CN110478350A - 草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用 - Google Patents
草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用 Download PDFInfo
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- CN110478350A CN110478350A CN201810841682.7A CN201810841682A CN110478350A CN 110478350 A CN110478350 A CN 110478350A CN 201810841682 A CN201810841682 A CN 201810841682A CN 110478350 A CN110478350 A CN 110478350A
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- drug
- bulleyaconitine
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- heroin
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- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用。经试验证明,草乌甲素及其衍生物具有明显的抑制因成瘾性药物引发的自发活动症状的作用,且在较低的剂量下就能达到显著的抑制效果。同时,本发明开发了草乌甲素及其衍生物的新用途,提高了草乌甲素及其衍生物的经济价值,也为草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用提供了理论和实践基础,且草乌甲素及其衍生物是已经在临床上使用的药物,其毒性较低,安全性能好,但目前尚未有人报道其在制备抑制药物成瘾性的药物中的相关用途,因而其在抑制药物成瘾性方面具有很好的应用前景。
Description
技术领域
本发明涉及草乌甲素及其衍生物的应用,尤其涉及草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用。
背景技术
毒品是指鸦片,海洛因,甲基苯丙胺(冰毒),吗啡,大麻,可卡因以及国家现管制的其它能够使人形成瘾癖的麻醉药品和精神药品。
全世界有170多个国家和地区涉及毒品贩运问题。130多个国家和地区存在毒品消费问题,2.5亿人沾染了毒品,所以,世界范围的毒品泛滥,极大的危害公众健康,同时也严重影响社会经济的发展和政治的稳定。
据联合国的一项报告指出,1978年后的十年间世界毒品贸易额增长了近三倍,约6000亿美元,占国际贸易额的9%,成为世界上仅次于军火交易的巨大产业。
近年来,毒品滥用呈现种类多元并存的情况,合成毒品滥用规模占首位,占比超过60%,其中,滥用阿片类毒品人员占近40%。因此,阿片类毒品是戒毒工作中一个非常值得注意的问题。
戒毒药研究是戒毒工作的一项必要措施,对于吸毒者来说也是一种人道主义工作,目前所研制的戒毒药基本上是针对阿片类药物的戒毒药。
目前涉及的戒毒方法有很多种,但大都使用不同的戒毒药进行替代和治疗。其中,药物替代方法,干戒法可以使吸毒者成功脱毒,而不能脱瘾。不同的药物功效不同,常用的戒毒药分三类:阿片类、非阿片类以及中药类。
阿片类戒毒药可以分为:1、弱激动剂,例如:美沙酮、阿片酊、右丙氯酚;2、部分激动剂:环唑星,丁丙诺啡;3、拮抗剂,如:纳洛酮,纳曲酮。
其中,美沙酮:从根本上来说是一种毒品,对人体是有伤害的。实际上是以小毒攻击大毒。美沙酮确实治好了许多病人,让他们少受很多痛苦。但是对于大多数吸毒者在服用美沙酮的同时仍继续服用海洛因。该药的副作用有便秘等,与所有的麻醉性镇痛药有协同作用。与纳洛酮,纳曲酮等阿片受体拮抗剂有拮抗作用。
