CN102258508A - Application of arylacrylic acid derivatives in epilepsy resistance - Google Patents
Application of arylacrylic acid derivatives in epilepsy resistance Download PDFInfo
- Publication number
- CN102258508A CN102258508A CN2011101057107A CN201110105710A CN102258508A CN 102258508 A CN102258508 A CN 102258508A CN 2011101057107 A CN2011101057107 A CN 2011101057107A CN 201110105710 A CN201110105710 A CN 201110105710A CN 102258508 A CN102258508 A CN 102258508A
- Authority
- CN
- China
- Prior art keywords
- epilepsy
- group
- model
- positive controls
- compare
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *C=C[C@@]1C=CC(*)=C(*)C1 Chemical compound *C=C[C@@]1C=CC(*)=C(*)C1 0.000 description 1
Abstract
The invention relates to application of arylacrylic acid derivatives in medicines for treating epilepsy. The invention provides application of arylacrylic acid derivatives disclosed as General Formula I in medicines for treating epilepsy. In General Formula I, R1 and R2 are respectively hydrogen, halogen, hydroxyl group, amino group or substituent amino group; and R3 is carboxylic acid, unsubstituted amide, methyl ester or ethyl ester.
Description
Technical field
The present invention relates to field of medicaments, epileptics treatment aromatic substituted acrylic acid derivant.
Background technology
Epilepsy popular name " epilepsy " is one group of not normal chronic disease of temporary central nervous system function due to the cerebral neuron paradoxical discharge that shows effect repeatedly.According to the scope about neuronic position and discharge diffusion, malfunction may show as different obstacles such as motion, sensation, consciousness, behavior, autonomic nerve; Clinical manifestation is characteristics with of short duration loss of consciousness, limb spasm, tic, paraesthesia, autonomic nervous dysfunction and the psychological problem of outbreak repeatedly.According to the difference of pathogenic factor, epilepsy can be divided into constitutional and Secondary cases.Essential epilepsy is meant that brain does not have to explain the structural change or the Developmental and Metabolic Disorder of symptom, and etiology unknown and inherited genetic factors have than confidential relation, and the various changes of inside and outside environment in physiological range can be brought out its morbidity.Essential epilepsy is many about 5 years old or the adolescence morbidity.Secondary epilepsy, be meant the epilepsy of the clear and definite cause of disease, maternal infuries, asphyxia of newborn, craniocerebral trauma, intracranial tumor, brain development deformity, cerebrovascular disease, intracranial infection (various encephalitis, meningitis, brain abscess etc.), cerebral parasitosis, poisoning (lead, hydrargyrum, carbon monoxide etc.) and some nutrition, metabolic disease etc. all can cause the generation of primary disease.Age of onset is generally before 2 years old and after 25 years old.
Epileptics is a kind of mentally deranged disease, when the patient falls ill, often causes severe traumatic, brain injuries easily, even dead.
According to the WHO statistics, present global epileptic has 5,000 ten thousand people approximately, and wherein 80% in developing country.2,000,000 new epileptics also appear every year.The epilepsy prevalence of developed country, the country that switches to a market economy, developing country and undeveloped country is respectively 5.0 ‰, 6.1 ‰, 7.2 ‰, 11.2 ‰.Point out in World Bank's " health input " report, nineteen ninety epilepsy almost account for 1% of world's disease burden.
The epilepsy prevalence of China is 7 ‰, and is approaching with the sickness rate of the developing country 7.2 ‰ of WHO report.China epileptic number has broken through 1,000 ten thousand more than at present, and 400,000 New Development patient is nearly arranged every year.In these epileptics, child and teenager are still the epilepsy group of people at high risk, and 0-9 year patient accounts for 38.5%, and it is nearly 40% that 10-29 year patient accounts for, the wherein treatment of the patient's never received more than 40%, and what 35% patient accepted is non-regular treatment.
