CN1269482C - 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 - Google Patents
钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 Download PDFInfo
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Abstract
本发明涉及能够与钠离子通道的α-亚单位的SS1或SS2部位的外端受体位点结合的钠离子通道阻断剂与阿片类镇痛剂的组合在制备用于对晡乳动物进行协同镇痛的药物中的应用。根据本发明的药物组合物可以增强镇痛效果，减少吗啡用量，从而相应降低副作用和不良反应。
Description
本发明涉及能够与钠离子通道的α-亚单位的SS1或SS2部位的外端受体位点结合的钠离子通道阻断剂与阿片类镇痛剂的组合在制备用于对哺乳动物进行协同镇痛的药物中的应用。根据本发明的药物组合物可以增强镇痛效果，减少吗啡用量，从而相应降低副作用和不良反应。
临床上对严重的疼痛通常用阿片类药作镇痛治疗，例如癌症和手术后疼痛。吗啡是经典的强效中枢性镇痛药，目前临床应用较多；但它也带来一系列不良后果和严重的副作用，包括有效镇痛持续时间短、呼吸困难、恶心、便秘、产生耐受性、依赖性和成瘾性等等。
此问题长期以来一直未得到解决，近期的研究热点是尝试寻找吗啡的衍生物，改变其化学结构可能减少副作用等，如Hartmann等(美国专利6,150,524；2000年11月21日)以及Nagase等(美国专利6,177,438；2001年1月23日)，由于发明时间短，实践支持的数据颇不足够。
曾有报导Adams等(Adams等人，Synergistic local anesthetic compositions，第4,022,899号美国专利，1977年5月10日)将河豚毒素或STX及其类似物作为几种局部麻醉药(属基烷苯甲盐类)的协同用药，使局部麻醉的持续时间增长，或者使达到同样局麻效果所需的上述麻醉药剂量减少，在此现有技术中，它的发明描述已指明是对一般局部麻醉药(特指有阻断神经传导性能的)来局部联合给药达致局部麻醉，而我们的发明是用河豚毒素与中枢神经镇痛药吗啡来协同给药，属于全身性给药，在机理上其差异是显而易见的。
伤害性感受(nociception)是中枢神经系统对伤害性感受器刺激而引起的传入信息的加工反应。伤害性刺激引起初级传入末梢去极化，使感受器兴奋，感受和传导伤害性刺激的传入纤维主要是有髓的Aδ类和无髓的C类纤维，感受器兴奋产生冲动经由背根神经节和三叉神经节中的中小型神经感受并传递，引起伤害性感受和疼痛。感觉作为一个报警系统，使机体对所受到的伤害性刺激作出逃避或防御反应。
河豚毒素对伤害性刺激引起疼痛的调节作用早已被关注，在受到伤害性刺激的大鼠疼痛试验模型上，河豚毒素抑制脊髓背根神经节(DRG)和脊髓背角(DH)异位放电，降低神经的兴奋性，提高痛感受器反应阈值(Catterall WA.Cellular andmolecular biology of voltage gated sodium channels.Physiol Rev.1992；72；15-18.)。在哺乳动物感觉神经的DRG，至少存在两种类型电压依赖的钠通道，即快速内流的河豚毒素敏感(TTX-S)钠通道和缓慢内流的河豚毒素不敏感(TTX-R)钠通道(Kostyun，P.G.，Veselovsky，N.S和Tsyndrenko，A.Y.，Ionic currents in the somaticmembrane of rat dorsal root ganglion neurons.I.Sodium current，Neuroscience，6(1981)2423-2430)。河豚毒素在外周可阻断电刺激引起的快兴奋性突触后电位(EPSPs)，对缓慢的EPSPs没有影响(Srdija Jeftinija，The role of tetrodotoxin-resistant Sodium channels of small primary afferent fibers.Brain Research 639(1994)125-134.)。这就能解释以前大鼠甲醛法试验中河豚毒素用到2.5μg/kg时其镇痛抑制率也只达到71.7％(替曲朵辛注射液主要药效学实验资料及文献资料《制剂资料12》)。
