CN103127106B - Purpose of phencynonate hydrochloride for treating or relieving myocardial damage induced by myocardial ischemia reperfusion and pharmaceutical compositions including phencynonate hydrochloride - Google Patents
Purpose of phencynonate hydrochloride for treating or relieving myocardial damage induced by myocardial ischemia reperfusion and pharmaceutical compositions including phencynonate hydrochloride Download PDFInfo
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Abstract
The invention relates to a function of phencynonate hydrochloride in preparing medicine for treating or relieving myocardial damage induced by myocardial ischemia reperfusion. In a myocardial ischemia reperfusion damage animal model of a rat or a rabbit, the phencynonate hydrochloride can obviously restrain the myocardial damage caused by the myocardial ischemia reperfusion, and the function is basically similar to positive therapeutic verapamil and is free of side effects of low blood pressure, slowing of heart rate of the verapamil.
Description
Technical field
The present invention relates to the purposes of benzene ring nonyl ester in the medicine of myocardial damage brought out for the preparation for the treatment of or alleviate myocardial ischemia Reperfu-sion and the pharmaceutical composition containing it.
Background technology
Benzene ring nonyl ester (phencynonate hydrocloride, 2 '-cyclopenta-2 '-phenyl-2 '-hydroxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride) structure as shown in the formula shown in (I), be a kind of selectivity anticholinergic agent.The clinical various motion sickness such as carsick for prevention and therapy, seasick and airsick.The purposes of benzene ring nonyl ester as anti-motion sickness (carsickness, ship, machine etc.) medicine is disclosed in Chinese patent (CN1089838A) and United States Patent (USP) (US6028198).The preparation method of benzene ring nonyl ester is disclosed in Chinese patent (CN97125424.9), British patent (GB2297255) and Spanish patent (ES549796A).
(I) benzene ring nonyl ester
Myocardial infarction is common lethal factor.According to WHO Report, underlying cause of death in the world will be become to the year two thousand twenty acute coronary occlusion.By thrombolytic, percutaneous transluminal coronary angioplasty or Coronary Artery Bypass, ischemic region being filled with in early days is again the prerequisite that ischemic myocardium is survived.But Reperfu-sion is considered to double-edged sword, the damage even more serious than simple ischemia can be caused, i.e. so-called ischemical reperfusion injury.Therefore, finding medicine myocardial ischemia reperfusion injury to clear and definite therapeutical effect, is the research emphasis in treating cardiovascular disease field from now on.
Through research of concentrating on studies, the present inventor finds that benzene ring nonyl ester has significant therapeutic effect to myocardial ischemia reperfusion injury tool, thus complete the present invention.
Summary of the invention
The object of this invention is to provide the medicine for the treatment of or alleviate myocardial ischemia reperfusion injury.
Through concentrating on studies, myocardial damage that the present inventor finds that benzene ring nonyl ester can effectively alleviate or stop myocardial ischemia-reperfusion to cause.Therefore, the present invention relates to the purposes of benzene ring nonyl ester in the medicine of the myocardial damage brought out for the preparation for the treatment of or alleviate myocardial ischemia Reperfu-sion.
The invention still further relates to the method for myocardial damage that treatment or alleviate myocardial ischemia Reperfu-sion bring out, comprise and give required patient by the benzene ring nonyl ester of effective dose.Described effective dose is within the scope of 0.1 ~ 30mg/kg, preferably within the scope of 0.5 ~ 20mg/kg, more preferably within the scope of 1 ~ 15mg/kg, preferred within the scope of 1 ~ 10mg/kg further, most preferably within the scope of 5 ~ 10mg/kg.
The invention still further relates to and be used for the treatment of or the pharmaceutical composition of myocardial damage that alleviate myocardial ischemia Reperfu-sion brings out, it comprises benzene ring nonyl ester and the conventional pharmaceutic adjuvant of pharmaceutical field.Described pharmaceutic adjuvant comprises solvent, cosolvent, cosolvent, emulsifying agent, chelating agen, antioxidant, reducing agent, antibiotic antiseptic, pH adjusting agent, buffer agent, raising agent, protective agent, diluent, filler, binding agent, wetting agent, absorption enhancer, surfactant, absorption carrier, disintegrating agent and lubricant etc.
