CN104177613A - Nonlinear polymer and preparation and use thereof - Google Patents
Nonlinear polymer and preparation and use thereof Download PDFInfo
- Publication number
- CN104177613A CN104177613A CN201310203619.8A CN201310203619A CN104177613A CN 104177613 A CN104177613 A CN 104177613A CN 201310203619 A CN201310203619 A CN 201310203619A CN 104177613 A CN104177613 A CN 104177613A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- compd
- group
- reacts
- 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
- SYFQYGMJENQVQT-UHFFFAOYSA-N NCCCCC(C(O)=O)N(CC(O)=O)CC(O)=O Chemical compound NCCCCC(C(O)=O)N(CC(O)=O)CC(O)=O SYFQYGMJENQVQT-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a new nonlinear polymer containing a metal ion structure, and a preparation method and use thereof. A compound with a branch structure is used for construction of the new nonlinear polymer, and the new structure is used for testing in cerebral palsy animal models, and the new compound has excellent therapeutic effect on the treatment of cerebral palsy disease.
Description
Technical field
The invention discloses preparation method and the purposes of a kind of non-linear polymer that contains metal ion structure and this polymkeric substance.
Background technology
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.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.
Using in the treatment of medicine, the line medication 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 and promotes the growth of brain cell and strengthen the compensatory capacity of cerebral tissue, but curative effect is limited when clinical application.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 the compound of new texture has 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
Of the present invention theing contents are as follows:
The invention discloses the novel polymer structure shown in following formula, its structure is as follows:
Wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between m=1-5000, the preferably integer between m=1-2000.
The preparation method of this compound, is characterized in that:
1) the structure A that contains nitrilotriacetic acid(NTA)-Methionin reacts and obtains Compound C with compd B in sodium hydrogen carbonate solution;
2) after Compound C and Compound D stirring reaction, obtain compd E;
3) compd E reacts to obtain product G with the compound F 17-hydroxy-corticosterone containing Y type polyoxyethylene glycol in solvent, and wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000;
4) compound G reacts to obtain compound H with Ni ionic compound;
Compd A;
Compd B;
Compound C;
Compound D;
Compd E;
Compound F 17-hydroxy-corticosterone;
Compound G;
End product H.
Wherein said chemical reaction step selects solvent to be selected from: one or more in acetic acid, formic acid, benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.Compound can be prepared into and be suitable for muscle, vein or the preparation of topical.Described preparation, it can be ordinary preparation, controlled release preparation, targeting preparation etc.Described part is head administration or other mode administrations.Described compound and pharmacologically acceptable salt thereof the purposes in the medicine of preparation treatment brain paralysis.
Preparation method of the present invention is specific as follows:
By compd A (being purchased) 10mg-10g and compd B (being purchased) 0.01g-5g as for 0.1-96 hour in solvent, cooling after 1-48 hour in 50 degree-100 degree heating, regulate PH to 2-5, after concentrating under reduced pressure, in ethanol, wash, after being dried, obtain Compound C, Compound D (being purchased) stirs 1-10 hour with C in phosphoric acid salt, concentrating under reduced pressure obtains compd E, and compd E reacts to obtain compound G, the NiCl of compound G and 1-5mol with the Y type compound F 17-hydroxy-corticosterone (being purchased) that contains polyoxyethylene glycol being purchased
2react 1-48 hour to obtain final product compound H.Freeze-drying obtains the freeze-dried preparation of end product.
Reaction scheme is:
Compd A
+
Compd B
Generate
Compound C;
Compound C
+
Compound D
Generate
Compd E;
Compd E
+
Compound F 17-hydroxy-corticosterone
Generate
Compound G:
Compound G
+
Ni ionic compound
Generate
Compound H
End product H.
The preparation that the end product of preparing at this patent is made treatment encephalopathy relatively in, the medication effect of this patent new compound is very good, very good by the preparation for treating brain of the making paralysis disease effects of this patent.
brief description of the drawings:
fig. 1the nuclear magnetic resonance map of preparing product of embodiment 1.
Embodiment
Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.