经典镇痛药吗啡的镇痛作用主要是通过脊髓背角表层的μ受体介导的(Besse，D.，Lombard，M-C.和Besson，J-M(1991)Autoradiographic distribution of mu，deltaand kappa opioid binging sites in the superficial dorsal horn，over the rostrocaudal axisof the rat spinal cord.Brain Res.，548：287-291)。最近实验发现，在大鼠疑核神经元密集区(AMBC)注入吗啡可使膜电位超极化并使自发兴奋性突触后电位(EPSP)消失(Zhang M，Nie L，Liu L，Wang YT，Neuman RS，Bieger D.Morphine blocked theexitatory amino acid mediated membrane current in ambignal motoneurons of the rat.Acta Physiologica Sinica，1995，47(3)，253-258)。由于K+通道可因激动μ受体开放所以吗啡增加K+电导引起超极化(Norht，R.A.和Willianms，J.T.(1985).On thepotassium conductance increased by opiates in rat brains coeruleus neurones.J.Physiol.，364，265-280)，此外自发EPSP消失也可能是影响Ca2+和Na+通透性的结果。进一步研究表明，吗啡抑制钠通道并非直接激动阿片受体所致，而是与延缓失活状态的钠通道恢复速率有关(C.-F.Hung，C.-H.Tsai和M-J.Su，Opioid receptorindependent effects of morphine on membrane currents in single cardiac myocytes，British Journal of Anesthesia 1998；81：925-931)。
为解决此问题，我们的思路是另一方向。我们发现河豚毒素能与吗啡起到较好的协同镇痛作用。河豚毒素具有对心血管系统、镇痛及局麻等方面的药理作用，尤其对多种钝痛及锐痛具有明显缓解作用，且无依赖性，正如在我们已递交的专利“全身给药的镇痛方法”(董庆滨，沈希光，中国专利申请号00124517.1，2000年9月18日)所述：其实施例中对小鼠辐射热刺激致甩尾的镇痛实验中，单独肌肉注射河豚毒素剂量用到5.0μg/kg时，甩尾潜伏期仍未超过对照潜伏期两倍，为了提高其应用的安全性，有必要研究降低剂量而仍然达到等同或较大镇痛作用的方法。
因此，本发明的目的是提供能够与钠离子通道的α-亚单位的SS1或SS2部位的外端受体位点结合的钠离子通道阻断剂与阿片类镇痛剂的组合在制备用于对哺乳动物进行协同镇痛的药物中的应用。
根据本发明，所述的钠离子通道阻断剂和阿片类镇痛剂可各自制成药剂独立给药；或者所述的钠离子通道阻断剂和阿片类镇痛剂可配制成组合一体的药剂而同时给药，以达成协同镇痛的作用。
所述钠离子通道阻断剂是河豚毒素及其衍生物，而所述的河豚毒素衍生物包括一种或多种选自于以下组中的化合物：去水河豚毒素、胺基河豚毒素、甲氧基河豚毒素、乙氧基河豚毒素、脱氧河豚毒素及河豚酸。所述河豚毒素及其衍生物的给药剂量范围为每公斤体重0.01μg至20μg。
所述阿片类镇痛剂是吗啡，其给药剂量范围为每公斤体重0.002mg至20mg。
所述钠离子通道阻断剂是蛤蚌毒素。所述蛤蚌毒素是分子式为C10H17N7O4的化合物及其衍生物。
以下将参考附图对本发明进行更为详细的描述，其中：
图1是TTX与吗啡的联合镇痛效应-大鼠甲醛致痛模型的结果。
河豚毒素与吗啡对钠通道的阻滞作用，是本研究的理论基础。我们设想用极微量的河豚毒素与小剂量吗啡联合给药，一方面通过河豚毒素对钠通道的阻断作用，减少或防止从炎症部位发出的伤害性神经冲动传入脊髓，加之吗啡的中枢Na+阻断作用，有可能产生协同镇痛效应。
在本发明中，研究之一采用大鼠甲醛致痛模型，观察极微量河豚毒素(im.用河豚毒素LD50的1/50，1/100分别为0.39μg/kg，0.19μg/kg)与小剂量吗啡合用对甲醛(福尔马林，Formaldehyde)足背注射引起的慢性疼痛的影响，以探讨河豚毒素与常用镇痛药临床联合应用的可能性。结果在228只大鼠上试验证明：ID50较单独应用吗啡下降了16倍以上，达到了我们予期发明的目标。另外，在第二项研究中采用小鼠辐射热致痛甩尾模型，用河豚毒素LD50的1/25、1/50这样微小且安全的剂量来与吗啡联合给药，结果在320只小白鼠上试验证明：ED50较单独应用吗啡下降了1～5倍，镇痛持续时间也明显延长。
大鼠甲醛试验是测定药物镇痛活性的常用试验，通过局部刺激造成炎症模型，研究药物对伤害性刺激引起慢性疼痛的镇痛效果。实验表明，将河豚毒素的LD50的1/100剂量(0.19μg/kg)与小剂量的吗啡(0.08，0.15，0.20，0.60，1.25，2.5mg/kg)联合应用，使镇痛抑制率由原来单用吗啡的3.4％，7.2％，10.2％，11.0％，24.6％，34.9％分别达到：47.7％，62.7％，63.7％，41.8％，44.7％，86.7％，联合用药的镇痛作用较为明显。河豚毒素在0.39μg/kg剂量(河豚毒素LD50的1/50)下与吗啡联合给药仅在0.15mg/kg吗啡组镇痛作用较明显，这一现象的原因有待深入探讨。
河豚毒素具有对心血管系统，镇痛及局麻等多方面药理作用，尤其对多种钝痛及锐痛具有明显缓解作用，且无依赖性，如果通过联合给药降低使用剂量，可以进一步提高用药的安全性，优化用药效果。镇痛药吗啡对各种疼痛均有显著作用，但由于其容易产生耐受性，依赖性和成瘾性而使其使用受到很大的限制。本发明的意义在于：突破了临床传统的镇痛方法，采用小剂量吗啡与极微量的河豚毒素联合应用，能明显提高镇痛效果，同时使不良反应显著降低，为临床急慢性疼痛的治疗提供了新途径。