The suitable dosage form of described pharmaceutic adjuvant and benzene ring nonyl ester can be the several formulations forms such as injection, tablet, capsule, powder, granule, lozenge, suppository or oral liquid.
Described pharmaceutical composition can make injection form.Injection such as can comprise and shares with reactive compound benzene ring nonyl ester the pharmaceutic adjuvant forming injection, wherein such as there are solvent and cosolvent (as ethanol, glycerol and Polyethylene Glycol etc.), cosolvent and emulsifying agent are (as hydroxy methocel, Tween 80 and sorbitol etc.), chelating agen is (as EDTA mono-sodium, disodium etc.), antioxidant and reducing agent are (as sodium sulfite, sodium glutamate etc.), antibiotic antiseptic is (as methaform, phenol etc.), pH adjusting agent and buffer agent are (as sodium acetate, acetic acid and glacial acetic acid etc.), raising agent and protective agent are (as alanine, albumin and glycerol etc.) etc.
Described pharmaceutical composition can make solid oral forms.Solid oral forms can comprise the diluent shared with reactive compound benzene ring nonyl ester, such as, and lactose, dextrose, disaccharide, sucrose, cellulose, corn starch or potato starch; Lubricant, such as, Silicon stone, Talcum, stearic acid, magnesium stearate or calcium and/or Polyethylene Glycol; Binding agent, such as starch based, arabic gum, gelatin, methylcellulose, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrating agent, such as starch, alginic acid, alginate or primojel; Boiling mixture; Dyestuff; Sweetener; Wetting agent is lecithin, Polysorbate, lauryl sulfate such as; With other acceptable non-toxic material that pharmaceutical preparation is conventional.
Described pharmaceutical composition can make oral liquid form.Oral liquid form can be dispersion liquid.Dispersion liquid can be such as syrup, Emulsion or suspension.Such as, syrup can comprise the sucrose as carrier, or sucrose and glycerol and/or mannitol and Sorbitol.Suspension and Emulsion can comprise as the natural gum of carrier, agar, sodium alginate, colloid, methylcellulose, carboxymethyl cellulose or polyvinyl alcohol.
The different dosage form of said medicine all can be prepared according to the conventional method of pharmaceutical field.Such as, by the method for mixing, granulation, film-making, sweet tablet or film Cotton seeds.
The invention still further relates to benzene ring nonyl ester levo form, d-isomer and homologue thereof the purposes in the medicine of the myocardial damage that preparation is treated or alleviate myocardial ischemia Reperfu-sion brings out.
Detailed description of the invention
The following examples and experimental example are used for describing the present invention in detail, but are not used for limiting the present invention.
The benzene ring nonyl ester used in the present invention can be prepared by the preparation method of benzene ring nonyl ester disclosed in Chinese patent (CN97125424.9), British patent (GB2297255) or Spanish patent (ES549796A).
Embodiment 1
Benzene ring nonyl ester injection
Preparation method; Take benzene ring nonyl ester 200g, put in 2000ml measuring bottle, inject and make dissolving in right amount with water, then add sodium sulfite 40g, jolting makes dissolving, and injects water to 2000ml, shakes up, and salt adding acid for adjusting pH value, to pH4, shakes up.With 0.2 μm of filtering with microporous membrane.Embedding, in 2ml ampoule, is total to embedding 1000 ampoules.Circulation steam sterilization (110 DEG C, 15 minutes), carries out clarity test, to obtain final product.
Embodiment 2
Phencynonate hydrochloride tablets agent
Preparation method; Benzene ring nonyl ester 300mg, magnesium stearate 25mg, sodium carboxymethyl cellulose 50mg and starch 125mg are mixed, carries out tabletting by tablet machine, obtained 500mg tablet.
Embodiment 3
Benzene ring nonyl ester capsule:
Benzene ring nonyl ester 200g
Starch 400g
Make 1000 capsules altogether, each capsule is containing principal agent 200mg.
Preparation method: 400g starch is first dry, crosses 120 mesh sieves, then mixs homogeneously with benzene ring nonyl ester, after twice 120 mesh sieves, fully mix, divide and be packed in hard capsule, to obtain final product.
