CN103724331A - Compound for treating cerebral palsy and use thereof - Google Patents
Compound for treating cerebral palsy and use thereof Download PDFInfo
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- CN103724331A CN103724331A CN201210385524.8A CN201210385524A CN103724331A CN 103724331 A CN103724331 A CN 103724331A CN 201210385524 A CN201210385524 A CN 201210385524A CN 103724331 A CN103724331 A CN 103724331A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a compound for treating cerebral palsy and its pharmaceutical composition and a novel use thereof. The novel use comprises that the compound is used for preparation of a drug for treating cerebral palsy. The compound has very obvious effects of treating cerebral palsy.
Description
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue of a class treatment cerebral plasy, the pharmaceutical composition of being prepared by above-claimed cpd and pharmacologically acceptable salt thereof and its analogue, and described compound or pharmaceutically acceptable salt thereof and the purposes of analogue in the medicine of preparation treatment cerebral plasy thereof.
Background technology
Cerebral plasy also claims brain paralysis clinically, is in utero to being born the hindbrain etap, and non-the carrying out property brain injury syndrome due to many reasons, is the principal disease that causes child limb deformity, and easily exists throughout one's life.Scientific circles are still underway to its pathogenetic research, and current carried arbitrary theory all cannot make an explanation for all patients with cerebral palsy causes of disease, and the further research of the science that needs discloses the pathogenesis of brain paralysis.
About the treatment of brain paralysis, there is no at present good method, bring huge spirit, economical load to patient, family and society.Along with enclosing the development of obstetrics' medical science, neonatal mortality ratio obviously declines, but due to inherited genetic factors or other external environment factors but make the sickness rate of brain paralysis present ascendant trend, therefore, the treatment of brain paralysis has become focus and the difficult point of countries in the world scientific research institution research.The method for the treatment of brain paralysis has medicine, operation, rehabilitation and other treatment both at home and abroad at present.
Using in the treatment of medicine, a line medication of often using clinically at present has diazepam, baclofen, dantrolene, tizanidine etc., is mainly used in relieve muscle spasms, but that treatment is held time is limited, prolonged and repeated application has certain side reaction, also has larger research space.In addition, some somatomedins, Cerebrolysin Vial etc. are also as the medicine for the treatment of brain paralysis, and it act as the growth that promotes brain cell and the compensatory capacity that strengthens cerebral tissue, but curative effect is limited during clinical application.In scientific research, meat poisoning rhzomorph etc. also can be used for treating brain paralysis, but still has query for its methods for the treatment of and injected dose, needs further research.
Use at present surgery operating technology operational risk higher, treatment is very limited, and less people takes operation.Rehabilitation is to treat at present the most popular a kind for the treatment of means of infant brain paralysis, because it can not cause excessive injury to infant, and can obtain suitable alleviation through the long-term treatment state of an illness.Rehabilitation mainly comprises: kinesitherapy, conductive education, apparatus assisting therapy etc.The variation of its form of therapy has obtained infant and kinsfolk's consistent favorable comment with interest and appeal, but there is no obvious data and prove its definite curative effect, through practice for many years, rehabilitation does not reach the result for the treatment of of expection, and rehabilitation does not also form a set of complete theoretical system, many therapies also, in the middle of clinical experiment, need a large amount of objectively experimental results to do further confirmation.
Above treatment means only can be alleviated some symptoms of cerebral palsy of children, can not fundamentally treat.Be badly in need of at present the pathogenesis of research brain paralysis, find out the total reason of various brain paralysis, and find a kind of medicine root, brain paralysis to be treated, reduce Their Incidence of Cerebral Palsy rate, alleviate the pressure bringing to family, society due to cerebral paralysis disease.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof have an unexpected effect on the medicine of preparation treatment cerebral plasy, there is no report for this compounds for treating cerebral plasy at present.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the medicine of preparation treatment cerebral plasy.
Technical scheme of the present invention is as follows:
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat cerebral palsy diseases, and analogue, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C).
Formula (I) compound and analogue thereof or its pharmacologically acceptable salt can be prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is the powder injection through head administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The inventor studies discovery: this compounds can greatly be alleviated cerebral plasy symptom, and from the result of pharmacodynamic experiment, the result for the treatment of of this compounds exceeds the medicine of current clinical application.The exploitation of this new indication is by for to play very large effect to the recovery of following cerebral palsy patients.For removing sufferer misery, alleviate the symptom of this class disease, improve patient and its household's quality of life, promote social harmony of far-reaching significance.