实施例
实施例1
本实施例通过对大鼠甲醛致痛模型联合给与吗啡和河豚毒素观察镇痛效果。
1.材料与方法
1.1动物
雄性Wistar大鼠，180～300克，由北京大学医学部实验动物中心提供，等级：一级，合格证为：013056。
1.2药品与试剂
替曲朵辛(河豚毒素，TTX)粉剂，纯度95％，由南宁枫叶药业有限公司提供，批号：032C，以醋酸缓冲液稀释至所需浓度，临用前配制。配制好的溶液保存在4℃冰箱。盐酸吗啡(morphine hydrochloride)粉剂，青海制药厂生产，批号：960802。甲醛(甲醛，Formaldehyde)，北京化工三厂生产，批号9401002，临用前配制成所需浓度。
1.3试验方法
大鼠甲醛试验(H.Gerhard Vogel，Wolfgang H.Vogel编著，杜冠华，李学军，张永祥等译，药理学实验指南-新药发现和药理学评价，科学出版社，2001年2月第一版，499-500)。选用雄性Wistar大鼠228只，体重180～240克，实验前12h禁食不禁水，按单纯随机抽样法分为24组，分别为对照组(生理盐水，NS)，盐酸吗啡组，TTX2组(0.39μg/kg，0.19μg/kg)协同给药组分别为：TTX(0.39μg/kg)+吗啡及TTX(0.19μg/kg)+吗啡。TTX和吗啡分别由大鼠肌肉注射(im.)，协同给药组同时由大鼠两侧肌肉注射，液量均为0.1ml/100g。40分钟后于右后足背皮下注射致痛剂2.5％的甲醛0.06ml/只。随后将大鼠单独置于透明的有机玻璃笼中(长×宽×高为：12×12×12cm)，观察并记录5分钟内的疼痛反应。如大鼠所有爪趾均停留在笼底，对注射爪没有明显偏爱，表明具有镇痛作用。指标：抽、抬、舔或咬后足。按下式计算痛反应评分：舔、咬后足秒数×3+抽动后足次数×2/3+抬后足秒数。将各给药组的痛反应分数与对照组的痛反应分数进行比较，按下式计算药物抑制痛反应分数的百分率：
抑制率(％)＝〔(对照组痛反应平均分-给药组痛反应平均分)/对照组痛反应平均分〕×100
用Logit法计算吗啡在该模型上的ID50值。
2.结果
经预试验，单用NS，单用缓冲液，NS+缓冲液三组结果无显著性差异，故以下实验仅以NS作为对照组，联合给药组中也不再考虑两侧及注射容量变化的影响。结果如下表1所示。
表1.TTX与吗啡联合给药的镇痛作用(大鼠甲醛法)
| 药物 | 剂量(mg/kg) | 动物数(只) | 评分 | 抑制率(％) | 吗啡ID50(mg/kg) |
| NSTTX吗啡TTX(0.39×10-3mg/kg)+吗啡TTX(0.19×10-3mg/kg)+吗啡 | 0.19×10-30.39×10-30.080.150.300.601.252.505.0010.000.080.150.300.601.252.500.080.150.300.601.252.505.00 | 8101088888888820141414881088888 | 252.3±105.4223.0±58.3169.1±47.2243.8±36.4234.0±26.9226.5±73.5274.3±119.5190.3±129.9164.3±82.049.8±34.15.6±6.5162.9±55.485.3±54.2138.0±50.7119.5±38.3109.3±64.471.6±44.2132.0±39.394.1±43.991.6±51.3146.8±66.6139.4±68.936.6±16.324.4±12.1 | 11.632.93.47.210.211.024.634.980.297.735.466.245.352.656.771.647.762.763.741.844.786.790.3 | 2.30(1.38～4.26) |
从表1以及图1可以看出.采用大鼠甲醛试验，单用吗啡的镇痛半数抑制量(ID50)为2.30mg/kg；极微量的TTX(即LD50的1/100为：0.19μg/kg)单独使用镇痛抑制率为11.6％，与小剂量吗啡联合应用后产生明显镇痛作用，如与0.30mg/kg吗啡组镇痛抑制率从单用吗啡时的10.2％达到63.7％，与2.50mg/kg吗啡组镇痛抑制率从单用吗啡时的34.9％达到86.7％；而TTX用LD50的1/50(0.39μg/kg)单独使用镇痛抑制率为32.9％，与吗啡联合给药仅在0.15mg/kg吗啡组出现最明显镇痛效应，其镇痛抑制率从单用吗啡时的7.2％升高到66.2％，其它组随着吗啡剂量加大，镇痛作用也相应增加，但不显著。
实施例2
本实施例通过对小鼠热辐射致痛甩尾模型联合给与吗啡和河豚毒素观察协同镇痛效果。
1材料与方法
1.1.动物
昆明种小白鼠，18～22克，雌雄各半，由北京大学医学部实验动物中心提供，合格证为：013056，等级：一级。
1.2.药品与试剂 替曲朵辛(河豚毒素，TTX)粉剂，纯度95％，由南宁枫叶药业有限公司提供，批号：0324C，药品稀释及配制采用该公司提供的醋酸缓冲液作为溶媒，TTX在临用前配制。配制好的溶液保存在温度为摄氏4度的冰箱。盐酸吗啡(morphine hydrochloride)粉剂，青海制药厂生产，批号960802。