丁丙诺啡:是半合成阿片类化合物。蒂巴因的衍生物,为阿片受体的激动剂—拮抗剂,有较强的镇痛作用。以成为阿片类药物成瘾的替代物,且在完成替代后能在较短时间内替减完毕。而且可抑制可卡因的渴求感。本品具有激动和拮抗阿片受体的双重作用,对消除海洛因成瘾停药后出现的戒毒症状作用明显。
纳洛酮和吗啡的结构相似,是常用的吗啡受体拮抗剂,其作用是丙烯吗啡的30倍。纳洛酮对内源性和外源性阿片样物质都具有特异的拮抗作用,对四种阿片受体都有拮抗作用(μκδθ受体,尤其对μ受体亲和力大于δ和κ受体,与阿片受体亲和力大于吗啡对正常人和动物产生很小的副作用。静脉注射可以快速翻转海洛因和吗啡的作用,近来对纳洛酮的作用研究较多,能阻断和逆转β-内啡肽的毒性作用。它本身对人体安全性高,副作用小,长期给予不产生依赖性。
对于上述阿片类戒毒药,其控制戒毒症状好,药物不良反应小,但易成瘾,控制不好,或使用不当又会成为一种新的毒品。
非阿片类戒毒药一般可分为:1、与神经递质有关的药物,例如:可乐宁,心得安,异搏定,拟胆碱药物等;2、与免疫活性有关的药物,例如:干扰素,环胞多肽,放射简素D等;3、激素,例如:促甲状腺释放激素,促肾上腺皮质激素等;4、中枢抑制药,例如:氯丙嗪,氯氮平,氟哌啶醇,安定,氯硝丙绊,冬眠合剂,溴化物等;5、莨蓉类,例如:车莨蓉碱,山莨蓉碱,颠茄等。
其中国内外一致公认的以可乐宁为代表。可乐宁传统上用于治疗高血压,但是目前很少用于高血压药。其是戒除阿片类药物成瘾的戒毒有效药物,既能解除戒毒症状本身又不具有成瘾性,其可以通过对α2肾上腺素能受体的作用,降低中枢去甲基肾上腺素能神经元的活性,使蓝斑神经元肽电减少。所以它不是通过阿片受体,但是可与阿片类引起相同的膜电导变化,方可影响K+导电,因而抑制戒毒症状的同时并不产生镇痛作用和欣快感,该药对中枢神经系统还有镇痛作用,减少自发活动。其能成功的减轻阿片成瘾后的戒断作用。因此,可乐宁的优点是:1、戒断效能明显;2、可控制阿片类药物戒断综合症中各种症状和体征;3、不产生欣快感、无成瘾性;4、不可能转化为滥用品。
非阿片类戒毒药,虽然其控制戒毒症状明显、无成瘾性,但药物不良反应明显,有的还很严重。
中药类戒毒药一般可分为:1、含替代药,如:阿片、罂粟壳、大麻仁等,因易产生依赖性,目前临床上只能在戒毒所中使用,无法用于家庭自愿戒毒;2、不含替代物的纯中药复方制剂等。
草乌甲素(Bulleyaconitine A),为现代植物药,毛莨科乌头属植物,从滇西嘟拉中分离出来的二萜双酯型生物碱,是不同于乌头碱、次乌头碱的一种生物碱,无耐受性,无成瘾性,是一种强效镇痛药和抗炎药,具有中枢镇痛和外用镇痛的双重药理作用,国内CFDA已批准草乌甲素注射剂和片剂用于慢性疼痛及类风湿性关节炎的治疗。目前临床上广泛用于治疗类风湿性关节炎、骨关节炎、肌纤维炎、颈椎病、癌性疼痛及各种原因导致的慢性疼痛。
草乌甲素对炎症和疼痛均有明显的抑制作用。前列腺素PGE2是在致炎因子作用下产生,局部组织产生和释放的具有致炎、致痛作用的炎症介质,使局部血管通透性增加,进一步加重炎症反应,并由此产生一系列的变化,例如:滑膜细胞和成纤维细胞增殖、血管新生、产生胶原酶等,使得骨和软骨细胞备破坏。降低血清PGE2是草乌甲素的抗炎作用的机理之一,PGE2能激活外周痛觉感受器,传递痛觉信号。β-内啡肽是一种具有较强镇痛作用的神经肽,草乌甲素的镇痛作用可能与其拮抗脑内5-羟色胺(5-HT),抑制PGE2释放,从而解除对β-内啡肽的抑制有关。
同时,据文献报道,草乌甲素A可以直接诱导脊髓小胶质细胞强啡肽A的表达,从而表现出镇痛作用,并且在脊髓后角的C-纤维突触面显示了对神经性疼痛的抑制作用,同时也证明了草乌甲素可以增强吗啡的镇痛作用,并抑制吗啡的镇痛耐受性,此外,草乌甲素尚可抑制炎性趋化因子。
目前,对于草乌甲素的研究及应用也仅仅局限于抗炎镇痛方面,例如:CN101468000公开了草乌甲素作为制备治疗原发性红斑肢痛症药物的应用;CN107245054A则公开了一种无定形草乌甲素化合物在制备治疗由风湿或类风湿性关节炎引起的疼痛疾病的药物中的用途;CN106943402A中的草乌甲素则用于制备防治骨质疏松或骨溶解的药物。
