 2 hours of its analgesic activity; 3 hours, 4 hours analgesic effect increases gradually after the administration, administration after 24 hours analgesic effect descend to some extent, 48 hours are still effective.Document sees reference: Zhao Nan, Yang Hongju, Wang Yanhua etc. and the anti-neuropathic pain pharmacodynamics of helicide is estimated [J]. Chinese pharmacology communication, 2005,22:38～39..
Gastrodine and helicide are safe and effective, take continuously and do not find to poison or other side reaction, and drug effect is constant.Its shortcoming be onset slowly, action intensity is weak, dosage is big, bioavailability is lower etc.This two chemical compound has similar chemical constitution, all is β-type pyranoside, and difference is the different of functional group and glycosyl.
The structural modification of medicine is to improve curative effect, and enhancing absorbs, and reduces the effective ways of side effect; Document sees reference: Weiguo Shi, He Liu, Yanping Zhang; Bohua Zhong, Hongju Yang.Design, synthesis; Andpreliminary Evaluation of gabapentin-pregabalin mutual prodrugs in relieving neuropathic pain [J] .Arch.Pharm.Chem.Life Sci.2005,338:358-364.The present invention is reference with gastrodine and helicide, its chemical constitution is modified, and the neuropharmacology activity of such analog is screened, and has obtained the potential new compound XH016 of treatment pathological pain.
Five, common chronic neuralgia drug evaluation model
Document sees reference: Yang Hongju; Jiang Zhongwei; Luo Zhipu. the diversity ratio of neuropathic pain animal model is [J]. Chinese clinical rehabilitation; 2003,7 (31): 4272-4273 and Yang Rong. with the helicide is neuropharmacology screening active ingredients research [M] .2007 of the micromolecule monoglycosides chemical compound of representative, Yunnan University's chemical science and engineering college.
Hot plate, whipping, turn round the classical animal model that body is the screening acute pain analgesic used always, but be not suitable for being used for screening the neuralgia medicine.The foundation of NP animal model in recent years development is played great impetus to mechanism of action and the drug research of NP.These have simulated clinically to a certain extent, and several kinds of conventional animal models of NP patient's symptom comprise: 1. peripheral nervous transection model (the sciatic nerve axotomy model); 2. the chronic compressing damage model of sciatic nerve (the chronicconstriction injury model, CCI), this method elder generation EXPOSED RATS sciatic nerve-trunk; Reuse chromic catgut untwisting is pricked 4 rings; Animal postoperative 5～7d occurs machinery, and hot and cold IR is strengthened, and 10～14d peaks; And sustainable one or two months, be the neuropathic pain animal model of using always; 3. sciatic nerve partly cut off model (the partial sciatic nerve ligationmodel, PSL); 4. spinal nerves ligation model (the L5/L6spinal nerve ligation model, SNL); 5. damage model (the spared nerve injury model) is selected by sciatic nerve branch.In addition, also have excitatory amino acid damage, dynorphin model, micro-duct injury model and diabetic neuralgia model or the like.
In recent years, the CCI model that people such as people's extensive use Bennette set up is simulated the rational pain of chronic neuropathic in clinical, inquires into hyperalgesic mechanism and exploitation NP curative.The CCI model document that sees reference: Bennett GJ, Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man [J] .Pain 1988; 33:87-107.The characteristics of this model are neural with the slight ligation of chromic suture, and the thick myelin fiber that has is optionally damaged, but still keep most of C fibrid that transmits pain.The animal of accepting this operation produces hyperpathia and allodynia to machinery and thermostimulation generation subsequently; The mensuration of subordinate act is found; The peripheral nerve injury of this state and human body, the symptom of the neuropathic chronic pain of bringing out like oncothlipsis, heavy metal ion poisoning, anoxia or Developmental and Metabolic Disorder etc. is very similar with the behavior performance.Simultaneously, CCI pain rat model is the ingenious combination of neuropathic pain and inflammatory pain just, and the inflammatory mediator molecule that the ectopic discharge that axonal injury causes because pain is and ligature place inflammatory cell discharge stimulates and produces due to the raising of dystopy sensitivity.
The present invention promptly utilizes CCI pain rat model that representation compound XH016 is carried out the active screening of anti-chronic neuralgia, measures mechanical allodynia and hyperpathia as evaluation index with Von-Frey Filament.