Preparation Example is as follows:
embodiment 1
Compd A (being purchased) 500mg is dissolved in 6ml water, with 600mg sodium bicarbonate and 500mg compd B (being purchased) as in same beaker 15 hours, cooling after heating 70 degree, acetic acid regulator solution PH to 3, after concentrating under reduced pressure, in ethanol, wash, crystallization obtains Compound C, filtering ethanol washs rear dry again, 400mg Compound D (being purchased) is dissolved in the phosphoric acid buffer of PH7.5, and stir 2 hours with Compound C, concentrating under reduced pressure, washing with alcohol, filter and wash again, the positive empty compd E that is dried to obtain, compd E and the Y type compound F 17-hydroxy-corticosterone that contains polyoxyethylene glycol being purchased, in methanol solution, stir 6 hours, react to obtain compound G, compound G reacts to obtain final product compound H with the NiCl2 of 2Mol.
embodiment 2
Compd A (being purchased) 1000mg is dissolved in 6ml water, with 900mg sodium bicarbonate and 1200mg compd B (being purchased) as in same beaker 24 hours, cooling after heating 75 degree, acetic acid regulator solution PH to 3.3, after concentrating under reduced pressure, in ethanol, wash, crystallization obtains Compound C, filtering ethanol washs rear dry again, 800mg Compound D (being purchased) is dissolved in the phosphoric acid buffer of PH7.5, and stir 2 hours with Compound C, concentrating under reduced pressure, washing with alcohol, filter and wash again, the positive empty compd E that is dried to obtain, compd E and the Y type compound F 17-hydroxy-corticosterone that contains polyoxyethylene glycol being purchased, in methanol solution, stir 8 hours, react to obtain compound G, the NiCl of compound G and 3Mol
2react to obtain final product compound H.
effect embodiment:
Effect experiment grouping:
Sample prepared by embodiment 1-2 is compared with the experiment of the effect of other various medicines.Be specially:
First group is embodiment 1 sample sets;
Second group is embodiment 2 sample sets;
The 3rd group is polyoxyethylene glycol group (molecular weight is 5000);
The 4th group is Ni ionic group, i.e. NiCl2(2Mol);
The 5th group of positive medicine baclofen group;
The 6th group of positive medicine dantrolene group
The provide protection of 1 compound to newborn rabbits brain paralysis
1.1 laboratory animal and grouping
Young rabbit in 24h after raw, mean body weight 50g, is divided into 7 groups at random by young rabbit, and 15 every group, i.e. Normal group, model group, positive drug baclofen group, polyoxyethylene glycol group, Ni ionic group and embodiment 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.When medicine preparation, need lucifuge operation and use in 1h.
1.2.2 each treated animal processing
Except Normal group, all the other groups all give abdominal injection bilirubin, each 100 mg/kg body weight, and the next day, injects 1 time, and totally 3 times, total amount 300 mg/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.After the young rabbit administration of each group, send back to immediately in female rabbit hutch, 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, 20 points of full marks, minimum 0 point, without negative point.5 points of muscular tension full marks, all have any one performance that enhancing, attenuating, migration strengthen and lower to detain 5 points; 5 points of involuntary action full marks, all have tremble, dance movement, wave that action, athetoid, spasm are reversed and any one performance of spasmodic torticollis detains 5 points; 5 points of autonomic activities full marks, allly respond that blunt, autonomic activities reduces, movement velocity slowly, kinematic dexterity reduce and stability of motion to reduce be 1 point, every each button; 5 points of posture full marks, all 2 points, each buttons of abnormal posture while having motor pattern abnormal and static, 1 point, the button 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 point 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, separate 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 DEG C of refrigerators and slowly thaws, strictly presses the operation of test kit operation instruction, parallel two-tube mensuration.
1.6 statistical method
Each group data represent with mean ± standard deviation, relatively adopt t to check between group, and there is statistical significance P≤0.05 for difference.
