CN1203860C - 钠离子通道阻断剂和阿司匹林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司匹林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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- CN1203860C CN1203860C CNB011159901A CN01115990A CN1203860C CN 1203860 C CN1203860 C CN 1203860C CN B011159901 A CNB011159901 A CN B011159901A CN 01115990 A CN01115990 A CN 01115990A CN 1203860 C CN1203860 C CN 1203860C
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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司匹林类药物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，减少阿司匹林用量，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司匹林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，减少阿司匹林用量，从而相应降低副作用和不良反应。
在药理学上，阿司匹林类药物和类固醇类药物分属抗炎药中的两大类。阿司匹林是一种使用非常广泛的非类固醇镇痛药，也作为消炎、镇痛药。水杨酸类的阿司匹林主要包括乙酰水杨酸(即阿司匹林)、水杨酸盐(主要为钠盐)以及二氟苯柳酸，水杨酸是水杨酸盐的活性成分。
阿司匹林类药物的药理学、治疗学及毒副作用的主要机制是抑制了体内的前列腺素(PG，prostaglandin)生物合成。阿司匹林的作用包括抑制前列腺素及其它痛觉兴奋物质(如缓激肽、组胺)的合成；抑制白细胞活力，并作用于下丘脑体温调节中枢，从而产生镇痛、消炎及解热作用；抑制血小板的前列腺素环氧酶，从而防止凝血酸素(TXAτ)生成，抑制血小板聚集(陈孝治，肖平田，王中森：新编实用药物手册，1994，SS10034400，超星数字图书馆。)。
阿司匹林的其镇痛效果很显著，可暂时缓解例如感冒引起的疼痛，一般神经紧张引起的头痛、发烧等。其主要用途包括：
1.感冒、发热、轻中度疼痛(头痛、牙痛、神经肌肉痛、月经痛等)；
2.抗风湿、风湿性关节炎；
3.防止血拴形成，需长期用小剂量口服。
阿司匹林也可能引起如下副作用(孙庆伟，侯奕，阿司匹林类药物的临床新用途及不良反应，1998，SS10034347，超星数字图书馆)：
1.胃痛、偶见诱发胃溃疡、胃出血；过敏者可发生哮喘、皮疹，偶见可逆性肝、肾功能受损。
2.过量中毒：轻者水杨酸反应，重者出现血尿、抽搐、幻觉、精神紊乱、呼吸困难。
3.长期用药者尿糖试验可出现假阳性、血清尿酸假性增高、转氨酶异常、胆固醇和血钾降低、凝血酶还原时间延长。
九十年代发现，常服阿司匹林对中年人防止中风和心脏病发作有统计学意义上显著的疗效，显然是因为阿司匹林温和的抗凝血性，防止了血栓生成，从而改善了血循环。
阿司匹林价格低、副作用小，医效好，作为非处方药它的使用已相当普及，然而有些情况下，特别是医疗上需用大剂量阿司匹林时，例如缓解由风湿病和关节炎引起的顽固疼痛时，大剂量阿司匹林会引起胃部溃疡、缺血、或上胃肠道出血，尽管出血量小，但定期服用大剂量阿司匹林会演变成大问题，特别是病人原先胃肠道已有病变时就严重了，过量阿司匹林甚至会造成死亡，或至少引起溃疡、胃扩张、胃前部变薄等等这些阿司匹林中毒症。Seifer等1985年在其美国专利4,491,574中提出同时或先服用维生素A从而使胃部增加粘液分泌，可减少阿司匹林中毒症状，提供了解决问题的一条途径。我们提出的另一途径是当需要大剂量应用阿司匹林以镇痛时，找到有效的协同镇痛药，使所需阿司匹剂量减少以降低不良反应。
河豚毒素(tetrodotoxin，TTX)是一种毒性极高的非蛋白神经毒素，具有镇痛、局麻、解痉等药理作用。TTX对多种钝痛及锐痛具有明显的缓解作用，且没有依赖性，但由于剂量的限制，使它的临床应用价值受到限制。我们从应用角度出发，从药物间协同作用入手，选用化学刺激法即小鼠醋酸扭体法(解热镇痛药敏感)，观察小剂量TTX与解热镇痛药阿司匹林间是否具有协同镇痛效果，以确定TTX作为协同镇痛药应用于临床的可能。
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司匹林类药物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司匹林类镇痛剂是独立给药，或者混合在一起同时给药，以达到协同镇痛的作用。给药的途径包括但不限于注射。
根据本发明，所述钠离子通道阻断剂是河豚毒素及其类似物，所述河豚毒素类似物至少包括以下化合物中的一种：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。它们的给药剂量范围为每公斤体重0.01μg至20μg。