6 kinds of antiepileptics that World Health Organization (WHO) was recommended in 1980 are: phenobarbital, desoxyphenobarbital, carbamazepine, phenytoin Sodium, sodium valproate, ethosuximide.Through 20 years of development, on the market, old product phenobarbital, carbamazepine, phenytoin Sodium, sodium valproate have still occupied the absolute market share at home.Simultaneously, existing in the world at present a plurality of novel antiepileptics comprise non-ammonia ester, gabapentin, lamotrigine, oxcarbazepine, tiagabine, vigabatrin and zonisamide etc.The oxcarbazepine products such as (Qu Lai) of the topiramate of the lamotrigine of GlaxoSmithKline PLC (Lamictal), Xi'an Yang Sen (appropriate Thailand), Novartis goes on the market in China., market growth active with external antiepileptic research and development rapidly compared, and the domestic market development is flat, does not have the novelty medicine to go into operation and goes on the market.In whole nervous system medicine, antiepileptic only accounts for 3.8% the market share.
At present domestic epilepsy therapy pharmaceutical market is occupied by the import medicine, on the high side, and general patient is difficult to bear and takes the economic problems of bringing for a long time, also is difficult to solve China's epileptics low problem of rate of seeking medical advice.Simultaneously, existing drug side effect is all bigger, takes for a long time to affect greatly health.
Chlocibutamine is the aromatic radical acrylamide derivative, belongs to a kind of cinnamyl amine of innovation, and it has stronger antiepileptic action the animal experiment proof, and has the little pharmacology characteristics of toxicity.In WO9708934, mentioned the aromatic substituted acrylic acid derivant as protein tyrosine phosphatase inhibitor in the progress aspect the treatment tumor.Bioorganic﹠amp; Disclosed the application of aromatic substituted acrylic acid among Medicinal Chemistry13 (2005) 4891-4899 as immunomodulator.Basis based on previous work, the inventor carries out structure of modification to chlocibutamine, find also have antiepileptic activity with the aromatic substituted acrylic acid derivant of its similar, and in the document before this not this compounds the different epilepsy of pathogeny is had the report of effective therapeutical effect, the present inventor confirms the earliest that clinically the aromatic substituted acrylic acid derivant is effective to the treatment epilepsy.
Summary of the invention
The application of aromatic substituted acrylic acid analog derivative in treatment epilepsy medicine, this aromatic substituted acrylic acid analog derivative structural formula is as follows:
Wherein: R
1, R
2Independently be hydrogen, halogen, hydroxyl, amino and substituted-amino separately;
R
3Be carboxylic acid, unsubstituted amide and methyl ester or ethyl ester.
Optimized technical scheme of the present invention is R
1, R
2Be respectively chlorine, R
3Be carboxylic acid.
Optimized technical scheme R of the present invention
1, R
2Be respectively chlorine, R
3Be amide.
Optimized technical scheme R of the present invention
1, R
2Be respectively fluorine, R
3Be amide.
Optimized technical scheme R of the present invention
1, R
2Be respectively fluorine, R
3Be ethyl ester
Animal experiment discovers that such aromatic substituted acrylic acid derivant and pharmaceutically acceptable salt thereof have the activity of treatment epilepsy, persistent period and death time in the time of can postponing epilepsy, reduces attack degree and attack rate.
The active best chemical compound of the present invention is 3,4-Dichlorobenzene base acrylic acid and 3, and 4-dichloropropylene amide, and 3,4-difluoro ethyl acrylate and 3,4-difluoro acrylamide.
Based on the pathogeny of epilepsy, this pilot system selects 3-mercaptopropionic acid (3-MP) to bring out the mice epilepsy model and to pentetrazole (PTZ) kindled rats Chronic Epilepsy model.3-MP can suppress synthesizing of γ-An Jidingsuan (GABA), makes the inhibit feature reduction that GABA can be neural in the brain, resists the antuepileptic that is caused epilepsy by 3-MP, and the epilepsy that 3-MP brings out belongs to the grand mal type.Rat chronic epilepsy and people's pyknolepsy that PTZ lights have very big similarity, cause that the focal position of pathological reaction determines that the pathological reaction of appearance has gradual and stable effect.
Test sample selects 3, the acid of 4-dichloropropylene, 3,4-dichloropropylene amide, 3,4-difluoro ethyl acrylate and 3,4-difluoro acrylamide.
Positive reference substance is selected sodium valproate slow releasing tablet and lamotrigine sheet.