Summary of the invention
It is the 3-carbethoxy phenyl-β-D-acidylate glucoside compound of part that the present invention proposes with the following formula: compound, or its officinal salt, ester or solvate, is used for treating the purposes of the medicine of neuropathic pain in preparation:
Wherein, glycosyl part is any pyranose or furanose, and representation compound is 3-carbethoxy phenyl-β-D-acidylate xyloside, is numbered XH016 certainly, and structural formula is following:
This chemical compound is the white particulate crystallization, no special odor.Dissolving fully in water, methanol, ethanol or dimethyl sulfoxine, most of dissolving in the methanol.Insoluble in the ether.
At present, do not find the report that this chemical compound is applied to neuralgia research.The present inventor is through discovering, above-claimed cpd can be used for treating neuropathic pain.
The objective of the invention is to propose a kind of new purposes of above-claimed cpd; Promptly the invention provides the purposes that chemical compound is used to prepare the medicine of treating the chronic neuropathic pains disease.
Invent the neuropathic pain of the complicacy that described neuropathic pain refers to cause because of peripheral nerve injury, compressing, neurotoxicity, infection, immunity, metabolic disease, tumor, vitamin deficiency or other reasons.
Chronic pain and intractable cancer pain that the spinal cord that the neuropathic pain that the present invention is directed to mainly is the phantom limb pain, central pain, phantom pain, stump pain, sympathetic nerve dependency pain after pain syndrome behind postherpetic neuralgia, trigeminal neuralgia, sciatica, the damaging neuropathic pain of metabolism, the apoplexy, the amputation, complicated local pain syndrome, spine disorders causes or nerve root compression pain, maincenter and periphery wound cause.
Wherein said sciatica refers in particular to sciatic nerve chronic constriction neuropathic pain; The damaging pain of said metabolism is refered in particular to diabetic neuralgia.
Officinal salt, ester or the solvate of 3-carbethoxy phenyl-β that this invention relates to-D-acidylate glucosides class or its analog and the anti-neuropathic pain medicine of quick-acting; Particularly gabapentin is combined to form composition of medicine, adds optional pharmaceutically acceptable excipient, diluent, carrier or adjuvant simultaneously with patent medicine and listing.
The present invention is on the chronic compressing damage model of the sciatic nerve of classics (CCI), and single filling stomach and continuous 7 days filling stomaches give 3-carbethoxy phenyl-β-D-acidylate glucosides and all shown clear and definite neuralgia therapeutical effect.On this model, single-dose and continuous 7 days administration effective doses are 45mg/KgBW.On this dose point, the compounds X H016 mechanical irritation threshold of pain that can significantly raise, neuralgia usefulness slightly is superior to equivalent control drug gabapentin, and duration of efficacy and gabapentin are roughly suitable.
Description of drawings:
Fig. 1 is the different time rat pressure threshold of pain, a CCI operation back change curve;
Fig. 2 is that CCI rat single is irritated behind stomach gabapentin, gastrodine, the 3-carbethoxy phenyl-β-D-acidylate xyloside Time-activity-curve in 24 hours;
Fig. 3 is that CCI rat seven days is irritated behind stomach gabapentin, gastrodine, the 3-carbethoxy phenyl-β-D-acidylate xyloside Time-activity-curve in 140 hours.
The specific embodiment
Concrete pharmacological evaluation is following:
One, receives the reagent thing
Title: 3-carbethoxy phenyl-β-D-acidylate xyloside (XH016)
Character: white crystals
The source: Yunnan University's natural resources pharmaceutical chemistry laboratory biochemical pharmacology group is synthetic voluntarily.
Medicine preparation, administration volume, and route of administration: face to grind and be suspended to desired concn with the pure water solution that before adds 0.2% sodium carboxymethyl cellulose.Rat gastric infusion every day once, the administration volume is 45mg/Kg, 10mL/Kg.
Two, control drug
1. gabapentin, available from Sigma company, CAS Number:60142-96-3.
2. gastrodine, Kunming pharmaceutical factory provides, lot number: 200610036.
The pure water solution grinding of facing with preceding 0.2% sodium carboxymethyl cellulose is suspended to 45mg/mL concentration.
Three, laboratory animal
The Sprague-Dawley rat: regular grade, male, body weight 180～220g during operation provides credit number by animal section of unming Medical College: SCXK (Yunnan) 2008～2011.