In the pharmacodynamics process evaluating the myocardial damage that benzene ring nonyl ester is treated or alleviate myocardial ischemia Reperfu-sion brings out, adopt rat and rabbit model animal.In order to evaluate medication effect objectively; the myocardial damage experimental animal model that rat and rabbit myocardial ischemia-reperfusion bring out is set up in this research in succession; there is the medicine-verapamil of clear and definite therapeutical effect as positive control drug using the myocardial damage brought out myocardial ischemia-reperfusion well known in the art, the comparative evaluation protective effect of benzene ring nonyl ester to the myocardial damage that rat and rabbit myocardial ischemia-reperfusion are brought out.
Experimental example 1 benzene ring nonyl ester is to the protective effect of the myocardial damage that rat myocardial ischemia and reperfusion brings out
1. experimental technique
The foundation of the myocardial injury models that 1.1 rat myocardial ischemia and reperfusions bring out
SD male rat, 20% urethane 2g/kg intraperitoneal injection of anesthesia, tracheotomy, connects meiofauna Ventilators (f 60 beats/min, VT 20ml/kg).Connect limbs II to lead recording ecg, femoral artery puncture puts pipe record ambulatory blood pressure.Left breast 3-5 rib opens thoracic cavity, stablizes 5min, during this period, and the slow administration of femoral vein.Expose heart, under left auricle, the little round needle of 1mm left coronary artery place ophthalmic rustless steel, 3-0 line are through myocardium shallow-layer, and diameter 3mm cotton thread is placed in the ligation together of coronary artery surface, and ligation rear left ventricular apex portion is dimmed by redness, electrocardiogram occurs that S-T section is raised, and illustrates that ischemia is formed.Cut off ligature after ischemia 30min, take out cotton thread, after recovering hemoperfusion 120min, put to death animal.
1.2 experiment grouping and administrations
48 SD male rats are divided into 6 groups altogether at random, often organize each 8 animals.Comprise: 1. sham operated rats: only open breast, vena femoralis injection normal saline 1mlkg
-1, not following coronary artery occlusion; 2. model group: open vena femoralis injection normal saline 1mlkg after breast
-1, ischemia 30min, Reperfu-sion 120min; 3. verapamil group: vena femoralis injection verapamil hydrochloride injection (being sometimes called for short verapamil below) 0.3mgkg before ischemia
-1; 4. ~ 6. benzene ring nonyl ester group: difference vena femoralis injection benzene ring nonyl ester 4,8 and 16mgkg before ischemia
-1.
1.3 experimental apparatus
Refrigerated centrifuge (German Sigma company model: 3-18K), ultraviolet spectrophotometer (Japanese GBC company model: GZNtRA20), biological electrocardiographic recorder (Meiyi Science & Technology Co., Ltd., Nanjing's model: Medlab-u/4CS), temperature chamber (Chongqing in China milky way test apparatus company limited model: WC/09-05), medical image analysis system (Backman company of U.S. model: HP IAS21000), image analyzer (Japanese Nikon company model: MP IAS2500), artificial respirator (Ji star experimental apparatus technological development company limited model: DW-2B).
1.4 dosage
1.4.1 benzene ring nonyl ester
Intravenous administration benzene ring nonyl ester 4,8 and 16mgkg
-1, by body surface area conversion, be equivalent to people respectively successively with dosage 0.64,1.28 and 2.56mgkg
-1.
1.4.2 verapamil
Verapamil hydrochloride injection is produced by Shanghai Hefeng Pharmaceutical Co., Ltd..Intravenous injection, 0.3mgkg
-1.
1.5 electrocardiograms and blood pressure detecting
SD rat connects limbs II and to lead recording ecg, after anesthesia tracheal intubation, after opening breast, after administration, during ligation arteria coronaria, ligation 10,30min, during open arteria coronaria, after open 10,30,60,120min records each time point heart rate, blood pressure, the change of ST section and T wave amplitude.
1.6 myocardial infarction areas measure
Put to death animal respectively at after perfusion 120min, take out heart, wipe out atrium, right ventricle for each group, retain left ventricle,-18 DEG C of freezing 15min, are evenly cut into 2mm totally 5, dewater with filter paper, above-mentioned 5 heart sections are carefully put into 1% red tetrazolium (TTC) phosphate buffer, 37 DEG C of lucifuges hatch 10 ~ 15min, and infarcted region is in white, and non-infarcted region is because dying redness containing complete lactic acid dehydrogenase, put in 10% formaldehyde fixing, digital camera is taken pictures.Med6.0 type medical image analysis system measures the infarcted region of every sheet cardiac muscle homonymy and non-infarcted region, calculates the percentage ratio that infarcted region accounts for the left ventricle gross area.