3-mercaptopropionic acid (3-MP) brings out in the mice epilepsy model, test sample 3, the acid of 4-dichloropropylene, 3,4-dichloropropylene amide, 3,4-difluoro ethyl acrylate and 3,4-difluoro acrylamide is used sodium carboxymethyl cellulose (CMCNa) dissolving respectively, final concentration is 15mg/ml and 5mg/ml, and the sodium valproate slow releasing tablet is dissolved with an amount of animal drinking water, and final concentration is 10mg/ml, the lamotrigine sheet dissolves with animal drinking water, and final concentration is 1mg/ml.
In the rat chronic epilepsy model that PTZ lights, test sample 3, the acid of 4-dichloropropylene, 3,4-dichloropropylene amide, 3,4-difluoro ethyl acrylate and 3,4-difluoro acrylamide is used sodium carboxymethyl cellulose (CMCNa) dissolving respectively, final concentration is 20mg/ml and 10mg/ml, and the sodium valproate slow releasing tablet is dissolved with an amount of animal drinking water, and final concentration is 15mg/ml, the lamotrigine sheet dissolves with animal drinking water, and final concentration is 1.5mg/ml.
The specific embodiment
Embodiment 1
Continuous 5 days per os of KM mice are irritated stomach and are given 3, the acid of 4-dichloropropylene, 1h subcutaneous injection 3-MP after the last administration: after the high dose group mice gives 3-MP in the 30min battle array convulsion incubation period compare significant prolongation (P＜0.01) with model control group and positive controls (lamotrigine sheet, sodium valproate slow releasing tablet); The persistent period and the death time of battle array convulsion are compared obvious prolongation (P＜0.05, P＜0.01) with model control group, but compare no significant difference (P＞0.05) with positive controls.An interior battle array convulsion persistent period of 30min was compared obvious prolongation (P＜0.05, P＜0.01) with the death time after the low dose group mice gave 3-MP with model control group, compared no significant difference (P＞0.05) with positive controls.The mortality rate of interior spasm of 30min and tonic epilepsy all is starkly lower than model contrast and positive controls (table 1) behind the high and low dose group mouse subcutaneous injection 3-MP.Dosage: high dose group is that 300mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 20mg/kg, sodium valproate slow releasing tablet 200mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 1
Embodiment 2
Continuous 5 days per os of KM mice are irritated stomach and are given 3,4-dichloropropylene amide, 1h subcutaneous injection 3-MP after the last administration: after the high dose group mice gives 3-MP in the 30min battle array convulsion incubation period compare obvious prolongation (P＜0.05) with model control group and positive controls (lamotrigine sheet, sodium valproate slow releasing tablet); The persistent period of battle array convulsion is compared significant prolongation (P＜0.01) with model control group; Death time is compared no significant difference with model control group, but compares obvious shortening (P＜0.05) with the sodium valproate positive control.An interior battle array convulsion persistent period of 30min was compared significant prolongation (P＜0.01) after the low dose group mice gave 3-MP with model control group, compared no significant difference (P＞0.05) with positive controls.The mortality rate of 30min interior battle array spasm and tonic epilepsy all is starkly lower than model contrast and positive controls (table 2) behind the high and low dose group mouse subcutaneous injection 3-MP.
Dosage: high dose group is that 300mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 20mg/kg, sodium valproate slow releasing tablet 200mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 2
Embodiment 3
Continuous 5 days per os of KM mice are irritated stomach and are given 3,4-difluoro ethyl acrylate, 1h subcutaneous injection 3-MP after the last administration: after the high dose group mice gives 3-MP in the 30min battle array convulsion incubation period compare significant prolongation (P＜0.01) with model control group and positive controls (lamotrigine sheet, sodium valproate slow releasing tablet); The persistent period and the death time of battle array convulsion are compared obvious prolongation (P＜0.01, P＜0.01) with model control group, but compare no significant difference (P＞0.05) with positive controls.An interior battle array convulsion persistent period of 30min was compared obvious prolongation (P＜0.05, P＜0.01) with the death time after the low dose group mice gave 3-MP with model control group, compared no significant difference (P＞0.05) with positive controls.The mortality rate of interior spasm of 30min and tonic epilepsy all is starkly lower than model contrast and positive controls (table 3) behind the high and low dose group mouse subcutaneous injection 3-MP.