1.7 result
1.7.1 study of behaviour appraisal result
Compared 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 wherein embodiment 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
| Group | Study of behaviour scoring | Content of bilirubin (μ mol/L) |
| Normal group | 20.0±0.00 | 42.19±6.39 |
| Model group | 14.26±5.09 ## | 509.32±20.2 ## |
| Positive drug group | 15.33±5.24** | 103.51±8.19** |
| Polyoxyethylene glycol group | 14.12±4.79 | 500.08±20.1 |
| Ni ionic group | 14.18±4.65 | 487.08±26.3 |
| Embodiment 1 | 19.74±5.01** | 71.22±4.98** |
| Embodiment 2 | 19.71±5.03** | 70.14±5.04** |
With relatively ##P<0.01 of Normal group, with relatively * * P<0.01 of model group
The provide protection of 2 medicines to mouse brain paralysis
2.1 laboratory animal and grouping
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 DEG C of room temperatures, illumination control 12 hours, free diet water.Suckling mouse is divided into 7 groups at random, 20 every group, i.e. control group, model group, positive drug dantrolene group, polyoxyethylene glycol group, Ni ionic group and embodiment 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 separates 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 processing
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.After the administration of each group suckling mouse, sending immediately female mouse back to raises 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, trains with diameter 28mm square column.Animal is placed in to the initiating terminal of spreader, stopwatch is counted it and is passed through the middle 80cm of spreader apart from the time that 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 of 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/l00g 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.lms 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 upwards 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 group data represent with mean ± standard deviation, relatively adopt t to 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 wherein embodiment group result for the treatment of is more obvious.
The impact (n=20) of table 2 medicine on postoperative 3 weeks, 7 week latent period of brain paralysis suckling mouse and metapedes landing number of times
With relatively #P<0.05##P<0.01 of control group, with relatively * P<0.05**P<0.01 of model group
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 embodiment group effect is more obvious.Refer to table 3.
The impact (n=20) of table 3 medicine on postoperative 3 weeks, 7 weeks rat CMAP of brain paralysis suckling mouse
| Group | Postoperative 3 week latent period (s) | Postoperative 7 week latent period (s) |
| Control group | 13.41±6.72 | 23.14±12.70 |
| Model group | 2.11±1.03 ## | 1.63±1.21 ## |
| Positive drug group | 8.25±3.38** | 11.25±5.76** |
| Polyoxyethylene glycol group | 2.10±1.01 | 1.59±1.16 |
| Ni ionic group | 2.06±1.06 | 1.60±1.20 |
| 1 group of embodiment | 11.32±5.06** | 19.67±5.76** |
| 2 groups of embodiment | 11.45±4.99** | 19.63±5.95** |
With relatively ##P<0.01 of control group, with relatively * * P<0.01 of model group.
Claims (9)
1. the new compound structure being shown below, its structure is as follows:
。
2. the polymkeric substance of claim 1, wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between m=1-5000, the preferably integer between m=1-2000.
3. the preparation method of compound as claimed in claim 1, is characterized in that:
1) the structure A that contains nitrilotriacetic acid(NTA)-Methionin reacts and obtains Compound C with compd B in sodium hydrogen carbonate solution;
2) after Compound C and Compound D stirring reaction, obtain compd E;
3) compd E reacts to obtain product G with the Y type compound F 17-hydroxy-corticosterone containing polyoxyethylene glycol in solvent, and wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000;
4) compound G reacts to obtain compound H with Ni ionic compound;
Compd A;
Compd B;
Compound C;
Compound D;
Compd E;
Compound F 17-hydroxy-corticosterone;
Compound G;
End product H.
4. the method for claim 3, wherein said chemical step 1-4 selects solvent to be selected from: one or more in acetic acid, formic acid, benzene, toluene, pyridine, tetrahydrofuran (THF), trifluoroacetic acid, chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.
5. the compound of claim 1 can be prepared into and be suitable for muscle, vein or the preparation of topical.
6. the described preparation of claim 5, it can be ordinary preparation, controlled release preparation, targeting preparation etc.
7. described in claim 5, part is head administration or other mode administrations of incidence.
8. compound and pharmacologically acceptable salt thereof the purposes in the medicine of preparation treatment encephalopathy described in claim 1.