草乌甲素在戒毒药物中的作用及功效未见相关报道。
发明内容
本发明的目的在于提供草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用。
根据本发明,草乌甲素的衍生物可以为其互变异构体或其药学上可接受的盐。
本发明中,所述的药学上可接受的盐较佳的为本发明化合物与药学上可接受的酸进行反应制得的酸加成盐,或者其中的酸性基团和碱性化合物反应生成的盐。其中,所述的酸较佳的选自无机酸(如盐酸、硫酸、磷酸或氢溴酸等),和有机酸(如醋酸、草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸或苯甲酸等);所述的碱性化合物较佳的选自氢氧化钠、氢氧化钾、氢氧化钙、氨水、碳酸钠或碳酸氢钾等。
相应地,制备得到的草乌甲素药学上可接受的盐为其碱加成盐,优选钠、钾、钙、镁、铁、亚铁、铵、锌盐等;或者其酸加成盐,优选硫酸盐、醋酸盐、盐酸盐、磷酸盐、草酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或苯甲酸盐等。
上述药学上可接受的盐容易分离,可采用常规分离方法提纯,如溶剂萃取、稀释、重结晶、柱色谱和制备薄层色谱等。
进一步地,上述草乌甲素及其衍生物在抑制因阿片类毒品引发的自发活动症状方面具有明显的作用。
更进一步地,草乌甲素及其衍生物在抑制因海洛因毒品引发的自发活动症状方面具有明显的作用。
进一步地,上述能抑制药物成瘾性的药物中还包括药学上可接受的载体、稀释剂、赋形剂。
进一步地,本发明的化合物可与药学上各种常用添加剂(如稀释剂和赋形剂等)制成药物组合物。根据治疗目的及使用方式,可将药物组合物制成各种类型的给药单位剂型,如口服剂、缓释剂、片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、口服剂、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋形剂。例如,载体,如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等;粘合剂,如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液,羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等;崩解剂,如干淀粉、藻酸钠、琼脂粉和海带粉,碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等;崩解抑制剂,如白糖、甘油三硬脂酸酯、椰子油和氢化油等;吸附促进剂,如季胺碱和十二烷基硫酸钠等;润湿剂,如甘油、淀粉等;吸附剂,如淀粉、乳糖、高岭土、膨润土和胶体硅酸等;以及润滑剂,如纯净的滑石,硬脂酸盐、硼酸粉和聚乙二醇等。如果需要的话,还可以用通常的涂渍材料使片剂作为糖衣片剂、肠衣片剂、涂膜片剂(如涂明胶膜片剂)、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋形剂,例如,载体,如乳糖,淀粉,椰子油,硬化植物油,高岭土和滑石等;粘合剂,如阿拉伯树胶粉,黄蓍胶粉,明胶和乙醇等;崩解剂,如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋形剂,例如,聚乙二醇,椰子油,高级醇,高级醇的酯,明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物,可将溶液和悬浮液消毒,并最好加入适量的氯化钠,葡萄糖或甘油等,制成与血液等渗压的针剂。在制备针剂时,也可使用本领域内任何常用的载体。例如,水,乙醇,丙二醇,乙氧基化的异硬脂醇,聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外,还可加入通常的溶解剂、缓冲剂和止痛剂等。