Dosage: high dose group is that 300mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 20mg/kg, sodium valproate slow releasing tablet 200mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 3
Embodiment 4
Continuous 5 days per os of KM mice are irritated stomach and are given 3,4-difluoro acrylamide, 1h subcutaneous injection 3-MP after the last administration: after the high dose group mice gives 3-MP in the 30min battle array convulsion incubation period compare obvious prolongation (P＜0.05) with model control group and positive controls (lamotrigine sheet, sodium valproate slow releasing tablet); The persistent period of battle array convulsion is compared significant prolongation (P＜0.01) with model control group; Death time is compared no significant difference with model control group, but compares obvious shortening (P＜0.05) with the sodium valproate positive control.An interior battle array convulsion persistent period of 30min was compared significant prolongation (P＜0.01) after the low dose group mice gave 3-MP with model control group, compared no significant difference (P＞0.05) with positive controls.The mortality rate of 30min interior battle array spasm and tonic epilepsy all is starkly lower than model contrast and positive controls (table 4) behind the high and low dose group mouse subcutaneous injection 3-MP.
Dosage: high dose group is that 300mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 20mg/kg, sodium valproate slow releasing tablet 200mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 4
Embodiment 5
To be lighted the Wistar rat and be given 3 every day, 4-dichloropropylene acid 1 time, successive administration 10 days, 1h lumbar injection PTZ causes epilepsy after the last administration, high and low dose group and positive controls give behind the PTZ in the 30min attack degree of animal grand mal time of occurrence and epilepsy behavior and compare no significant difference (P＞0.05) with model control group and positive controls, compare prolongation to some extent, attack degree and attack rate than model control group and compare decrease (table 5) with model control group but high and low dose gives behind the PTZ in the 30min animal grand mal time of occurrence.
Dosage: high dose group is that 200mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 15mg/kg, sodium valproate slow releasing tablet 150mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Epilepsy intensity: 0 grade-reactionless, 1 grade-rhythmicity mouth and facial the twitch, 2 grades-body fluctuation sample migration spasm, 3 grades-whole body muscular spasm, buttocks upwarp, and 4 grades-body changes to a rollover, 5 grades-face upward and turn over position, complete tetanus convulsion.
Table 5
Embodiment 6
To be lighted the Wistar rat and be given 3 every day, 4-dichloropropylene amide 1 time, successive administration 3 days, 1h lumbar injection PTZ causes epilepsy after the last administration, and ask when occurring to PTZ kindled rats Chronic Epilepsy, attack degree compares no significant difference (P＞0.05) with model and positive controls by outbreak for high dose group; Low dose group is compared no significant difference (P＞0.05) to PTZ kindled rats Chronic Epilepsy outbreak time of occurrence with model and positive control, attack degree is compared obvious reduction (P＜0.05) with model and sodium acrylate positive control, attack rate is starkly lower than model and positive controls (table 6).
Dosage: high dose group is that 200mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 15mg/kg, sodium valproate slow releasing tablet 150mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 6
Embodiment 7
To be lighted the Wistar rat and be given 3 every day, 4-difluoro ethyl acrylate 1 time, successive administration 10 days, 1h lumbar injection PTZ causes epilepsy after the last administration, high, low dose group and positive controls give behind the PTZ in the 30min attack degree of animal grand mal time of occurrence and epilepsy behavior and compare no significant difference (P＞0.05) with model control group and positive controls, but high, the interior animal grand mal time of occurrence of 30min was compared prolongation to some extent than model control group after low dosage gave PTZ, attack degree and attack rate are compared decrease (table 7) with model control group.