根据本发明，所述阿司匹林类药物为水杨酸成水杨酸盐，其给药剂量范围为每公斤体重0.02mg至200mg。
所述钠离子通道阻断剂还包括蛤蚌毒素，其是分子式为C10H17N7O4的化合物及其衍生物。
根据本发明的实施方案，在于对于一些用解热镇痛药疗效不佳的急、慢性疼痛，联合应用小剂量TTX能明显提高镇痛疗效，减少药物用量，从而降低不良反应，为临床疼痛的治疗开辟了新的途径。
以下将参考实施例对本发明进行更为详细的说明。
TTX镇痛机理主要是通过阻断对TTX敏感的(TTX-Sensitive，TTX-S)Na+通道，阻断Na+内流，从而阻断神经冲动的产生及传导。解热镇痛药阿司匹林则是通过抑制环氧酶，减少前列腺素(prostaglandin，PG)合成及前列腺素PG(PGE2)引起的疼痛及痛觉增敏作用，也减轻缓激肽(bradykinin)的致痛作用，发挥镇痛疗效。
有关文献指出(Cesare P，Mcnaughton P，Peripheral pain mechanisms.CurrOpin Neurobiol 7(4)：493-9，1997 Aug)，组织损伤引起的痛觉敏感，至少与两种机制有关，即缓激肽增大热刺激引起的钠电流和前列腺素PGE2影响几种离子通道的电压阈值，也包括对TTX不敏感的(TTX-resistant，TTX-R)钠通道。PGE2的致痛作用与TTX-R钠通道的关系密切(Khasar SG；Gold MS；Levine JD，Atetrodotoxin-resistant sodium current mediates inflammatory pain in the rat.Neurosci Lett，256(1)：17-20，1998 Oct 30)，PGE2增加TTX不敏感钠电流(TTX-resistant sodium current，TTX-RINa)的幅度，即增加TTX-R钠通道的活性。慢性疼痛状态下，痛感受器的敏感化是通过TTX-R钠通道介导的(Tanaka M；CumminsTR：Ishikawa K；Dib-Hajj SD；Black JA；Waxman SG，SNS Na+ channel expressionincreases in dorsal root ganglion neurons in the carrageenan in flammatory painmodel.Neuroreport，9(6)：967-72 1998 Apr 20)(Kral MG；Xiong Z；StudyRE，Alteration of Na+ currents in dorsal root ganglion neurons from rats witha painful neuropathy.Pain 81(1-2)：15-24 1999 May)，阻断TTX-R钠通道可以产生镇痛作用(Akopian AN；Souslova V；England S；Okuse K；Ogata N；Ure J；Smith A；Kerr BJ；McMahon SB；Boyee S；Hill R；Stanfa LC；Dickenson AH；WoodJN，The tetrodotoxin-resistant sodium channel SNS has a specialized functionin pain pathways.Nat Neurosci，2(6)：541-8 1999 Jun)。这也能解释原先小鼠热辐射甩尾实验中TTX的镇痛效应并不随剂量增加而明显增强。阿司匹林通过减少PGE2的合成减弱TTX-R介导的钠电流而发挥镇痛效应，所以设想阿司匹林与TTX联合应用可能通过对TTX敏感和非敏感的钠通道同时起抑制作用而发挥协同镇痛效果。
小鼠醋酸扭体镇痛实验表明，单独使用TTX LD50的1/25、1/50剂量(0.79μg/kg、0.39μg/kg)，扭体抑制率分别为40.6％，27.7％，与文献报道相符。与阿司匹林联合应用，可使阿司匹林的扭体半数抑制量(ID50)从单独应用的44.1mg/kg分别下降到5.0mg/kg、10.0mg/kg，95％抑制量(ID95)从361.8mg/kg下降到94.5mg/kg、154.3mg/kg，经等效线法检验证明阿司匹林和TTX联合应用具有明显协同效应。
实施例
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：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，以柠檬酸缓冲液稀释至所需浓度。阿司匹林(aspirin，ASP)粉剂，纯度99％，山东新华制药厂生产，批号：0005564，临用时碾磨后用0.5％羧甲基纤维素钠(CMC)溶液稀释。冰醋酸，分析纯，北京五二九五二华工厂生产，批号：991117。
1.3实验方法