1.3.实验方法 小鼠辐射热刺激法：根据改良寇氏法设计要求，进行预备实验和正式实验，分别确定吗啡单独使用及与微量TTX(选用LD50的1/25和1/50分别为0.79，0.39μg/kg)协同给药(分别两侧肌肉注射)时的每组吗啡剂量以痛阈增加1倍为标准，用概率单位法去计算半数有效量(ED50)。
药物剂量确定：通过预试验确定单独给予吗啡时的上、下限剂量，确定公比，计算出四组动物每组给药剂量。同法确定与TTX(选用LD50的1/25和1/50分别为0.79，0.39μg/kg)协同给药组的吗啡剂量。
动物分组：选取筛选过的小白鼠320只，雌雄各半，实验前12小时禁食不禁水，随机分为16组，分别为对照组(生理盐水，NS)，单用盐酸吗啡组，单用TTX 2组(选用TTX的LD50的1/25和1/50分别为0.79μg/kg，0.39μg/kg)，协同给药12组分别为：TTX(0.79μg/kg)+吗啡及TTX(0.39μg/kg)+吗啡。
辐射热测痛仪由12V、50W、8.75mm的电影放映灯的光源制成，光线经聚光灯孔聚光后照射于距小鼠尾部下1/3约1～2mm处。
TTX和吗啡分别由小鼠臀部肌肉注射(im)，协同给药组同时由小鼠两侧臀部肌肉注射，液量均为0.1ml/10g，给药后分别于15，30，45，60，90，120，150，180分钟，测量并记录小鼠出现甩尾反应的时间。连续测三次，每次相隔1分钟，记录其平均值作为痛阈。若痛阈超过20秒钟不甩尾时立即终止照射，时间以20秒计算。按下列公式计算各剂量组的反应抑制百分率，用以评定药物的镇痛强度：
反应抑制百分率(％)＝〔(实验潜伏期-对照潜伏期)〕/中断照射时间〕×100。
1.4.统计处理 采用SPSS软件进行结果处理，吗啡作用最明显时甩尾半数有效量(ED50)、半数抑制量(ID50)的计算采用概率单位法；检验药物联合作用的性质采用等效线法(徐端正编著，生物统计学在药理学中的应用，科学出版社1986年出版，第357-366页。)。
2.结果
从表2和表3可以看出，采用小鼠辐射热甩尾法，以痛阈延长1倍为指标：给药45分钟后，单用吗啡的半数有效量(ED50)为0.41mg/kg；与TTX LD50的1/25联合应用，吗啡的ED50下降到0.07mg/kg；与TTX LD50的1/50联合应用，吗啡的ED50下降到0.21mg/kg。
以基础痛阈为指标：给药45分钟后，单用吗啡的半数抑制量(ID50)为0.33mg/kg；与小剂量的TTX联合应用，吗啡的ID50下降到0.08mg/kg、0.15mg/kg；吗啡与0.79μg/kg TTX联合应用ID50下降幅度超过4倍；与0.39μg/kg TTX联合应用ID50下降幅度约为1倍。
表2.TTX与吗啡联合给药的镇痛作用-半抑制剂量(小鼠热辐射致痛甩尾法，甩尾潜伏期X±SD，n＝20)与吗啡的半抑制剂量比较
| 分组 | 剂量(mg/kg) | 痛阈 | 给药后痛阈 | 抑制率(％) | ID50&95％可信限 |
| 对照组(生理盐水)TTX盐酸吗啡TTX(0.79ug/kg)+盐酸吗啡TTX(0.39ug/kg)+盐酸吗啡 | 0.79×10-30.39×10-30.010.060.331.800.0040.0160.0730.3300.010.050.281.50 | 5.36±0.965.25±0.595.56±0.815.48±1.445.83±1.495.21±1.395.63±1.315.83±1.266.37±1.085.78±1.296.31±1.105.76±0.895.84±0.735.55±0.885.61±0.86 | 5.43±0.896.04±0.765.88±1.006.35±1.878.67±2.5410.04±2.4918.94±1.027.22±1.149.96±2.4011.82±2.6517.21±2.238.17±1.9410.16±1.8512.50±3.4616.28±2.53 | 1.2912.065.4413.7032.7648.1170.2719.2536.0451.0963.3329.5042.5255.6065.54 | 0.33(0.21～0.55)0.08(0.05～0.14)0.15(0.08～0.33) |
表3.TTX与吗啡联合给药的镇痛作用-半有效剂量(小鼠热辐射致痛甩尾法，n＝20)吗啡的半有效剂量(ED50)与给药后45分钟的痛阈比较
| 组 | 剂量(mg/kg) | n(正作用) | 正作用率(％) | ED50&95％可信限 | ED95&95％可信限 |
| 对照(N.S)TTX盐酸吗啡TTX(0.79ug/kg)+盐酸吗啡TTX(0.39ug/kg)+盐酸吗啡 | 0.79×10-30.39×10-30.010.060.331.800.0040.0160.0730.3300.010.050.281.50 | 02720021020121420 | 010351000105010051070100 | 0.41(0.30～0.84)0.07(0.06～0.10)0.21(0.16～0.29) | 0.77(0.54～1.91)0.13(0.10～0.22)0.42(0.33～0.62) |
