CN1823785A - 噻萘普汀在制备治疗或预防mdma神经毒性的药中的应用 - Google Patents
噻萘普汀在制备治疗或预防mdma神经毒性的药中的应用 Download PDFInfo
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Abstract
本发明公开了噻萘普汀在治疗或预防3,4亚甲二氧甲基苯丙胺(MDMA)所致神经毒性的药中的应用。在对实验大鼠给予MDMA之后5小时给予噻萘普汀(30mg/kg,灌胃,每天两次),在对实验大鼠给予MDMA之前7天、在对实验大鼠给予MDMA之后半小时给予噻萘普汀(15mg/kg,灌胃,每天两次)均能减少额叶皮层、海马和纹状体三个脑区5-HT的耗竭,并对SERTmRNA的表达下调具有明显的抑制作用;神经病理学的结果显示:噻萘普汀还能抑制MDMA所致的银染色阳性面积的减少,并使胶质纤维酸性蛋白(GFAP)的表达下调,这间接反映神经损伤的程度有所减轻。
Description
技术领域
本发明涉及抗抑郁药物噻萘普汀的用途,尤其是在制药领域中的用途。
背景技术
3,4亚甲二氧甲基苯丙胺(3,4-methylenedioxy-methamphetamine,MDMA,我国俗称“摇头丸”,在该说明书的后续内容中,以“MDMA”代表“3,4亚甲二氧甲基苯丙胺”)属于苯丙胺类兴奋剂,能诱导新奇感觉、增强快感、提高兴奋性,是娱乐场所易获得的非法药品(Kaplan HI,and Sadock BJ.Synopsis of Psychiatry.8th ed.Baltimore:Maryland Composition publishers,Inc.1998,pp:407-412)。近年来以MDMA为代表的苯丙胺类兴奋剂在国际上迅速泛滥,我国也面临着继海洛因之后MDMA流行性滥用的威胁。MDMA能破坏实验动物及人类不同脑区的5-HT能神经末梢,引起长期的神经毒性(Hegadoren KM,Baker GB,Bourin M.3,4-methylenedioxy analogues of amphetamine:defining therisks to humans.Neurosci Biobehav Rev,1999;24:539-553)。目前主要的治疗及干预方向集中在用药物诱导低热或阻止MDMA所致高热。中国专利ZL 200410022529.X公开了舒必利在制备治疗或预防3,4亚甲二氧甲基苯丙胺所致神经毒性的药中的应用,对MDMA中毒的治疗提供了一种有效的新药品,但由于MDMA等苯丙胺类兴奋剂的泛滥,开发出更多的新药是社会的需要。
噻萘普汀,化学名称为7-[(3-氯-6,11-二氢-5,5-二氧-6-甲基二苯并-[c,f][1,2]噻唑平-11-基)氨基]庚酸钠盐,分子式C21H24ClN2NaO4S,分子量:458.9,化学结构式如下:
噻萘普汀(Tianeptine)是新型的三环类抗抑郁剂,目前主要用于治疗抑郁症,其剂型为片剂。
发明内容
本发明的目的在于证明噻萘普汀的新用途,即在制药中的新用途,为治疗或预防MDMA所致神经毒性提供新的药品。
本发明通过实验证明:在与人类娱乐性使用的剂量相似时,可导致实验动物的神经毒性损害,多次使用可导致5-HT的长期耗竭。以实验大鼠为例,MDMA造成其5-HT能神经毒性,功能改变包括前脑组织5-HT及其代谢产物5-HIAA的长期减少,5-HT摄取位点(即5-HT转运体SERT)减少及色氨酸羟化酶的活性降低;形态学上可引起5-HT能神经末梢的损害。
本发明通过实验证明:在对实验大鼠给予MDMA之后5小时给予噻萘普汀(30mg/kg,灌胃,每天两次)治疗,能减少额叶皮层、海马和纹状体三个脑区5-HT的耗竭,并对SERTmRNA的表达下调具有明显的抑制作用;神经病理学的结果显示:噻萘普汀还能抑制MDMA所致的银染色阳性面积的减少,并使胶质纤维酸性蛋白(GFAP)的表达下调,这间接反映神经损伤的程度有所减轻;在对实验大鼠给予MDMA之前7天、在对实验大鼠给予MDMA之后半小时给予噻萘普汀(15mg/kg,灌胃,每天两次)治疗,也有上述效果。因此可将噻萘普汀用来治疗或预防MDMA所致神经毒性的药品。