Embodiment
The present invention's formula (I) compound used can be purchased, and also can be prepared according to disclosed preparation method, and it does not limit the scope of the invention.
Medicine Preparation Example
Described compd A structure is:
Compound (A);
Described compd B structure is:
Compound (B);
Described Compound C structure is:
Compound (C).
Preparation containing compd A lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (A) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd B lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (B) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing Compound C lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (C) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Effect embodiment:
The provide protection of 1 compound (A-C) to newborn rabbits brain paralysis
1.1 laboratory animal and grouping
After raw, the interior young rabbit of 24h is 90, and mean body weight 50g, is divided into 6 groups at random by young rabbit, i.e. Normal group, model group, positive drug baclofen group and medicine A, B, C group.
1.2 experimental technique
1.2.1 bilirubin solution compound method
The bilirubin of getting aequum is dissolved in NaOH solution, and to make PH be 7.4, then uses 0.9%NaCl solution dilution to volume required.During medicine preparation, need lucifuge operation and use in 1h.
1.2.2 each treated animal is processed
Except Normal group, all the other groups all give abdominal injection bilirubin, each 100mg/kg body weight, and the next day, injects 1 time, and totally 3 times, total amount 300mg/kg body weight, control group gives the physiological saline of abdominal injection Isodose, and the next day, injects 1 time, totally 3 times.After modeling, each medicine group all gives relative medicine (1mg.kg-1) once every 3d intravenous injection, and control group gives isopyknic physiological saline, successive administration 5 times, altogether 15d.Each is sent back in female rabbit hutch after organizing young rabbit administration immediately, and in equal constant temperature, constant humidity, lucifuge environment, natural breast-feeding is to 45d.
1.3 Behavioral assessment
The young rabbit nurture laggard row Behavior Examination of 45d and scoring, full marks 20 minutes, minimum 0 minute, without negative minute.Muscular tension full marks 5 minutes, all have any one performance that enhancing, attenuating, migration strengthen and lower to detain 5 minutes; Involuntary action full marks 5 minutes, all have tremble, dance movement, wave that action, athetoid, spasm are reversed and any one performance of spasmodic torticollis detains 5 minutes; Autonomic activities full marks 5 minutes, allly respond that blunt, autonomic activities reduces, movement velocity slowly, kinematic dexterity reduces and stability of motion reduces and is every and detains 1 minute; Posture full marks 5 minutes, all while having motor pattern abnormal and static abnormal posture respectively detain 2 minutes, the button 1 minute of can not standing, after every young rabbit is scored respectively and is averaged by 5 people, average as the study of behaviour score of this group together with other animal averagings of income on the same group divide, mark is accurate to 0.01 minute again.
1.4 serum bilirubin levels are measured
After treating young rabbit scoring, be fixed on operating table, cut open chest and expose heart, heart puncturing extracting blood 0.5ml.Adopt 1500rpm/min, after centrifugal 5min, separated upper serum, doazo reaction method is measured serum total bilirubin content.
1.5 serum myelin basic proteins (MBP) assay
12h and 45d after modeling, get blood centrifugation serum.Serum MBP adopts enzyme-linked immunoassay method, after freezing serum is moved to 4 ℃ of refrigerators and slowly thaws, strictly presses the operation of test kit operation instruction, parallel two-tube mensuration.
1.6 statistical method
Each is organized data and represents by mean ± standard deviation, relatively adopts t check between group, and there is statistical significance P≤0.05 for difference.
1.7 result
1.7.1 study of behaviour appraisal result
Compare with Normal group, the young rabbit study of behaviour scoring of model group obviously reduces (P < 0.01), with model group comparison, each medication therapy groups study of behaviour scoring obviously increases (P < 0.01), and its Chinese traditional medicine A-C group result for the treatment of is more obvious.Can obviously improve the behavior disorder producing because of young rabbit brain paralysis due to bilirubin.Refer to table 1.