Claims (8)
1.能够与钠离子通道的α-亚单位的SS1或SS2部位的外端受体位点结合的钠离子通道阻断剂与阿片类镇痛剂的组合物在制备用于对哺乳动物进行协同镇痛的药物中的应用，其中，所述的钠离子通道阻断剂包括一种或多种选自由河豚毒素、去水河豚毒素，胺基河豚毒素，甲氧基河豚毒素，乙氧基河豚毒素，脱氧河豚毒素及河豚酸组成的组或者为蛤蚌毒素，并且，所述的阿片类镇痛剂是吗啡。
2.如权利要求1所述的应用，其中，所述的药物是所述的钠离子通道阻断剂和阿片类镇痛剂组合一体的药剂。
3.如权利要求1所述的应用，其中，所述的药物是所述的钠离子通道阻断剂和阿片类镇痛剂各自独立的药剂。
4.如权利要求1所述的应用，其中，所述的药物是通过注射进行给药的药剂。
5.如权利要求1所述的应用，其中，所述的钠离子通道阻断剂是河豚毒素。
6.如权利要求5所述的应用，其中，所述的河豚毒素的给药剂量范围为每公斤体重0.01μg至20μg。
7.如权利要求1所述的应用，其中，所述吗啡的给药剂量范围为每公斤体重0.002mg至20mg。
8.如权利要求1所述的应用，其中，所述的钠离子通道阻断剂是蛤蚌毒素。
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011180986A CN1269482C (zh) | 2001-05-18 | 2001-05-18 | 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
| US10/062,483 US6780866B2 (en) | 2001-05-18 | 2002-02-05 | Analgesic composition and method |
| ES02734980T ES2344631T3 (es) | 2001-05-18 | 2002-05-20 | Composicion analgesica que comprende un opiaceo y un bloqueante de los canales del sodio. |
| PCT/CN2002/000339 WO2002094272A1 (en) | 2001-05-18 | 2002-05-20 | Analgesic composition and method |
| DE60236077T DE60236077D1 (de) | 2001-05-18 | 2002-05-20 | Analgetische zusammensetzung enthaltend ein opioid und einen natriumkanalblocker |
| JP2002590989A JP2004529959A (ja) | 2001-05-18 | 2002-05-20 | 鎮痛剤組成物と手法 |
| AT02734980T ATE464903T1 (de) | 2001-05-18 | 2002-05-20 | Analgetische zusammensetzung enthaltend ein opioid und einen natriumkanalblocker |
| CA002485337A CA2485337C (en) | 2001-05-18 | 2002-05-20 | Analgesic composition and method |
| EP02734980A EP1387685B1 (en) | 2001-05-18 | 2002-05-20 | Analgesic composition comprising an opioid and a sodium channel blocker |
| US10/849,240 US20040214842A1 (en) | 2001-05-18 | 2004-05-20 | Analgesic composition and method |
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| CNB011180986A CN1269482C (zh) | 2001-05-18 | 2001-05-18 | 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
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| CN1269482C true CN1269482C (zh) | 2006-08-16 |
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| US (2) | US6780866B2 (zh) |
| EP (1) | EP1387685B1 (zh) |
| JP (1) | JP2004529959A (zh) |
| CN (1) | CN1269482C (zh) |