Four, data statistics is handled
Data result is represented with mean+SD (
); Adopt SPSS 13.0 statistical packages as statistical tool; Not not on the same group and relatively adopt a plurality of independent sample Kruskal-Wallis H check in the non parametric tests between the normal group, with P＜0.05 for statistical significance is arranged.
Five, experimental technique
1. the foundation of rat CCI model
Reference material is seen: Bennett GJ, Xie YK.A peripheral mononeuropathy in rat that produces disordersof pain sensation like those seen in man [J] .Pain 1988; 33:87-107.
Rat is got the ventricumbent position fixing limbs in the rat operating-table with 40mg/Kg BW pentobarbital sodium ip. administration anesthesia; The right hind thigh stage casing outside is with bending operating scissors QUMAO, 70% alcohol disinfecting skin; Cut cortex, the mosquito forceps passivity is separated leg muscle, exposes sciatic nerve-trunk; Play the place for about 3 millimeters at the front end of sciatic nerve bifurcated, sciatic nerve is separated with surrounding tissue with aseptic glass hook; Prick 4 rings with No. 4 aseptic chromic sutures (diameter 0.15mm) untwisting on sciatic nerve-trunk, each ring spacing is about 1mm, ligation intensity to cause the slight vibration of Calf muscle but link can on nerve, move and be advisable; With silk thread layer-by-layer suture muscular tissue and skin, behind the operation ventrolateral compartment injection 40mg/Kg penicillin sodium normal saline solution, place the cage that is covered with cork dust.The sham operated rats rat only exposes sciatic nerve, and remaining processing is identical with model group.
2. the rat mechanicalness pain sensation is measured unusually
Reference material is seen: Tabo E; Jinks SL; Eisele Jr JH; Carstens E.Behavioral manifestations ofneuropathic pain and mechanical allodynia, and changes in spinal dorsal horn neurons, followingL4-L6dorsal root constriction in rats [J] .Pain 1999; 80:503-20.
The threshold of reaction of mechanical stimulus is with Touch Test sense of touch test pack (VON-FREY FILAMENT), 58011 types, and North Coast Medical Inc. product is measured, and table 1 is seen in threshold of pain rank and the contrast of ballast gram number.
The animal of experimental selection postoperative 14～31d is measured the pressure of foundation threshold of pain before administration, eliminate the basic threshold of pain greater than 5.88 or less than 1.65 animal, all the other animal random packet; Single perhaps gave specific medication in continuous 7 days.
The mechanicalness pain sensation of METHOD FOR CONTINUOUS DETERMINATION animal is unusual after the last administration, surveys before the pain earlier experimental rat is placed in several metal cylinder moulds tranquillization 30min at least respectively, makes it to be familiar with environment and is in quiescent condition, and the process of surveying is bitterly carried out under the glitch-free environment of peace and quiet.
The unusual assay method of the mechanicalness pain sensation: rat is placed metal cage; Adopt a series of survey pain pins that can produce different pressures vertically to stimulate its operation parapodum foot heart position from small to large successively from bottom to top; Make its mao hettocyrtosis and keep 5s, each stimulus intervals 5s.Find 10 times this cause that 4～6 rats lift the cellosilk of foot reaction in stimulating, write down this filametntary numerical value and be the rats withdraw foot threshold of reaction (paw withdrawal threshold, PWT).Maximum pain threshold is set at 6.95.Regulation surpasses 12s when 6.65 value cellosilks stimulate the sufficient heart, and rat does not all have reaction fully in 8 times stimulate be 6.95.
Table 1:Touch Test sense of touch test pack pressure and threshold of pain numerical value synopsis
Six, experimental result
1.CCI the different number of days rat pressure threshold of pain, operation back changes
Measure blank control group, sham operated rats, CCI organizes in back 3 days to 31 days pressure threshold of pains of operation.Changing contrast according to the sham operated rats pain learns; CCI model group rat, after operation 8 days, surgical injury can be ignored; Its pain is regarded as the allodynia that neural ligation causes, and shows as the operation lateral pressure threshold of pain and is starkly lower than non-operation side and blank control group and sham operated rats.
As index, the ultra quick phenomenon of CCI model group rat pain presents little radian inverted U and changes, and presents minor swing in back 11 days to 28 days in operation with the pressure threshold of pain; And after 28 days, raise gradually; Point out neural ligation to absorb gradually with chromic catgut, the compressing phenomenon alleviates gradually, and the result sees accompanying drawing 1.