进一步地,上述能抑制药物成瘾性的药物中还包括至少一种已知的能抑制药物成瘾性的药物。
更进一步地,所述已知的能抑制药物成瘾性的药物选自美沙酮、阿片酊、右丙氯酚、环唑星、丁丙诺啡、纳洛酮、纳曲酮。
进一步地,所述能抑制药物成瘾性的药物在应用中的草乌甲素的用量小于2.7mg/kg。
本发明还提供了一种抑制药物成瘾性的药物。
所述抑制药物成瘾性的药物,其包括草乌甲素或其互变异构体或其药学上可接受的盐;以及,所述草乌甲素药学上可接受的盐为其碱加成盐,选自钠、钾、钙、镁、铁、亚铁、铵或锌盐;或酸加成盐,选自硫酸盐、醋酸盐、盐酸盐、磷酸盐、草酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或苯甲酸盐。
更具体而言,本发明的实验结果显示:草乌甲素及其衍生物具有明显抑制因成瘾性药物引发的自发活动症状的作用,表明其在抑制药物成瘾性方面具有巨大的作用。
具体地:发明人通过不同的试验组和空白组分析草乌甲素对于注射毒品后小鼠躁动反应的影响,发现:预先口服草乌甲素的小鼠,其因注射毒品出现的明显竖尾、绕笼走动等躁动行为能得到显著的抑制,其总路程数也明显下降。
进一步地,发明人利用文献[1]中的试验方法研究草乌甲素对于注射毒品后的小鼠敏化反应的影响,同样发现:一段时间后,当小鼠被再次注射毒品时,预先服用草乌甲素能有效抑制小鼠竖尾、颤抖、不停绕笼走动等敏化行为。
进一步地,发明人采用文献[2]中的模型研究了草乌甲素对于依赖纳洛酮催促戒断症状的影响,发现:草乌甲素对于依赖纳洛酮催促戒断症状有明显的改善效果。
发明人还进一步发现:草乌甲素对于上述自发活动症状的改善均呈现剂量依赖趋势。
综上所述:本申请已经证明草乌甲素具有明显抑制因毒品引发的自发活动症状的作用,表明草乌甲素及其衍生物在抑制药物成瘾性方面具有巨大的应用潜力,同时为草乌甲素及其衍生物在制备抑制药物成瘾性的药物中提供了强有力的理论和实践基础,而目前尚未有人报道其在制备抑制药物成瘾性的药物中的相关用途,因而具有重要的研发意义及开发价值。
[1]Wang Jun-Qin,Yan-Ting Wang,Min Zhang,et al.Molecular chaperoneheat shock protein70participates in the labile phase of the development ofbehavioural sensitization induced by a single morphine exposure inmice.International Journal of Neuropsychopharmacology,2013,16,647-659.
[2]许盈,谢捷明等,小鼠吗啡依赖纳洛酮催促戒断跳跃反应模型的建立,福建医科大学学报,2005,39(3).
本发明的有益效果是:
1、经试验证明,草乌甲素具有明显的抑制因成瘾性药物引发的自发活动症状的作用,且在较低的剂量下就能达到显著的抑制效果。
2、本发明开发了草乌甲素的新用途,提高了草乌甲素的经济价值,也为草乌甲素在制备抑制药物成瘾性药物中的应用提供了理论和实践基础。
3、草乌甲素是植物药,低成本、无成瘾性、无副作用,且其已经在临床上使用,安全性高。
具体实施方式
下面进一步列举实施例以详细说明本发明。同样应理解,以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,本领域技术人员根据本发明阐述的原理做出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例,即本领域技术人员可以通过本文的说明做合适范围内的选择,而并非要限定于下文示例的具体数据。
试验用品与仪器:
草乌甲素,纯度≥98%,购于上海源叶生物科技有限公司。
草乌甲素使用时,用无水乙醇将其配制成1mg/mL的溶液,然后用去离子水稀释成所需浓度。
ICR小鼠,雄性,体重18~20g,购于上海西普尔-必凯实验动物有限公司。
无水乙醇:分析纯(AR),购于国药集团化学试剂有限公司。