9. the purposes of claim 8, the encephalopathy described in it refers to cerebral plasy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310203619.8A CN104177613A (en) | 2013-05-28 | 2013-05-28 | Nonlinear polymer and preparation and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310203619.8A CN104177613A (en) | 2013-05-28 | 2013-05-28 | Nonlinear polymer and preparation and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104177613A true CN104177613A (en) | 2014-12-03 |
Family
ID=51958976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310203619.8A Pending CN104177613A (en) | 2013-05-28 | 2013-05-28 | Nonlinear polymer and preparation and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104177613A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211946A (en) * | 2013-05-31 | 2014-12-17 | 韩文毅 | Metal-ion-containing non-linear polymer, and preparation and application thereof |
| CN104211945A (en) * | 2013-05-29 | 2014-12-17 | 韩文毅 | Non-linear polymer containing metal ion structure, preparation method and applications thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120244075A1 (en) * | 2011-03-24 | 2012-09-27 | Nanoprobes, Inc. | 5 NM Nickel-NTA-Gold Nanoparticles |
-
2013
- 2013-05-28 CN CN201310203619.8A patent/CN104177613A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120244075A1 (en) * | 2011-03-24 | 2012-09-27 | Nanoprobes, Inc. | 5 NM Nickel-NTA-Gold Nanoparticles |
Non-Patent Citations (4)
| Title |
|---|
| JUNGKYU K. LEE, ET AL.: ""Grafting Nitrilotriacetic Groups onto Carboxylic Acid-Terminated Self-Assembled Monolayers on Gold Surfaces for Immobilization of Histidine-Tagged Proteins"", 《J. PHYS. CHEM. B》 * |
| KAREN L. CHRISTMAN, ET AL.: ""Positioning Multiple Proteins at the Nanoscale with Electron Beam Cross-Linked Functional Polymers"", 《J. AM. CHEM. SOC.》 * |
| S. RAHIMA BENHABBOUR，ET AL.: ""In vitro and in vivo assessment of targeting lipid-based nanoparticles to the epidermal growth factor-receptor (EGFR) using a novel Heptameric ZEGFR domain"", 《JOURNAL OF CONTROLLED RELEASE》 * |
| SHARON WAICHMAN，ET AL.: ""Maleimide Photolithography for Single-Molecule Protein-Protein Interaction Analysis in Micropatterns"", 《ANALYTICAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211945A (en) * | 2013-05-29 | 2014-12-17 | 韩文毅 | Non-linear polymer containing metal ion structure, preparation method and applications thereof |
| CN104211946A (en) * | 2013-05-31 | 2014-12-17 | 韩文毅 | Metal-ion-containing non-linear polymer, and preparation and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103724280A (en) | Compound for treating cerebral palsy and use thereof | |
| CN104177613A (en) | Nonlinear polymer and preparation and use thereof | |
| CN103977010A (en) | Compound xylazine injection for dogs and preparation method thereof | |
| CN104177611A (en) | Nonlinear polymer and preparation and application thereof | |
| CN103724350A (en) | Compound for treating cerebral palsy and use thereof | |
| CN103724331A (en) | Compound for treating cerebral palsy and use thereof | |
| CN103720692A (en) | Compound for treating cerebral palsy and use thereof | |
| CN103721240A (en) | Compound formulation for treating bacterial infection of digestive tract of livestock and poultry and preparation method of compound formulation | |
| CN103724349A (en) | Compound for treating cerebral palsy and use thereof | |
| CN103724351A (en) | Compound for treating cerebral palsy and use thereof | |
| CN103330898B (en) | Traditional Chinese medicine composition for curing impotence and prospermia, as well as preparation method and application of traditional Chinese medicine composition | |
| CN103720694A (en) | Compound for treating cerebral palsy and use thereof | |
| Kasper et al. | Influence of adjuvant chemotherapy on skeletal muscle and fatigue in women with breast cancer | |
| CN103720691A (en) | Compound for treating cerebral palsy and use thereof | |
| Todd | An anti-serum for scorpion venom | |
| CN113143871B (en) | Drop pills for treating sciatica and preparation method | |
| CN102813888A (en) | Chinese herbal composition for treating epilepsy | |
| Bury | A CONTRIBUTION TO THE SYMPTOMATOLOGY OF FRIEDREICH'S DISEASE. | |
| CN103623184B (en) | The Chinese medicine for the treatment of prolapse of lumbar intervertebral disc and manufacture method | |
| EA201101527A1 (en) | METHOD OF REMOVAL OF STRESSES, CANCELLATION OF SMOKING AND TREATMENT OF DISEASES BY MEANS OF MAMATROPIC RESPIRATION | |
| Guthrie | Pellagra-Like Skin Lesions Appearing in the Course of a Ketogenic Diet | |
| Gould | The Student's Medical Dictionary: Including All the Words and Phrases Generally Used in Medicine, with Their Proper Pronunciation and Definitions-- | |
| Fox | THE VARIETIES OF RHEUMATOID ARTHRITIS. | |
| Obukhova et al. | Test problems in physiology state licensing examination KROK-1 | |
| Moldovan | The Role of Kinetotherapy in the Treatment of Scapulohumeral Periarthritis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141203 |