Dosage: high dose group is that 200mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 15mg/kg, sodium valproate slow releasing tablet 150mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 7
Embodiment 8
To be lighted the Wistar rat and be given 3 every day, 4-difluoro acrylamide 1 time, successive administration 3 days, 1h lumbar injection PTZ causes epilepsy after the last administration, and high dose group is compared no significant difference (P＞0.05) to PTZ kindled rats Chronic Epilepsy outbreak time of occurrence, attack degree with model and positive controls; Low dose group is compared no significant difference (P＞0.05) to PTZ kindled rats Chronic Epilepsy outbreak time of occurrence with model and positive control, attack degree is compared obvious reduction (P＜0.05) with model and sodium acrylate positive control, attack rate is starkly lower than model and positive controls (table 8).
Dosage: high dose group is that 200mg/kg, low dose group are 100mg/kg; Positive controls lamotrigine sheet 15mg/kg, sodium valproate slow releasing tablet 150mg/kg; Model and blank group give equal-volume 0.5%CMCNa.
Table 8
Can find out from The above results, the aromatic substituted acrylic acid derivant, especially 3, the acid of 4-dichloropropylene, 3,4-dichloropropylene amide, 3,4-difluoro ethyl acrylate and 3, persistent period and death time when 4-difluoro acrylamide can postpone epilepsy, reduce attack degree and attack rate, can confirm effective epilepsy.
Should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.
Claims (5)
1. the application of aromatic substituted acrylic acid analog derivative in treatment epilepsy medicine, this aromatic substituted acrylic acid analog derivative structural formula is as follows:
Wherein: R
1, R
2Independently be hydrogen, halogen, hydroxyl, amino and substituted-amino R separately
3Be carboxylic acid, unsubstituted amide and methyl ester or ethyl ester.
2. the described chemical compound of claim 1, R
1, R
2Be respectively chlorine, R
3Be carboxylic acid.
3. the described chemical compound of claim 1, R
1, R
2Be respectively chlorine, R
3Be amide.
4. the described chemical compound of claim 1, R
1, R
2Be respectively fluorine, R
3Be amide.
5. the described chemical compound of claim 1, R
1, R
2Be respectively fluorine, R
3Be ethyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101057107A CN102258508A (en) | 2011-04-14 | 2011-04-14 | Application of arylacrylic acid derivatives in epilepsy resistance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101057107A CN102258508A (en) | 2011-04-14 | 2011-04-14 | Application of arylacrylic acid derivatives in epilepsy resistance |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102258508A true CN102258508A (en) | 2011-11-30 |
Family
ID=45005474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101057107A Pending CN102258508A (en) | 2011-04-14 | 2011-04-14 | Application of arylacrylic acid derivatives in epilepsy resistance |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102258508A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301124A (en) * | 2013-06-15 | 2013-09-18 | 迪沙药业集团有限公司 | Medicine composition for treating epilepsy |
| CN103315987A (en) * | 2013-06-15 | 2013-09-25 | 迪沙药业集团有限公司 | Pharmaceutical composition for treating epilepsy |
| CN103315989A (en) * | 2013-06-15 | 2013-09-25 | 迪沙药业集团有限公司 | Pharmaceutical composition |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125938A (en) * | 1993-05-11 | 1996-07-03 | 惠尔康基金会集团公司 | Bicyclic amide derivatives and their use as muscle relaxants |
| WO2008074755A2 (en) * | 2006-12-18 | 2008-06-26 | Neurosearch A/S | Novel cinnamic amide derivatives useful as ion channel modulators |
| WO2008110008A1 (en) * | 2007-03-12 | 2008-09-18 | Neuromed Pharmaceuticals Ltd. | Amide derivatives as calcium channel blockers |
| CN101568542A (en) * | 2006-12-22 | 2009-10-28 | 埃科特莱茵药品有限公司 | 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine derivatives |
| CN101851170A (en) * | 2010-05-24 | 2010-10-06 | 迪沙药业集团有限公司 | Chlocibutamine type II crystals |
-
2011
- 2011-04-14 CN CN2011101057107A patent/CN102258508A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125938A (en) * | 1993-05-11 | 1996-07-03 | 惠尔康基金会集团公司 | Bicyclic amide derivatives and their use as muscle relaxants |