小鼠醋酸扭体法(徐叔云、卞如濂、陈修主编，药理实验方法学)。选取小白鼠380只，实验前12小时禁食不禁水，随机分为19组，分别为对照组(CMC溶液)，单用ASP组(分别为25mg/kg、50mg/kg、100mg/kg、150mg/kg、200mg/kg五个剂量组)，单用TTX组(选用LD50的1/25和1/50分别为0.79、0.39μg/kg)，协同用药组分别为：TTX(0.39μg/kg)+ASP(6mg/kg、12.5mg/kg、25mg/kg、50mg/kg、75mg/kg)，TTX(0.79μg/kg)+ASP(3mg/kg、6mg/kg、12.5mg/kg、25mg/kg、50mg/kg、75mg/kg)，TTX和ASP分别由小鼠肌肉注射(im)，协同给药组同时由小鼠两侧肌肉注射，液量均为0.1ml/10g，40分钟后，腹腔注射致痛剂0.6％冰醋酸溶液0.1ml/10g，观察并记录15分钟内小鼠扭体反应次数。扭体反应指标：以小鼠出现腰部肌肉反复收缩，腹部内凹，躯干与后肢伸张、臀部抬高等为扭体反应阳性。按下列公式计算各剂量组的扭体抑制率：
阿司匹林的扭体半数抑制量(ID50)的计算采用概率单位法。
1.4统计处理：
采用SPSS软件进行结果处理，检验药物联合作用的性质采用等效线法(徐端正编著，生物统计在药理学中的应用，科学出版社，1986，357-359)(杨树勤，医学统计学，中国医学百科全书，上海科学技术出版社，1985，197)。
2结果
从表1可以看出，采用小鼠醋酸扭体实验，单用阿司匹林的小鼠扭体半数抑制量(ID50)为44.11mg/kg，与小剂量TTX(即LD50的1/25、1/50)联合应用，阿司匹林的ID50下降至5.01mg/kg和9.96mg/kg。95％抑制量(ID95)从361.77mg/kg下降到94.47mg/kg、154.33mg/kg。ID50和ID95下降幅度均超过两倍。
表1：小鼠扭体法肌肉注射TTX和阿司匹林协同作用研究
剂量
分组 动物数 平均扭体次数 抑制率(％) ID50及95％可信限(mg/kg) ID95及95％可信限(mg/kg)
(mg/kg)
羧甲基纤维素钠溶液对照 50 20 39.0±15.4 -
TTX 0.79×10-3 20 23.2±11.7 40.6
0.39×10-3 20 28.2±9.65 27.7
ASP 25 20 25.1±14.5 35.6
50 20 19.3±13.8 50.6
100 20 12.0±9.2 69.3
150 20 5.2±5.7 86.6 44.1(24.9~61.9) 361.8(197.3~1689.2)
200 20 2.7±1.9 93.2
TTX(0.79μg/kg)+ASP 3.0 20 23.0±8.3 40.9
6.0 20 20.3±12.2 47.9
12.5 20 9.5±9.0 75.7
25.0 20 7.2±6.9 81.6 5.0(3.8~6.3) 94.5(62.7~170.7)
50.0 20 4.0±4.6 89.9
75.0 20 1.8±1.2 95.4
TTX(0.39μg/kg)+ASP 6.0 20 25.0±10.9 35.8
12.5 20 17.0±8.9 56.4
25.0 20 10.0±11.1 74.5
50.0 20 5.8±5.3 85.2 10.0(7.6~12.3) 154.3(99.8~301.1)
75.0 20 4.5±3.3 88.6
Claims (12)
1.至少一种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和一种环氧酶抑制剂的组合在制备用于对哺乳动物进行协同镇痛作用的药物中的应用，其中，所述的钠离子通道阻断剂为选自由河豚毒素、去水河豚毒素、氨基河豚毒素、甲氧基河豚毒素、乙氧基河豚毒素、脱氧河豚毒素、河豚酸、蛤蚌毒素组成的组；所述的环氧酶抑制剂选自乙酰水杨酸、水杨酸盐和二氟苯柳酸组成的组。
2.如权利要求1所述的应用，其中，所述的钠离子通道阻断剂化合物是河豚毒素。
3.如权利要求1所述的应用，其中，所述的环氧酶抑制剂是乙酰水杨酸。
4.如权利要求1所述的应用，其中，所述的钠离子通道阻断剂化合物是蛤蚌毒素，所述的蛤蚌毒素是分子式为C10H17N7O4的化合物及其衍生物。
5.一种用于镇痛的药物制剂，包含至少一种与钠离子通道的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和至少一种环氧酶抑制剂，所述的钠离子通道阻断剂为选自由河豚毒素、去水河豚毒素、氨基河豚毒素、甲氧基河豚毒素、乙氧基河豚毒素、脱氧河豚毒素、河豚酸、蛤蚌毒素组成的组；所述的环氧酶抑制剂选自乙酰水杨酸、水杨酸盐和二氟苯柳酸组成的组；并且，所述的制剂每剂量提供按患者每千克体重计0.01-20μg的所述钠离子通道阻断剂，以及提供按患者每千克体重计0.02-200mg的所述环氧酶抑制剂。
7.如权利要求5所述的制剂，其中，所述的钠离子通道阻断剂是河豚毒素。
8.如权利要求5所述的制剂，其中，所述的环氧酶抑制剂是乙酰水杨酸。
9.如权利要求5所述的制剂，其中，所述的制剂是注射用制剂。
10.如权利要求9所述的制剂，其中，所述的注射用制剂是肌肉注射用制剂。
11.如权利要求5所述的制剂，其中，所述的制剂包含独立的所述的至少一种环氧酶抑制剂的制剂和所述的至少一种钠离子通道阻断剂的制剂。
12.如权利要求5所述的制剂，其中，所述的制剂包含至少一种环氧酶抑制剂和所述的至少一种钠离子通道阻断剂化合物的混合物的制剂。