The impact (n=15) of table 1 medicine on the scoring of brain paralysis study of behaviour and serum bilirubin level due to bilirubin
Compare ##P < 0.01 with Normal group, with model group comparison
*p < 0.01
1.7.2 serum bilirubin level result
The content of the young rabbit anteserum mesobilirubin of Normal group is starkly lower than model group (P < 0.01); Through the treatment of medicine, each treatment group all can make the content of young rabbit anteserum mesobilirubin reduce, and relatively have significant difference (P < 0.01), and medicine A-C group effect is better than positive drug group with model group.Refer to table 1.
1.7.3 serum MBP content results
After model group modeling, in 12h serum, MBP content is than the obvious rising of control group (P < 0.01), and after 45d, two groups relatively still have statistical significance (P < 0.05); With model group comparison, each medicine A-C treatment group all can reduce MBP content in serum (P < 0.05 or P < 0.01), can obviously improve the young rabbit brain injury of brain paralysis situation.Refer to table 2.
The impact (μ g/L, n=15) of table 2 medicine on brain paralysis serum MBP content due to bilirubin
Compare #P < 0.05##P < 0.01 with control group, with model group comparison
*p < 0.05
*p < 0.01
The provide protection of 2 medicines (A-C) to mouse brain paralysis
2.1 laboratory animal and grouping
120 of healthy 7 day-old Wistar suckling mouses, clean level, male and female are not limit, body weight 14 ± 0.5g, raising condition is 21 ± 2 ℃ of room temperatures, illumination is controlled 12 hours, free diet water.Suckling mouse is divided into 6 groups at random, i.e. control group, model group, positive drug dantrolene group and medicine A-C group.
2.2 experimental technique
2.2.1 mouse cerebral palsy model preparation
The 7th day Wisrar suckling mouse isofluranum inhalation anesthesia after being born, 75% ethanol disinfection skin of neck, the descending neck of operating microscope center longitudinal incision, is about 0.5cm, carefully separated subcutaneous and fascia superficialis, dual ligation arteria carotis communis from breaking, skin suture otch.Postoperative anesthesia recovery is positioned over after 2 hours and mixes in 8% oxygen+92% nitrogen anoxic case 2 hours.Control group will be given birth to latter 7 days Wisrar children mouse isofluranum inhalation anesthesias equally, 75% ethanol disinfection skin of neck, the descending neck median incision of operating microscope, sews up the incision after exposure right carotid, puts back to female mouse free diet water at one's side after its holonarcosis recovery 2h.
2.2.2 each treated animal is processed
After modeling, each medicine group all gives relative medicine (2mg.kg-1) once every 3d intravenous injection, and control group gives isopyknic physiological saline, successive administration 5 times, altogether 15d.Each is organized and sends immediately female mouse back to after suckling mouse administration and raise at one's side.
2.3 Beam balance test
Rat to postoperative 3 weeks, 7 weeks carries out Beam balance test detection.Training stage, moves into laboratory by animal from receptacle, adapts to 60 minutes, with diameter 28mm square column, trains.Animal is placed in to the initiating terminal of spreader, stopwatch is counted it and is passed through the time that the middle 80cm distance of spreader enters magazine, i.e. latent period.Setting long latency is 60 seconds.Every animal is trained 10 times every day, for three days on end.Test phase, adapt to after 60 minutes, test respectively rat latent period, left and right metapedes slippage number of times on diameter cross bar, every mouse is measured 10 times and averages, after every mouse walks to average for 10 times, with the landing number of times at this time point as this group of averaging together with the landing number of times mean value of every mouse on the same group, after being completed, send receptacle back to, with 70% ethanol washing test device again.All tests must keep laboratory temperatures, humidity, intensity of illumination consistent.
2.4 Motion Evoked Potentials detect
In going out each group rat to be carried out respectively to the compound muscular movement of quadriceps muscle of thigh in postoperative 3 weeks, 7 weeks to bring out current potential (CMAP) detection.Rats by intraperitoneal injection 10% Chloral Hydrate 0.4ml/100g body weight, top skin unhairing, the tincture of iodine, ethanol disinfection, center, top sagittal is cut scalp, pushes periosteum open, exposes coronal suture and sagittal suture, with 3mm after coronal suture, the other 2mm that opens of center line, for stimulating central point, keeps local skull moistening.Bipolar stimulation electrode stimulating zona rolandica surface skull, stimulus intensity 2mA-10mA, the wide 0.1ms of ripple, single stimulates.Needle-like recording electrode is placed in quadriceps muscle of thigh.Reference electrode is placed in homonymy tibialis anterior, filtering 30Hz-300Hz, and sensitivity 5 μ V, repeat 1-5 time.Ground-electrode is placed in root of the tail portion.Record current potential, find maximum amplitude stimulus intensity, analyze wave amplitude and peak latent period of first negative wave making progress of Motion Evoked Potential (MEP).Thorn electric current increases to twice and closes electric current still cannot to draw waveform negative.