2. the single gastric infusion is to the influence of the CCI rat pressure threshold of pain
After the single gastric infusion blank solvent, gastrodine, 3-carbethoxy phenyl-β-D-acidylate xyloside, gabapentin 45mg/Kg1 hour, measure Time-activity-curve in the medicine 24 hours, see accompanying drawing 2.
Results suggest, the allodynia that CCI causes is all alleviated in each administration group administration 1 hour to 23 hours in various degree.Wherein, 3-carbethoxy phenyl-β-D-acidylate xyloside, gabapentin 45mg/Kg can significantly improve mechanical hyperalgesia pressure pain threshold value, and analgesia time continues 23 hours; Onset time, persistent period and effect are superior to gastrodine.Explanation is on this model, and it is active that gastrodine, 3-carbethoxy phenyl-β-D-acidylate xyloside, gabapentin all can embody anti-chronic neuropathic pains.Prompting 3-carbethoxy phenyl-β-D-acidylate xyloside possibly become effective neuralgia prodrug.
Back 7 days successive administration timeliness situation 3.CCI perform the operation
Behind continuous 7 days gastric infusion blank solvent, gastrodine, 3-carbethoxy phenyl-β-D-acidylate xyloside, the gabapentin 45mg/Kg, from last administration 1 hour, Time-activity-curve in the METHOD FOR CONTINUOUS DETERMINATION 140 hours, the result sees accompanying drawing 3.
Results suggest, each administration group administration is all alleviated the allodynia that CCI causes after 1 hour to 96 hours in various degree.Wherein, 3-carbethoxy phenyl-β-D-acidylate xyloside administration 45mg/Kg can obviously improve mechanical hyperalgesia pressure pain threshold value, and analgesia time continues 70 hours (with sham operated rats contrast back), and the persistent period is superior to gabapentin; Gabapentin administration analgesia duration is 1 hour to 43 hours; 1～32 hour gastrodine persistent period.It is active that gastrodine, 3-carbethoxy phenyl-β-D-acidylate xyloside, gabapentin all can embody anti-chronic neuropathic pains, and wherein the drug effect of 3-carbethoxy phenyl-β-D-acidylate xyloside and persistent period and gabapentin are the most remarkable.
Seven, conclusion
1.3-it is active that carbethoxy phenyl-β-D-acidylate xyloside, gastrodine all can embody anti-chronic neural source pain at single-dose in 24 hours;
2.3-the carbethoxy phenyl-β-drug effect of D-acidylate xyloside, persistent period all are superior to contrasting the medicine gabapentin, have embodied good anti-neuropathic pain effect.
Explanation thus, this chemical compound can be prepared into the medicine of the various dosage forms that are used for and so on the neuropathic pain disease.Such compound effects time is long, and toxicity is low, is fit to take for a long time, and good new drug development prospect is arranged.
Claims (3)
1. the following 3-carbethoxy phenyl-β-D-acidylate xyloside of structural formula or its officinal salt are used for treating the purposes of the medicine of chronic neuropathic pains in preparation:
2. purposes as claimed in claim 1 is characterized in that: said neuropathic pain is a sciatica.
3. purposes as claimed in claim 2 is characterized in that: said sciatica is a sciatic nerve chronic constriction neuropathic pain.
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| CN1569009A (en) * | 2004-05-11 | 2005-01-26 | 刘智 | Dripping pills of acetylgastrodin for treating nervous headache and its preparing method |
| CN1634089A (en) * | 2003-12-29 | 2005-07-06 | 昆明贝克诺顿制药有限公司 | Application of P-benzaladehyde-O-beta-D-allopyranose for the treatment of neurogenic pain |
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| CN1634089A (en) * | 2003-12-29 | 2005-07-06 | 昆明贝克诺顿制药有限公司 | Application of P-benzaladehyde-O-beta-D-allopyranose for the treatment of neurogenic pain |
| CN1569009A (en) * | 2004-05-11 | 2005-01-26 | 刘智 | Dripping pills of acetylgastrodin for treating nervous headache and its preparing method |
Non-Patent Citations (1)
| Title |
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| 韩武建等.酚性2-乙酰氨基-2-脱氧-β-D-吡喃葡萄糖苷的合成及抗抑郁活性.《中国药物化学杂志》.2009,第19卷(第2期), * |
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