本发明采用高效液相色谱法(HPLC)检测5-HT,原位杂交法检测SERTmRNA的表达,银染色法显示神经末梢的损害,免疫组化SP法检测GFAP的表达。
本发明具有以下有益效果:
1、本发明对已知化合物噻萘普汀发掘了新的医疗用途,开拓了一个新的应用领域。
2、本发明对MDMA中毒的治疗提供了一种有效的新药品,可抵御毒品对人们的危害,具有明显的社会效益和经济效益。
附图说明
图1是各组实验大鼠额叶皮层5-HT的含量图;
图2是各组实验大鼠海马5-HT的含量图;
图3是各组实验大鼠纹状体5-HT的含量图;
图4是用原位杂交法检测MDMA组的SERTmRNA表达结果图;
图5是用原位杂交法检测既给予MDMA、又给予噻萘普汀(给予MDMA之后半小时给予噻萘普汀,15mg/kg,灌胃,每天两次)治疗实验组的SERTmRNA表达结果图;
图6是用原位杂交法检测生理盐水对照组的SERTmRNA表达结果图;
图7是给予MDMA实验组的银染色结果图;
图8是既给予MDMA、又给予噻萘普汀(给予MDMA之后半小时给予噻萘普汀,15mg/kg,灌胃,每天两次)治疗实验组的银染色的结果图;
图9是生理盐水对照组的银染色结果图;
图10是免疫组化SP法检测MDMA组的GFAP表达结果图;
图11是免疫组化SP法检测既给予MDMA、又给予噻萘普汀(给予MDMA之后半小时给予噻萘普汀,15mg/kg,灌胃,每天两次)治疗实验组的GFAP表达结果图;
图12是免疫组化SP法检测生理盐水对照组的GFAP表达结果图。
具体实施方式
1、材料与方法
1.1材料
1.1.1动物 Wistar雄性大鼠90只,体重180±2克,购自四川大学实验动物中心,将动物随机分为6组,每组15只。实验前让动物在清洁恒温(20℃±2℃)恒湿(湿度50%)饲养室适应3天,每天抓取一次,并单笼饲养,整个实验过程中自由饮水及进食。
1.1.2药品和试剂 MDMA由中国药品生物制品检定所提供。噻萘普汀为法国施维雅药厂生产(批号OE3086)。以上药品均用生理盐水溶解,给药体积为1ml/kg。SERTmRNA原位杂交试剂盒购自武汉博士德公司。10%水合氯醛(由四川大学华西医院药房提供,批号020524),用于动物麻醉。胶质纤维酸性蛋白GFAP(兔单克隆抗体,稀释度为1∶300)购自北京中山公司。
1.2、方法
1.2.1动物实验过程 6组中随机选取一组为MDMA实验组(B组),另一组为生理盐水组(A组),噻萘普汀高剂量干预组(C组)和低剂量干预组(D、E、F组)。B组给予MDMA(8×20mg/kg每天两次,8am 8pm i.p×4天)制成亚急性中毒模型(Hegadoren KM,Baker GB,Bourin M.3,4-methylenedioxy analogues of amphetamine:defining therisks to humans.Neurosci Biobehav Rev,1999;24:539-553);C组在给予MDMA之后5小时给予噻萘普汀(30mg/kg,灌胃,每天两次));D、E、F组分别在给予MDMA之前7天、在给予MDMA的同时、在给予MDMA之后30分钟给予噻萘普汀(15mg/kg,灌胃,每天两次);A组注射等体积的生理盐水。
1.2.2取材过程 每组随机选5只大鼠在末次给药后4小时经10%水合氯醛(30mg/kg)腹腔注射麻醉,断头处死,剥离脑组织,经矢状位切开,随机取一侧半球,参照《The rat brain in stereotaxic coordinates》(Paxinos G,Watson C.The rat brain in stereotaxiccoordinates,1986;2nd edition.Academic Press INC.(London)LTD,London.Figure1~25),修块后迅速置于冰冻切片机中,行8μm连续冠状切片,取含有纹状体、海马及额叶皮层等脑结构的切片,置于-70℃冰箱中备用。另一侧大脑半球置于10%福尔马林中固定,石蜡包埋,制成厚度为8μm的连续切片备用(因Bielschowsky及Glee Marsland氏改良银浸染法需要在损伤后短时间内处死,方能取得最佳染色效果(Gallyas F,Zaborszky L,Wolff JR.Experimental studies of mechanisms involved in methods demonstrating axonal and terminal degeneration.Stain Technol,1980,55:281-290)。