13.如权利要求5所述的制剂，其中，所述的钠离子通道阻断剂化合物是蛤蚌毒素，所述的蛤蚌毒素是分子式为C10H17N7O4的化合物及其衍生物。
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| CNB011159901A CN1203860C (zh) | 2001-06-22 | 2001-06-22 | 钠离子通道阻断剂和阿司匹林在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
| ES02754135T ES2296975T3 (es) | 2001-06-22 | 2002-06-18 | Uso de compuestos bloqueantes de canales de sodio y aspirina en la produccion de farmacos para producir efectos analgesicos sinergisticos en mamiferos. |
| PCT/CN2002/000428 WO2003000268A1 (en) | 2001-06-22 | 2002-06-18 | Use of na+ channel blockers and aspirin in manufacturing drugs for producing analgesia synergistically in mammals |
| CA002493885A CA2493885C (en) | 2001-06-22 | 2002-06-18 | Use of sodium channel blocking compounds and aspirin in manufacturing drugs for producing synergistically analgesic effect in mammals |
| DE60223681T DE60223681T2 (de) | 2001-06-22 | 2002-06-18 | Verwendung von natriumkanalblockern und aspirin zur herstellung von medikamenten zum erzeugen eines synergistischen analgetischen effekts in säugetieren |
| EP02754135A EP1405639B1 (en) | 2001-06-22 | 2002-06-18 | Use of sodium channel blocking compounds and aspirin in manufacturing drugs for producing synergistic analgesic effect in mammals |
| JP2003506913A JP2004534821A (ja) | 2001-06-22 | 2002-06-18 | 哺乳動物に相乗的鎮痛効果をもたらすための薬剤製造におけるナトリウムチャンネル遮断化合物とアスピリンの使用 |
| US10/480,288 US20040192659A1 (en) | 2001-06-22 | 2002-06-18 | Use of na+ channel blockers and aspirin in manufacturing drugs for producing analgesia synergistically in mammals |
| US12/249,802 US20090105197A1 (en) | 2001-06-22 | 2008-10-10 | Use of Sodium Channel Blocking Compounds and Aspirin in Manufacturing Drugs for Producing Analgesia Synergistically in Mammals |
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| CA (1) | CA2493885C (zh) |
| DE (1) | DE60223681T2 (zh) |
| ES (1) | ES2296975T3 (zh) |
| WO (1) | WO2003000268A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| CN100438873C (zh) * | 2006-06-26 | 2008-12-03 | 黄致强 | 将河鲀毒素作为镇痛药的耐受抑制剂在制备复方镇痛制剂中的应用 |
| CN104118237A (zh) * | 2013-04-27 | 2014-10-29 | 王静娴 | 编号文件夹 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966934A (en) * | 1971-12-08 | 1976-06-29 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