本发明中涉及的毒品由上海市公安局物证鉴定中心提供。
JLBehv动物行为分析系统,自发活动视频分析系统:上海吉量软件科技有限公司生产。
实施例1:草乌甲素对海洛因引起的小鼠躁动反应的影响
试验方法:
(1)将体重为20g左右的小鼠适应性饲养1天,分为7组,分别为:
A:空白(不注射海洛因和草乌甲素);
B:海洛因10mg/kg;
C:海洛因10mg/kg+草乌甲素2.7mg/kg;
D:海洛因10mg/kg+草乌甲素0.9mg/kg;
E:海洛因10mg/kg+草乌甲素0.3mg/kg;
F:海洛因10mg/kg+草乌甲素0.1mg/kg;
G:海洛因10mg/kg+草乌甲素0.03mg/kg。
A、B两组各5只小鼠,其余每组3只,每次测试时,C~G组均需放1只A组和1只B组小鼠,以便每次实验时都有对照,除A和B组外,草乌甲素预先2小时灌胃给药,然后皮下注射10mg/kg海洛因,后将小鼠放入自主活动箱,用JLBehv动物行为分析系统和自发活动视频分析系统记录小鼠10分钟的自发活动情况。草乌甲素口服给药(Po.)2h对海洛因致小鼠自发活动10min的影响结果见表1,如果p<0.05则被认为具有统计学意义。
表1
编号 | 组别 | 总路程(mm) |
A | 空白 | 21002.13±4697.47 |
B | 海洛因10mg/kg | 77069.83±8373.96<sup>###</sup> |
C | 海洛因10mg/kg+草乌甲素2h Po.2.7mg/kg | 1757.89±349.66<sup>***</sup> |
D | 海洛因10mg/kg+草乌甲素2h Po.0.9m g/kg | 23135.34±2314.14<sup>***</sup> |
E | 海洛因10mg/kg+草乌甲素2h Po.0.3mg/kg | 26140.90±1364.34<sup>***</sup> |
F | 海洛因10mg/kg+草乌甲素2h Po.0.1mg/kg | 42278.82±16705.59<sup>**</sup> |
G | 海洛因10mg/kg+草乌甲素2h Po.0.03mg/kg | 54552.70±14233.76<sup>*</sup> |
注:与空白组比较,P#<0.05,P##<0.01,p###<0.001;与海洛因组比较,P*<0.05,P**<0.01,p***<0.001。
(2)将体重为20g左右的小鼠适应性饲养1天,分为6组,分别为:
Ⅰ:空白(不注射海洛因和草乌甲素);
Ⅱ:草乌甲素2.7mg/kg;
Ⅲ:草乌甲素0.9mg/kg;
Ⅳ:草乌甲素0.3mg/kg;
Ⅴ:草乌甲素0.1mg/kg;
Ⅵ:草乌甲素0.03mg/kg。
每组5只小鼠,除Ⅰ组外,草乌甲素预先2小时灌胃给药,后将小鼠放入自主活动箱,用JLBehv动物行为分析系统和自发活动视频分析系统记录小鼠10分钟的自发活动,草乌甲素口服2h后与正常小鼠的自主活动比较结果见表2。
上述数据以均数和标准差表示,采用SPSS16.0软件进行单因素方差分析(one way ANOVA)比较各组差异,如果p<0.05则被认为具有统计学意义。
表2
编号 | 组别 | 总路程(mm) |
Ⅰ | 空白 | 25151.52±9521.88 |
Ⅱ | 草乌甲素0.03mg/kg | 26343.43±7741.75 |
Ⅲ | 草乌甲素0.1mg/kg | 26803.15±8704.55 |
Ⅳ | 草乌甲素0.3mg/kg | 19740.45±7225.53 |
Ⅴ | 草乌甲素0.9mg/kg | 24299.94±2615.35 |
Ⅵ | 草乌甲素2.7mg/kg | 2211.73±670.34<sup>##</sup> |
注:与空白组比较,P#<0.05,P##<0.01,P###<0.001。
结论:
(1)由表1可知:相比于A组,B组总路程数明显增加,且肉眼可以明显观察到小鼠出现竖尾、绕笼走动等躁动行为,但预先口服草乌甲素给药组,其总路程数相对于B组均出现下降的趋势,且随着草乌甲素的含量的增加而减少,呈现剂量依赖趋势,这说明草乌甲素能够明显抑制单独给予海洛因所引起的小鼠躁动反应,包括竖尾、绕笼走动等行为,但当草乌甲素的含量增加至2.7mg/kg时,小鼠的总路程数远小于海洛因组(B组),甚至远小于正常组,这说明当小鼠恢复正常时如再进一步加大草乌甲素的剂量,则会表现一定的抑制作用。
(2)由表2可知:与Ⅰ组相比,小鼠口服草乌甲素0.03mg/kg、0.1mg/kg、0.3mg/kg、0.9mg/kg,2h后,总路程均无明显变化,即:没有降低小鼠的自主活动,这说明草乌甲素不影响正常小鼠的自主活动,但当草乌甲素的含量达到2.7mg/kg时,其对小鼠会产生一定的抑制作用,这说明对于正常的小鼠,当草乌甲素超过一定量时,会对小鼠产生副作用。
实施例2:草乌甲素对海洛因致小鼠行为敏化反应的影响[1]
试验方法:
将体重为18~20g左右的小鼠,随机分为8组,分别为:
a、空白(不注射海洛因和草乌甲素);
b、海洛因10mg/kg+海洛因1mg/kg;
c、海洛因+草乌甲素2.7mg/kg
d、海洛因+草乌甲素0.9mg/kg
e、海洛因+草乌甲素0.3mg/kg;
f、海洛因+草乌甲素0.1mg/kg;
g、海洛因+草乌甲素0.03mg/kg。
a和b组每组各5只小鼠,其余每组各3只,每次测试时,c~g组均需放1只a组和1只b组小鼠,以便每次实验时都有对照,除a组外,其余各组第1天皮下注射10mg/kg海洛因,第2天到第7天各组均不给药,第8天时c、d、e、f和g组按照各组既定剂量给予草乌甲素,给药两小时后,c~g组皮下注射1mg/kg海洛因,同时给予b组皮下注射1mg/kg海洛因,随后将各组放入自主活动箱,用JLBehv动物行为分析系统和自发活动视频分析系统记录小鼠10分钟的自发活动,第8天草乌甲素对海洛因致小鼠自发活动10分钟影响的结果见表3。
数据以均数和标准差表示,采用SPSS16.0软件进行单因素方差分析(oneway ANOVA)比较各组差异,如果p<0.05则被认为具有统计学意义。
表3
编号 | 组别 | 总路程(mm) |
a | 空白 | 19750.38±5667.95 |
b | 海洛因10mg/kg+海洛因1mg/kg | 62292.25±7965.63<sup>##</sup> |
c | 海洛因+草乌甲素2.7mg/kg | 1876.89±287.41<sup>***</sup> |
d | 海洛因+草乌甲素0.9mg/kg | 23397.33±1305.38<sup>***</sup> |
e | 海洛因+草乌甲素0.3mg/kg | 27031.09±4263.10<sup>**</sup> |
f | 海洛因+草乌甲素0.1mg/kg | 39215.61±5232.02<sup>**</sup> |
g | 海洛因+草乌甲素0.03mg/kg | 47481.07±3157.58<sup>**</sup> |
注:与空白组比较,P#<0.05,P##<0.01,p###<0.001;与海洛因组比较,P*<0.05,P**<0.01,p***<0.001。
结论:
当一段时间后,b组小鼠被再次注射海洛因时,其呈现竖尾、颤抖、不停绕笼走动等敏化行为,而预先给予草乌甲素的c~g组能够明显抑制竖尾、颤抖、不停绕笼走动等敏化行为,且呈剂量依赖趋势。
由表3可知:与空白组相比,b组的总路程数明显增加,这说明b组能明显增强小鼠自主活动,但草乌甲素给药组(c~g组)相对于b组能明显降低小鼠自发活动的总路程,且呈量效关系。
以上说明草乌甲素能明显改善小鼠的敏化行为。
实施例33:草乌甲素对海洛因依赖纳洛酮催促戒断症状的影响
试验方法:
本试验采用文献[2]中的方法进行试验,具体如下:
小鼠适应性饲养1~2天,分为7组,分别为:
α:空白(不注射海洛因和草乌甲素);
β:海洛因10mg/kg;
γ:海洛因+草乌甲素2.7mg/kg;
δ:海洛因+草乌甲素0.9mg/kg;
ε:海洛因+草乌甲素0.3mg/kg;