每组剩下的10只大鼠中随机选5只在末次药物注射后7天断头处死,取材方法同上,冰冻切片为8μm连续冠状切片,石蜡切片为4μm的连续切片备用。
每组中最后5只大鼠在末次药物注射后7天,将之拉脱颈髓并断头,快速剥离脑组织,在冰上分离出海马、前脑额叶皮层和纹状体,置于液氮中速冻后,储存于-70℃冰箱中备测。测定前将上述组织融化,称重,在超声匀浆机(型号Sonics&materials Inc.(203)-744-4400)上匀浆。
1.2.3神经递质5-HT的检测 将前述匀浆置于高效液相色谱仪(HPLC)进行检测。方法如下:取用流动相稀释的5-羟色胺(5-HT)标准溶液100μl(或大鼠脑组织100μl),加入2ml离心管内,分别加入16ng/ml2,4-二羟基苄胺(I.S)和10%HClO4溶液30μl,混匀,高速离心(12000/min,4℃)8min,取上清液100μl进样,记录色谱峰高,由标准系列中5-HT与I.S的峰高比对浓度作标准曲线,求出回归方程。然后由样品中5-HT与I.S的峰高比在回归方程上求出浓度。
仪器与色谱条件:Waters510泵,Gilson 141-ECD(玻璃碳工作电极,Ag-AgCl参比电极),U6K进样器,460电化学检测器,高速离心机,旋涡振荡器。江苏淮阴KROMASILC18柱(250mm×4.6mm,5μm),流动相为0.05mol/L NaAc-Hac(PH3.0)∶CH3OH∶0.05mol/LEDTA-Na2(78∶20∶2),流速1.0ml/min,每1L流动相加入十二烷基硫酸钠100mg;氧化电压为0.69V。
1.2.4SERTmRNA原位杂交检测 按试剂盒说明书提供的方法进行:设计的探针为针对Serotenin transporter(SERT)的寡核苷酸探针,经地高辛标记。试剂盒内容:胃蛋白酶(×10;Pepsin)2ml;预杂交液2ml;Serotenin transporter寡核苷酸探针杂交液2ml;封闭液5ml;生物素化鼠抗地高辛5ml;SABC-POD 5ml;生物素化过氧化物酶5ml。
SERT靶基因的mRNA序列为:
①5’-GGCGC TTCCC CTACA TATGT TCCCA GAATG-3’
②5’-AGGTG GTGTG GGTGA CAGCC ACCTT CCCTT-3’
③5’-TGGTT CTGGA GGATC TGCTG GGTGG CCATC-3’
实验中所用缓冲液及其配制:
3%柠檬酸-100ml蒸馏水中加柠檬酸(C6H8O7·H2O),pH2.0;
2×SSC-1000ml蒸馏水中加NaCl 17.6g,柠檬酸三钠(C6H5O7Na3·2H2O,分子量294)8.8g;
0.5×SSC-300ml蒸馏水中加100ml 2×SSC即可;
0.2×SSC-270ml蒸馏水中加30ml 2×SSC即可;
0.5MPBS-1000ml蒸馏水中加NaCl 30g,Na2HPO4·12H2O 6g,NaH2PO4·2H2O0.4g,pH7.2-7.6。
操作程序如下:
1)冷冻切片按下述方法固定:固定液为4%多聚甲醛/0.1M PBS(PH7.2-7.4),含有1/1000DEPC。室温固定20-30min,蒸馏水分洗涤;
2)新鲜配制0.5%H2O2/甲醇室温处理30min以灭活内源性过氧化物酶,蒸馏水洗涤3次;
3)暴露mRNA核酸片段:切片上滴加3%柠檬酸新鲜稀释的胃蛋白酶,37℃消化2min,0.5M PBS洗3次×5min,蒸馏水洗1次;
4)预杂交:按每张切片20μl加预杂交液,放入湿盒,置于37℃恒温箱孵育4小时,吸取多余液体,不洗;
5)杂交:按每张切片20μl杂交液,加在切片上,将原位杂交专用盖玻片的保护膜揭开后,盖在切片上,恒温箱37℃杂交过夜;
6)杂交后洗涤:揭掉盖玻片,37℃左右水温的2×SSC洗涤,5min×2次,0.5×SSC洗涤15min×1次,0.2×SSC洗涤15min×1次;
7)滴加封闭液:37℃30min,甩去多余液体,不洗;