1.7 the detection of serum enzyme index
Get blood in Reperfu-sion 120min from carotid artery, at 4 DEG C by the centrifugal 10min of 3500 turns/min, get serum.Creatine kinase (CK) and lactic acid dehydrogenase (LDH) value in serum is detected according to the appended description of corresponding reagent box (production of Beijing Zhong Sheng biotechnology company).
1.8 statistical analysis
Test data with
represent, compare and adopt the one-way ANOVA of SPSS16.0 software kit to analyze between many groups, the neat person of variance is set up to compare and is adopted LSD inspection, and heterogeneity of variance person adopts Games-Howell to check.
2. experimental result
2.1 benzene ring nonyl esters are on the impact of the myocardial damage rat infarct size percentage ratio that myocardial ischemia-reperfusion brings out
Result is as shown in table 1, and compared with model group, verapamil and each administration group of benzene ring nonyl ester all significantly can suppress myocardial ischemia reperfusion injury (P < 0.01); Compare with positive drug verapamil, 8 and 16mg/kg benzene ring nonyl ester administration group substantially suitable to the inhibitory action of myocardial damage and verapamil, compare without significant difference between group.
Table 1 benzene ring nonyl ester (CPG) on the impact of the myocardial damage rat myocardial infarction model area percentage that myocardial ischemia-reperfusion brings out (
n=8)
*p < 0.01, compares with model group, #P < 0.05, compares with verapamil group
The impact that 2.2 benzene ring nonyl esters change myocardial ischemia-reperfusion injury in rats serum CK and LDH
Result is as shown in table 2, compares with model group, and verapamil and each administration group of benzene ring nonyl ester all significantly can suppress the rising (P < 0.05) of LDH; But the LDH of above-mentioned each group does not recover normal level completely, still have marked difference (P < 0.01) compared with sham operated rats; Compare between verapamil and benzene ring nonyl ester each administration group group, the above-mentioned each group of inhibitory action to the abnormal LDH raised is without marked difference.In addition, although each administration treated animal serum CK value all has reduction trend, not statistically significant compared with model group animal, compare without marked difference between group.
Table 2 benzene ring nonyl ester (CPG) on the impact of creatine kinase (CK) and lactic acid dehydrogenase (LDH) in myocardial ischemia-reperfusion injury in rats serum (
n=8)
*p < 0.05, compares with model group;
△ △p < 0.01, compares with sham operated rats
2.3 benzene ring nonyl esters are on the impact of myocardial ischemia-reperfusion injury in rats heart rate and blood pressure
Result is as shown in table 3, and after verapamil administration, administration treated animal blood pressure reduces rapidly, but benzene ring nonyl ester administration treated animal blood pressure has no similar significant change; After this, on each time point upon administration, verapamil administration treated animal blood pressure maintains reduced levels all the time, with equal tool marked difference before administration and compared with in the of other each group; And benzene ring nonyl ester administration treated animal blood pressure before administration after each time point there is no significant change, after showing benzene ring nonyl ester administration, animal blood pressure is had no significant effect.
To on Heart rate influences, also observe similar results.Namely after verapamil administration, upon administration on each time point, its administration treated animal heart rate significantly reduces rapidly, all there is marked difference with before administration and compared with time point other each group; And benzene ring nonyl ester administration treated animal heart rate has no remarkable change in whole experimentation.