| US4022899A (en) * | 1973-06-12 | 1977-05-10 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
| US3892847A (en) * | 1973-08-14 | 1975-07-01 | Astra Pharma Prod | Spinal anesthesia using small amount of saxitoxin |
| JPS5594319A (en) * | 1979-01-09 | 1980-07-17 | Yoshio Otaka | Drug for external use consisting of liver oil of swellfish |
| US6759057B1 (en) * | 1986-06-12 | 2004-07-06 | The Liposome Company, Inc. | Methods and compositions using liposome-encapsulated non-steroidal anti-inflammatory drugs |
| US5814655A (en) * | 1996-11-14 | 1998-09-29 | Insite Vision Incorporated | Non-steroidal ophthalmic mixtures |
| WO1998043619A2 (en) * | 1997-04-02 | 1998-10-08 | The Regents Of The University Of California | Method of local anesthesia |
| GB2339534A (en) * | 1998-07-16 | 2000-02-02 | Edko Trading Representation | Epidural or intrathecal administration of NSAID's |
| 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 |
-
2001
- 2001-06-22 CN CNB011159901A patent/CN1203860C/zh not_active Expired - Fee Related
-
2002
- 2002-06-18 US US10/480,288 patent/US20040192659A1/en not_active Abandoned
- 2002-06-18 EP EP02754135A patent/EP1405639B1/en not_active Expired - Lifetime
- 2002-06-18 JP JP2003506913A patent/JP2004534821A/ja active Pending
- 2002-06-18 ES ES02754135T patent/ES2296975T3/es not_active Expired - Lifetime
- 2002-06-18 CA CA002493885A patent/CA2493885C/en not_active Expired - Fee Related
- 2002-06-18 DE DE60223681T patent/DE60223681T2/de not_active Expired - Lifetime
- 2002-06-18 WO PCT/CN2002/000428 patent/WO2003000268A1/zh not_active Ceased
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2008
- 2008-10-10 US US12/249,802 patent/US20090105197A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE60223681T2 (de) | 2008-10-30 |
| WO2003000268A8 (en) | 2004-03-04 |
| WO2003000268A1 (en) | 2003-01-03 |
| CN1393223A (zh) | 2003-01-29 |
| CA2493885A1 (en) | 2003-01-03 |
| US20090105197A1 (en) | 2009-04-23 |
| EP1405639A1 (en) | 2004-04-07 |
| EP1405639B1 (en) | 2007-11-21 |
| EP1405639A4 (en) | 2004-08-04 |
| JP2004534821A (ja) | 2004-11-18 |
| CA2493885C (en) | 2007-08-21 |
| ES2296975T3 (es) | 2008-05-01 |
| DE60223681D1 (de) | 2008-01-03 |
| US20040192659A1 (en) | 2004-09-30 |
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