8)滴加生物素化鼠抗地高辛:37℃孵育60min,0.5M PBS洗5min×4次;
9)滴加SABC:37℃孵育20min,0.5M PBS洗5min×3次;
10)滴加生物素化过氧化物酶:37℃孵育20min,0.5M PBS洗5min×4次;
11)DBA显色:使用DBA显色试剂盒-1ml蒸馏水加显色剂A,B,C各一滴,混匀,加至标本上显色,用自来水适时终止;
12)酒精脱水,二甲苯透明,加拿大胶封片。
阴性对照:切片上不加含探针的杂交液,以PBS替代,其余步骤相同。
1.2.5Bielschowsky及Glee Marsland氏改良银浸染法:观察各组神经元、轴索及树突的变化。以上切片均请病理学专家盲法读片。改良银浸染方法如下:
1)石蜡切片8μm,二甲苯脱蜡,浸入纯酒精;
2)用0.2%火棉胶封盖切片,以免脱片;
3)擦掉多余的火棉胶,再入70%酒精硬化,蒸馏水洗三次;
4)入20%硝酸银水溶液25~30min,置于37℃孵箱;
5)蒸馏水洗2次,入10%甲醛自来水溶液浸二次,每次10秒,切片呈黄色,除掉多余的甲醛溶液;
6)切片浸于Glee氏铵银液30秒;
7)排去切片上多余的铵银液,浸入10%甲醛自来水溶液,每次1min,切片呈棕黄色,甲醛呈黑色,蒸馏水洗;
8)调色于0.2%氯化金水溶液5min;
9)蒸馏水洗后入5%硫代硫酸钠溶液固定5min,自来水清洗;
10)吸干、酒精脱水(因金属沉淀常附于火棉胶膜上,纯酒精浸泡可溶解胶膜),二甲苯透明,树胶封固。
1.2.6免疫组织化学染色采用SP法(Streptavidin-biotin immuno peroxidase methed),步骤如下:
1)4μm厚石蜡组织切片裱于经3-氨基丙基三乙氧硅烷(3-amino-propyltriethoxylsilane,APES,Sigma)硅化的切片上,置37℃恒温箱48小时;
2)二甲苯脱蜡10min×2,依次通过梯度乙醇(100%、95%、80%、70%)水化各5min,蒸馏水洗5min×2;
3)置于新鲜配制的3%过氧化氢溶液,避光室温放置20min,以阻断内源性过氧化物酶;
4)蒸馏水洗5min×2;
5)切片放入0.01M枸橼酸盐缓冲液内(pH6.0),微波抗原修复15min,冷却至室温后取出切片,0.01MPBS(pH7.2)洗5min×2;
6)用正常羊血清(即用型)37℃孵育25min,封闭非特异性抗原抗体反应;
7)弃去多余血清,直接滴加一抗(稀释度1∶300),37℃孵育30min后,置4℃冰箱过夜;
8)0.01M PBS洗5min×3,滴加生物素标记二抗(即用型),37℃孵育30min;
9)0.01M PBS洗5min×3,滴加链亲和素-过氧化物酶复合物(即用型),37℃,孵育30min;
10)0.01M PBS洗5min×3,用新鲜配制的DAB在光学显微镜观察下显色,自来水冲洗,适时终止;
11)Harris苏木素复染细胞核,1%盐酸酒精分化,充分水洗返蓝,梯度酒精脱水,二甲苯透明,中性树胶封片。
2、结果
2.1神经递质5-HT的检测结果
给予MDMA7天后,与生理盐水组比较,大鼠额叶皮层、海马和纹状体的5-HT均有下降(P<0.05),三个脑区的下降率分别为68.14%、74.27%和37.38%,其中海马的5-HT降低最明显。在给予MDMA之前7天、在给予MDMA之后半小时再给予噻萘普汀(15mg/kg,灌胃,每天两次),5-HT降低不明显;在给予MDMA之后5小时再给予噻萘普汀(30mg/kg,灌胃,每天两次),5-HT降低也不明显,说明两个剂量之间的噻萘普汀对5-HT功能的损害具有预防和治疗作用。详情见表1-1、表1-2和图1、图2、图3。
表1-1大鼠不同脑区5-HT的检测结果(ng/g)(噻萘普汀15mg/kg)