η:海洛因+草乌甲素0.1mg/kg;
θ:海洛因+草乌甲素0.03mg/kg。
每组5只小鼠,除α组和β组外,其余组每天连续皮下注射剂量倍增的海洛因,共6天,每日剂量分别为5,10,20,40,80,160mg/kg;第6天时,草乌甲素预先2小时灌胃给药,然后皮下注射海洛因160mg/kg,给予海洛因3h后腹腔注射纳洛酮10mg/kg,观察小鼠的状态和30min内的跳跃反应,同时给予β组海洛因10mg/kg,并给予海洛因3h后腹腔注射纳洛酮10mg/kg,观察小鼠的状态和30min内的跳跃反应。
数据以均数和标准差表示,采用SPSS16.0软件进行单因素方差分析(oneway ANOVA)比较各组差异,如果p<0.05则被认为具有统计学意义,结果见表4。
表4
编号 | 组别 | 跳跃次数 | 跳跃反应率(%) |
α | 空白 | 0 | 0 |
β | 海洛因10mg/kg | 90.37±23.41 | 100 |
γ | 海洛因+草乌甲素2h Po.2.7mg/kg | 0<sup>***</sup> | 0 |
δ | 海洛因+草乌甲素2h Po.0.9mg/kg | 0.45±0.23<sup>***</sup> | 0 |
ε | 海洛因+草乌甲素2h Po.0.3mg/kg | 5.17±0.94<sup>***</sup> | 0 |
η | 海洛因+草乌甲素2h Po.0.1mg/kg | 10.68±2.05<sup>***</sup> | 20 |
θ | 海洛因+草乌甲素2h Po.0.03mg/kg | 33.67±11.32<sup>***</sup> | 50 |
注:与海洛因组比较,P*<0.05,P**<0.01,p***<0.001。
结论:
给予纳洛酮的β组,小鼠呈现竖尾、颤抖、直立、跳跃等戒断行为,而预先给予草乌甲素的γ~θ组能够明显抑制小鼠跳跃等戒断行为,跳跃次数和跳跃反应率均显著降低,且呈剂量依赖性趋势。
Claims (10)
1.草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用。
2.根据权利要求1所述的应用,其特征在于:所述草乌甲素的衍生物为其互变异构体或其药学上可接受的盐。
3.根据权利要求2所述的应用,其特征在于:所述草乌甲素药学上可接受的盐为其碱加成盐,选自钠、钾、钙、镁、铁、亚铁、铵或锌盐;或酸加成盐,选自硫酸盐、醋酸盐、盐酸盐、磷酸盐、草酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或苯甲酸盐。
4.根据权利要求1所述的应用,其特征在于:所述成瘾性的药物为阿片类毒品。
5.根据权利要求1所述的应用,其特征在于:所述能抑制药物成瘾性的药物中还包括药学可接受的载体、稀释剂、赋形剂。
6.根据权利要求1所述的应用,其特征在于:所述能抑制药物成瘾性的药物为口服剂、缓释剂、片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、口服剂、栓剂和针剂。
7.根据权利要求1所述的应用,其特征在于:所述能抑制药物成瘾性的药物中还包括至少一种已知的能抑制药物成瘾性的药物。
8.根据权利要求7所述的应用,其特征在于:所述已知的能抑制药物成瘾性的药物选自美沙酮、阿片酊、右丙氯酚、环唑星、丁丙诺啡、纳洛酮、纳曲酮。
9.根据权利要求1-8任一项所述的应用,其特征在于:所述能抑制药物成瘾性的药物在应用中的草乌甲素的用量小于2.7mg/kg。
10.一种抑制药物成瘾性的药物,其特征在于:其包括草乌甲素或其互变异构体或其药学上可接受的盐;以及,所述草乌甲素药学上可接受的盐为其碱加成盐,选自钠、钾、钙、镁、铁、亚铁、铵或锌盐;或酸加成盐,选自硫酸盐、醋酸盐、盐酸盐、磷酸盐、草酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或苯甲酸盐。
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