Experimental example 2 benzene ring nonyl ester is to the protective effect of the myocardial damage that rabbit myocardial ischemia-reperfusion brings out
Rabbit is also the common experimental animal evaluating myocardial ischemia reperfusion injury medicine; for this reason; setting up on myocardial ischemia-reperfusion injury model basis; rabbit Model of Myocardial Ischemia-Reperfusion Injury is set up again in this research; adopt medicine verapamil as positive control drug; observe the protective effect of benzene ring nonyl ester to the myocardial damage that rabbit myocardial ischemia-reperfusion brings out, concrete grammar and result as follows:
1. experimental technique
The foundation of 1.1 rabbit Model of Myocardial Ischemia-Reperfusion Injuries
Healthy Male New Zealand large ear rabbit pentobarbital sodium 35mgkg
-1auricular vein injecting anesthetic, lies on the back fixing, and conventional record limbs II leads.Be separated left side jugular vein to be used for getting blood, be separated left femoral vein and be used for administration, along chest center line rip cutting skin, expose breastbone and cartilage portion.3,4 costicartilages are cut off along left sternal margin, avoid blood vessel in damage pleura and thorax, expose heart, cut off pericardium, find left anterior descending coronary artery at left auricle lower edge 0.3cm place, at left anterior descending branch underpass (3/0 silk thread), adopt ejector sleeve method ligation left anterior descending branch 30min, Reperfu-sion 60min, with ECG T wave obviously raise with ligature below cardiac muscular tissue's color by normally lose color or darkviolet for markers of cardiac ischemia.
1.2 experiment grouping and administrations
56 rabbits are divided into 7 groups at random, often organize 8.1. sham operated rats: a left anterior descending coronary artery threading not ligation; 2. ischemic reperfusion note group: before left anterior descending coronary artery ligation, continues 15min intravenous drip and the isopyknic normal saline of administration group, after this ligation 30min, Reperfu-sion 60min; 3. ~ 5. high, medium and low three dosage groups of benzene ring nonyl ester: before left anterior descending coronary artery ligation, continue 15min intravenous drip various dose (12,6 and 3mgkg
-1) benzene ring nonyl ester, ligation 30min, Reperfu-sion 60min; 6. verapamil (VP) 0.2mgkg
-1group: method with 3. ~ 5.; 7. Normal group: only blood drawing measures serum enzyme values.
1.3 experimental apparatus
Identical with the instrument used in the pharmacodynamics test that " experimental example 1 " carries out on rat.
1.4 dosage
1.4.1 benzene ring nonyl ester
Intravenous injection benzene ring nonyl ester 12,6 and 3mgkg
-1, by body surface area conversion, be equivalent to people respectively successively with dosage 0.97,1.94 and 3.89mgkg
-1.
1.4.2 verapamil
Verapamil hydrochloride injection is produced by Shanghai Hefeng Pharmaceutical Co., Ltd..Intravenous injection verapamil hydrochloride 0.2mgkg
-1.
The detection of 1.5 myocardial infarction areas mensuration and serum enzyme index
After perfusion 60min, put to death animal, carry out myocardium TTC dyeing and serum enzyme mensuration, the pharmacodynamics test that its method is carried out on rat with " experimental example 1 " is substantially identical, does not repeat.
1.6 statistical analysis
Identical with the statistical analysis adopted in the pharmacodynamics test that " experimental example 1 " carries out on rat.
2. experimental result
2.1 affect myocardial infarction area
Result is as shown in table 4, and verapamil (0.2mg/kg) and benzene ring nonyl ester (12,6 and 3mg/kg) each dosage group all significantly can reduce myocardial infarction area (P < 0.01).Compare between each administration group group, verapamil is substantially suitable with the effect of benzene ring nonyl ester high, middle dosage group, its effect is all better than benzene ring nonyl ester low dosage administration group (P < 0.01), but compares without significant difference between above-mentioned three groups of groups.
Table 4 benzene ring nonyl esters etc. are on myocardial ischemia reperfusion injury rabbit myocardial infarction area impact (n=8)
* P < 0.01, compares with model group;
#p < 0.05, compares with benzene ring nonyl ester low dose group
2.2 affect LDH and CK
CK and LDH value in serum is detected according to the appended description of corresponding reagent box (production of Beijing Zhong Sheng biotechnology company).Result is as shown in table 5, and each administration group all effectively can reduce the abnormal LDH value (P < 0.01) increased.Compare between benzene ring nonyl ester each administration group group, high, middle dosage group LDH value lower than low dose group (P < 0.05), but compares without remarkable significant difference between the above two groups.In addition, although compared with model group, each administration group CK value all significantly reduces (P < 0.05/0.01), but in verapamil, benzene ring nonyl ester, the CK value of dosed administration group is wanted significantly lower than benzene ring nonyl ester low dose group (P < 0.05).