组别 | 皮层5-HT | P值 | 海马5-HT | P值 | 纹状体5-HT | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(-7d)噻萘普汀+MDMA(同时)噻萘普汀+MDMA(+1/2h) | 29.06±0.18u9.26±1.4412.55±0.52*9.71±0.5611.98±0.82* | 0.0000.0050.5400.009 | 38.16±1.27*9.82±2.8324.90±1.16*11.48±1.6914.92±0.60* | 0.0000.0000.3000.014 | 50.56±0.70*31.66±0.1137.93±2.20*32.04±0.9635.60±1.96* | 0.0000.0010.5700.007 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
表1-2大鼠不同脑区5-HT的检测结果(ng/g)(噻萘普汀30mg/kg)
组别 | 皮层5-HT | P值 | 海马5-HT | P值 | 纹状体5-HT | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(+5h) | 29.06±1.18*9.26±1.4411.18±0.84* | 0.0000.04 | 38.16±1.27*9.82±2.8314.01±2.09* | 0.0000.031 | 50.56±0.70*31.66±0.1133.88±0.95* | 0.0000.009 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
2.2SERTmRNA原位杂交检测结果
生理盐水组的SERTmRNA原位杂交结果见图6和表2-1、表2-2,MDMA组的SERTmRNA原位杂交结果见图4和表2-1、表2-2,给予MDMA 7天之后大鼠额叶皮层、海马和纹状体的SERTmRNA的表达均有一定程度的降低(P<0.05),说明MDMA可导致SERTmRNA的表达下调。在给予MDMA之前7天、在给予MDMA之后半小时给予噻萘普汀(15mg/kg,灌胃,每天两次),SERTmRNA的表达有上调,见表2-1和图5;在给予MDMA之后5小时再给予噻萘普汀(30mg/kg,灌胃,每天两次),SERTmRNA的表达也有上调,见表2-2。说明不同时间给予噻萘普汀对大鼠额叶皮层、海马和纹状体的SERTmRNA表达的降低具有抑制作用(P<0.05)。
表2-1三个脑区SERTmRNA原位杂交结果(阳性细胞计数
x±S)(噻萘普汀15mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(-7d)噻萘普汀+MDMA(同时)噻萘普汀+MDMA(+1/2h) | 34.60±1.14*13.00±1.5821.20±1.30*13.80±2.5917.80±1.92* | 0.0000.0000.5750.003 | 49.80±1.92*17.20±1.9222.20±2.28*19.40±2.6121.60±2.41* | 0.0000.0060.1710.014 | 34.80±3.27*21.80±3.0326.00±2.55*23.00±2.7424.80±2.39 | 0.0000.0460.5300.123 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
表2-2三个脑区SERTmRNA原位杂交结果(阳性细胞计数
x±S)(噻萘普汀30mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(+5h) | 34.60±1.14*13.00±1.5815.00±2.55 | 0.0000.182 | 49.80±1.92*17.20±1.9220.80±2.39* | 0.0000.032 | 34.80±3.27*21.80±3.0326.60±2.07* | 0.0000.022 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
2.3银染色的结果
生理盐水组的银染色结果见图9、表3-1、表3-2,MDMA组的银染色结果见图7、表3-1、表3-2,与生理盐水组比较,MDMA可造成神经元轴索脱髓鞘改变,树突减少,在5-HT能神经元集中的脑区上述变化显著;在给予MDMA之前7天、在给予MDMA之后半小时给予噻萘普汀(15mg/kg,灌胃,每天两次),以及在给予MDMA之后5小时再给予噻萘普汀(30mg/kg,灌胃,每天两次),银染色阳性面积接近生理盐水组,神经毒性损害较单用MDMA组明显减轻,见表3-1、表3-2和图8。