| WO2008074755A2 (en) * | 2006-12-18 | 2008-06-26 | Neurosearch A/S | Novel cinnamic amide derivatives useful as ion channel modulators |
| CN101568542A (en) * | 2006-12-22 | 2009-10-28 | 埃科特莱茵药品有限公司 | 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine derivatives |
| WO2008110008A1 (en) * | 2007-03-12 | 2008-09-18 | Neuromed Pharmaceuticals Ltd. | Amide derivatives as calcium channel blockers |
| CN101851170A (en) * | 2010-05-24 | 2010-10-06 | 迪沙药业集团有限公司 | Chlocibutamine type II crystals |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103301124A (en) * | 2013-06-15 | 2013-09-18 | 迪沙药业集团有限公司 | Medicine composition for treating epilepsy |
| CN103315987A (en) * | 2013-06-15 | 2013-09-25 | 迪沙药业集团有限公司 | Pharmaceutical composition for treating epilepsy |
| CN103315989A (en) * | 2013-06-15 | 2013-09-25 | 迪沙药业集团有限公司 | Pharmaceutical composition |
| CN103315987B (en) * | 2013-06-15 | 2018-05-11 | 迪沙药业集团有限公司 | A kind of pharmaceutical composition for treating epilepsy |
| CN103315989B (en) * | 2013-06-15 | 2018-05-11 | 迪沙药业集团有限公司 | A kind of pharmaceutical composition |
| CN103301124B (en) * | 2013-06-15 | 2018-05-25 | 迪沙药业集团有限公司 | A kind of pharmaceutical composition for treating epilepsy |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nuckolls et al. | Tongue force and tongue motility are differently affected by unilateral vs bilateral nigrostriatal dopamine depletion in rats | |
| WO2023202477A1 (en) | Dihydromyricetin tetrahydropyrrole complex and preparation method therefor, and application | |
| CN102786414A (en) | Compound for treating and/or preventing neurodegenerative related disease | |
| US5643954A (en) | Method of preventing and alleviating stress in a healthy mammal in need thereof | |
| CN102258508A (en) | Application of arylacrylic acid derivatives in epilepsy resistance | |
| Liu et al. | Intravenous administration of vitamin c in the treatment of herpes zoster-associated pain: two case reports and literature review | |
| JUDGE et al. | Diphenhydramine (Benadryl) and tripelennamine (Pyribenzamine) intoxication in children | |
| Arslonova et al. | Evaluation of the Clinical Efficacy of Phenytoin in the Treatment of Epileptic Seizures in Children | |
| CN106265713B (en) | Purposes of the cordycepin in the drug for preparing depression and its quick anti-depression drug being prepared | |
| CN112089709A (en) | New application of vitamin K2 in preparation of medicines for delaying brain aging | |
| US10058524B2 (en) | Methods for improving joint function | |
| RU2570399C1 (en) | Method of treating severe acute psychopharmaceutical poisoning in children | |
| CN102512435A (en) | Application of 5,6,4'-trihydroxyl flavone-7-O-beta-D-glucuronide methyl ester and medicinal composition as well as preparation thereof | |
| Yadav | Pharmacology & Toxicology | |
| CN105998023B (en) | Application of demethylsinomenine in preparation of analgesic | |
| CN101411700B (en) | Use of 5,7,4'-trihydroxy flavanone or derivative thereof for analgesia | |
| Cobb | Stiff man syndrome: is the lesion at spinal cord or brain stem level | |
| CN102462696B (en) | Purpose of black-bone silky fowl melanin extractive in preparation of medicament for controlling depression | |
| CN107823643B (en) | Prevention or drug, target spot and its application for the treatment of Alzheimer's disease | |
| CN110179784A (en) | A kind of application of syringaresinol in the drug of preparation treatment depression | |
| CN101888842A (en) | Pharmaceutical preparation comprising stephaglabrin sulfate for treating demyelinating diseases of the nervous system and for promoting restoration of the myelin sheath of nerve fibers | |
| WO2004064849A1 (en) | Means for normalising structure and functions of organs and tissues, stimulating injury recovery and exhibiting antiviral activity | |
| CN117899062A (en) | Application of sodium butyrate in preventing and/or treating lead poisoning | |
| CN116059206A (en) | Application of 2-aminoquinoline in medicine for treating diarrhea | |
| CN103833564A (en) | L-ornithine glutamic acid double salt and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20111130 |