2.3 affect SOD and MDA
Superoxide dismutase (SOD) and malonaldehyde (MDA) is detected according to the appended description of corresponding reagent box (Bioengineering Research Institute is built up in Nanjing).Result is as shown in table 6, and model group animal serum SOD and MDA value have no remarkable change compared with sham operated rats, and each administration treated animal SOD and MDA value are also without significantly increase and decrease.
Table 5 benzene ring nonyl esters etc. are on myocardial ischemia reperfusion injury rabbit anteserum LDH and CK value impact (n=8)
●p < 0.05 * * P < 0.01, compares with model group;
●
#p < 0.05, compares with benzene ring nonyl ester low dose group
Table 6 benzene ring nonyl esters etc. are on myocardial ischemia reperfusion injury rabbit anteserum superoxide dismutase (SOD) and malonaldehyde (MDA) value impact (n=8)
The above results comprehensively shows, benzene ring nonyl ester significantly can suppress myocardial ischemia reperfusion injury, and its effect and positive treatment medicine verapamil are substantially suitable, and without the apparent side effect such as hypotension, bradycardia that verapamil has.Therefore show that benzene ring nonyl ester is efficient, low toxic and side effects myocardial ischemia-reperfusion medicine.
Benzene ring nonyl ester has two chiral enantiomer; i.e. levo form and d-isomer; pharmacotoxicological effect in view of benzene ring nonyl ester may be the superposition of two chiral enantiomer pharmacotoxicological effects; therefore show that the chiral enantiomer pharmacotoxicological effect of benzene ring nonyl ester may be similar with its DL body, the protective effect to myocardial ischemia reperfusion injury may be had equally.
Claims (9)
1. the purposes of the benzene ring nonyl ester shown in following formula (I) in the medicine of the myocardial damage that preparation is treated or alleviate myocardial ischemia Reperfu-sion brings out
2. purposes according to claim 1, the dosage of wherein said benzene ring nonyl ester is 0.1 ~ 30mg/kg.
3. purposes according to claim 1, the dosage of wherein said benzene ring nonyl ester is 0.5 ~ 20mg/kg.
4. purposes according to claim 1, the dosage of wherein said benzene ring nonyl ester is 1 ~ 15mg/kg.
5. purposes according to claim 1, the dosage of wherein said benzene ring nonyl ester is 1 ~ 10mg/kg.
6. purposes according to claim 1, the dosage of wherein said benzene ring nonyl ester is 5 ~ 10mg/kg.
7. purposes according to claim 1, wherein said benzene ring nonyl ester is levo form or d-isomer.
8. the purposes according to any one of claim 1-7, wherein benzene ring nonyl ester and pharmaceutic adjuvant form pharmaceutical composition, and described pharmaceutic adjuvant comprises diluent, filler, binding agent, wetting agent, absorption enhancer, surfactant, absorption carrier and lubricant.
9. purposes according to claim 8, described pharmaceutical composition is the form of injection, tablet, capsule, powder, granule, lozenge, suppository or oral liquid.
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|---|---|---|---|
| CN201110398113.8A CN103127106B (en) | 2011-12-05 | 2011-12-05 | Purpose of phencynonate hydrochloride for treating or relieving myocardial damage induced by myocardial ischemia reperfusion and pharmaceutical compositions including phencynonate hydrochloride |
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| CN201110398113.8A CN103127106B (en) | 2011-12-05 | 2011-12-05 | Purpose of phencynonate hydrochloride for treating or relieving myocardial damage induced by myocardial ischemia reperfusion and pharmaceutical compositions including phencynonate hydrochloride |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1312073A (en) * | 2001-02-28 | 2001-09-12 | 中国人民解放军军事医学科学院毒物药物研究所 | New application of benzene ring pelargonate hydrochloride |
-
2011
- 2011-12-05 CN CN201110398113.8A patent/CN103127106B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1312073A (en) * | 2001-02-28 | 2001-09-12 | 中国人民解放军军事医学科学院毒物药物研究所 | New application of benzene ring pelargonate hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 陈小飞.盐酸苯环壬酯等对实验性脑缺血再灌注损伤的治疗效果及相关作用机制研究.《中国优秀硕士学位论文全文数据库(电子期刊)》.2011,第2011年卷(第04期),第29至30页. * |
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