表3-1大鼠三个脑区银染的阳性面积(
x±S)(噻萘普汀15mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(-7d)噻萘普汀+MDMA(同时)噻萘普汀+MDMA(+1/2h) | 66.98±3.45*53.89±3.1862.03±2.65*56.47±1.7458.24±1.48* | 0.0000.0020.1600.034 | 58.89±2.72*51.16±2.0555.10±2.12*51.78±1.5953.96±1.16* | 0.0010.0170.6060.036 | 75.38±2.63*65.26±1.8070.04±2.98*66.28±1.5468.82±2.55* | 0.0000.0190.3650.037 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
表3-2大鼠三个脑区银染的阳性面积(
x±s)(噻萘普汀30mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(+5h) | 66.98±3.45*53.89±3.1856.16±2.15 | 0.0000.226 | 58.89±2.72*51.65±1.2753.76±0.97* | 0.0000.045 | 75.38±2.63*65.26±1.8068.76±2.13* | 0.0000.024 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
2.4GFAP免疫组织化学染色的结果
生理盐水组的GFAP表达结果见图12和表4-1、表4-2,MDMA组的GFAP表达结果见图10、和表4-1、4-2,从上述图和表中可以看出,给予MDMA 7天之后,额叶皮层、海马、纹状体的GFAP表达较生理盐水组增多;在给予MDMA之前7天、在给予MDMA之后半小时给予噻萘普汀(15mg/kg,灌胃,每天两次),以及在给予MDMA之后5小时再给予噻萘普汀(30mg/kg,灌胃,每天两次),三个脑区的GFAP表达显著减少,见表4-1、表4-2和图11。
表4-1GFAP阳性细胞计数(
x±S)(噻萘普汀15mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(-7d)噻萘普汀+MDMA(同时)噻萘普汀+MDMA(+1/2h) | 6.20±2.39*24.80±2.3911.60±1.14*22.40±2.4120.40±1.14* | 0.0000.0000.1520.011 | 8.00±1.58*22.40±1.9519.40±1.14*21.00±2.9219.60±1.14* | 0.0000.0230.4020.030 | 6.20±1.64*25.80±1.9217.60±2.07*24.80±1.9220.40±2.07* | 0.0000.0000.4350.003 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
表4-2GFAP阳性细胞计数(
x±S)(噻萘普汀30mg/kg)
组别 | 额叶皮层 | P值 | 海马 | P值 | 纹状体 | P值 |
生理盐水组MDMA组噻萘普汀+MDMA(+5h) | 6.20±2.39*24.80±2.3921.20±1.79* | 0.0000.029 | 8.00±1.58*22.40±1.9519.80±0.84* | 0.0000.037 | 6.20±1.64*25.80±1.9221.00±2.35* | 0.0000.008 |
*P<0.05,与MDMA组比较,在统计学上有显著性差异。
Claims (2)
1、噻萘普汀在制备治疗或预防3,4亚甲二氧甲基苯丙胺所致神经毒性的药中的应用。
2、根据权利要求1所述的应用,其特征在于所给噻萘普汀的剂量为15mg/kg~30mg/kg。
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