2.5 statistical method
Each is organized data and represents by mean ± standard deviation, relatively adopts t check between group, and there is statistical significance P≤0.05 for difference.
2.6 result
2.6.1 Beam balance test result
Experimental result is in Table 3, and freely, Harmony is good for control group experimental mouse bilateral hind leg joint motion.It is indefinite that model group experimental mouse expression before by balance beam cross bar is hesitated, exploratory behaviour is more, during by cross bar, bilateral hind leg joint motion is stiff, the coordination ability is poor, according to postoperative 3 weeks, 7 weeks average latencies and metapedes landing number of times result show, with control group ratio, have statistical significance (P < 0.05 or P < 0.01); With model group comparison, postoperative 3 weeks of each medication therapy groups, 7 weeks average latencies and metapedes landing number of times all reduce (P < 0.05 or P < 0.01), and its Chinese traditional medicine A-C group result for the treatment of is more obvious.
The impact (n=20) of table 3 medicine on postoperative 3 weeks, 7 week latent period of brain paralysis suckling mouse and metapedes landing number of times
Compare #P < 0.05##P < 0.01 with control group, with model group comparison
*p < 0.05
*p < 0.01
2.6.2 potentiometric detection result
With control group comparison, within postoperative 3 weeks, 7 weeks, model group experimental mouse hind leg CMAP wave amplitude obviously reduces (P < 0.01), reaches the required stimulus intensity of maximum amplitude and increases; With model group comparison, each treatment group all can make experimental mouse hind leg CMAP wave amplitude obviously raise (P < 0.01), and medicine A-C group effect is more obvious.Refer to table 4.
The impact (n=20) of table 4 medicine on postoperative 3 weeks, 7 weeks rat CMAP of brain paralysis suckling mouse
Compare ##P < 0.01 with control group, with model group comparison
*p < 0.01.
Claims (6)
1. a class can be treated the compound or pharmaceutically acceptable salt thereof of encephalopathy, and analogue, and the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C).
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and pharmacologically acceptable salt and its analogue.
3. the pharmaceutical composition of claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc.
4. the pharmaceutical composition of claim 2, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
5. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation treatment encephalopathy described in claim 2.
6. the purposes of claim 5, the encephalopathy described in it refers to cerebral plasy.
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| CN201210385524.8A CN103724331A (en) | 2012-10-11 | 2012-10-11 | Compound for treating cerebral palsy and use thereof |
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| CN201210385524.8A CN103724331A (en) | 2012-10-11 | 2012-10-11 | Compound for treating cerebral palsy and use thereof |
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| CN103724331A true CN103724331A (en) | 2014-04-16 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804365A (en) * | 2012-11-05 | 2014-05-21 | 徐冰冰 | Compound for treatment of contact dermatitis and application thereof |
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| CN1968926A (en) * | 2004-04-28 | 2007-05-23 | 卫材R&D管理有限公司 | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride thereof |
| CN101370792A (en) * | 2005-11-01 | 2009-02-18 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN103664936A (en) * | 2012-09-17 | 2014-03-26 | 杨育新 | Compounds for treating traumatic brain injury diseases and application thereof |
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- 2012-10-11 CN CN201210385524.8A patent/CN103724331A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684964A (en) * | 2002-08-14 | 2005-10-19 | 阿斯利康(瑞典)有限公司 | Use of and some novel imidazopyridines |
| CN1968926A (en) * | 2004-04-28 | 2007-05-23 | 卫材R&D管理有限公司 | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride thereof |
| CN101370792A (en) * | 2005-11-01 | 2009-02-18 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN103664936A (en) * | 2012-09-17 | 2014-03-26 | 杨育新 | Compounds for treating traumatic brain injury diseases and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103804365A (en) * | 2012-11-05 | 2014-05-21 | 徐冰冰 | Compound for treatment of contact dermatitis and application thereof |
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