| AT (1) | ATE464903T1 (zh) |
| CA (1) | CA2485337C (zh) |
| DE (1) | DE60236077D1 (zh) |
| ES (1) | ES2344631T3 (zh) |
| WO (1) | WO2002094272A1 (zh) |
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| CN1284536C (zh) * | 2000-09-18 | 2006-11-15 | 威克斯医药有限公司 | 河豚毒素或蛤蚌毒素及其类似物在制备用于全身镇痛的镇痛药中的应用 |
| CN1269482C (zh) * | 2001-05-18 | 2006-08-16 | 威克斯医药有限公司 | 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
| ES2401570T3 (es) * | 2001-11-15 | 2013-04-22 | Phytotox Limited | Composiciones farmacéuticas que contienen 3,4-propinoperhidropurinas y usos de las mismas para bloquear la transmisión neuronal |
| CN1568999A (zh) * | 2003-07-14 | 2005-01-26 | 南宁枫叶药业有限公司 | 稳定的医药用河豚毒素冷冻干燥制剂 |
| CN101123967A (zh) * | 2004-05-07 | 2008-02-13 | 菲特托克斯有限公司 | 藻毒素的经皮给药 |
| AU2005244105B2 (en) * | 2004-05-07 | 2011-10-06 | Algenis Spa | Phycotoxins and uses thereof |
| WO2006032459A1 (en) * | 2004-09-22 | 2006-03-30 | Laboratorios Del Dr. Esteve S.A. | Tetrodotoxin and its derivatives for the treatment of peripheral-nervously derived neuropathic pain |
| EP1702627A1 (en) * | 2005-03-18 | 2006-09-20 | Laboratorios Del Dr. Esteve, S.A. | Analgesic combination of sodium channel blockers with opioid antagonists |
| US20100144767A1 (en) * | 2005-08-25 | 2010-06-10 | Wex Pharmaceuticals, Inc. | Use of sodium channel blockers for the treatment of visceral pain or pain caused by cancer treatment |
| CA2619668A1 (en) * | 2005-08-25 | 2007-03-01 | Edge Renfeng Wang | Use of sodium channel blockers for the management of musculoskeletal pain |
| GB0603008D0 (en) * | 2006-02-14 | 2006-03-29 | Portela & Ca Sa | Method |
| CN101563079B (zh) | 2006-03-27 | 2012-12-05 | 威克斯药业有限公司 | 钠通道阻滞剂在制备治疗由于化疗而产生的神经病理性疼痛的药物中的用途 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4022899A (en) | 1973-06-12 | 1977-05-10 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
| US4906779A (en) * | 1986-07-10 | 1990-03-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | N,N'-disubstituted guanidines and their use as excitatory amino acid antagonists |
| US5262568A (en) * | 1990-03-02 | 1993-11-16 | State Of Oregon | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| SG50624A1 (en) * | 1991-12-30 | 1998-07-20 | Neurex Corp | Methods of producing analgesia and enhancing opiate analgesia |
| AU686203B2 (en) | 1993-07-23 | 1998-02-05 | Toray Industries, Inc. | Morphinan derivative and medicinal use |
| AU1882395A (en) * | 1994-02-23 | 1995-09-11 | Cambridge Neuroscience, Inc. | Blockers of ion channels and methods of use thereof |
| RU2168331C2 (ru) * | 1994-03-17 | 2001-06-10 | Наннинь Мапле Лиаф Фармацевтикал Ко., Лтд. | Применение соединений аминогидрогенизированного хиназолина и их производных для лечения наркотической зависимости |
| GB9513180D0 (en) * | 1995-06-28 | 1995-08-30 | Univ London | Ion channel |
| DE19602959A1 (de) | 1995-12-20 | 1997-07-31 | Nycomed Arzneimittel Gmbh | Neue Morphinderivate, Verfahren zu deren Herstellung und deren Verwendung |
| CN1072486C (zh) * | 1996-09-24 | 2001-10-10 | 王维国 | 用于戒毒、镇痛的药剂及其制法 |
| CN1081034C (zh) * | 1997-03-07 | 2002-03-20 | 潘心富 | 一种双胍基氢化嘌呤环类化合物的戒毒药 |
| WO1998043619A2 (en) * | 1997-04-02 | 1998-10-08 | The Regents Of The University Of California | Method of local anesthesia |
| AU7389098A (en) * | 1997-05-16 | 1998-12-08 | Brigham And Women's Hospital | Local anesthetic formulations |
| DE19936719A1 (de) * | 1999-08-06 | 2001-02-15 | Gruenenthal Gmbh | Substituierte 1,5-Dihydropyrrol-2-on-Derivate |
| CN1284536C (zh) | 2000-09-18 | 2006-11-15 | 威克斯医药有限公司 | 河豚毒素或蛤蚌毒素及其类似物在制备用于全身镇痛的镇痛药中的应用 |
| CN1203857C (zh) * | 2000-09-18 | 2005-06-01 | 威克斯医药有限公司 | 局部麻醉与镇痛的新方法 |
| CN1236773C (zh) * | 2000-11-22 | 2006-01-18 | 南宁枫叶药业有限公司 | 用于镇痛、麻醉或治疗药物依赖性的制剂 |
| CN1269482C (zh) * | 2001-05-18 | 2006-08-16 | 威克斯医药有限公司 | 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
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| US20040214842A1 (en) | 2004-10-28 |
| US6780866B2 (en) | 2004-08-24 |
| US20020198226A1 (en) | 2002-12-26 |
| DE60236077D1 (de) | 2010-06-02 |
| CA2485337A1 (en) | 2002-11-28 |
| EP1387685A4 (en) | 2007-05-23 |
| JP2004529959A (ja) | 2004-09-30 |
| CN1386505A (zh) | 2002-12-25 |
| CA2485337C (en) | 2007-08-28 |
| ES2344631T3 (es) | 2010-09-02 |
| EP1387685B1 (en) | 2010-04-21 |
| WO2002094272A1 (en) | 2002-11-28 |
| ATE464903T1 (de) | 2010-05-15 |
| EP1387685A1 (en) | 2004-02-11 |
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