CN1092939C - 一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 - Google Patents
一种抑制酗酒者的脱瘾综合症和饮酒欲望并预防健康人体滥用酒精的组合物 Download PDFInfo
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- CN1092939C CN1092939C CN98810325A CN98810325A CN1092939C CN 1092939 C CN1092939 C CN 1092939C CN 98810325 A CN98810325 A CN 98810325A CN 98810325 A CN98810325 A CN 98810325A CN 1092939 C CN1092939 C CN 1092939C
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
公开了一种含有L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的联合组合物，它可以作为抑制酗酒者的脱瘾综合症和饮酒欲望的药物组合物，并可以作为预防基本健康的个体，尤其是年轻人滥用酒精的饮食补充物、健康食品或营养品。
Description
本发明涉及一种由L-肉碱与低级链烷酰基L-肉碱或其药理学可接受的盐组成的用于治疗酒精中毒的联合组合物。此联合组合物抑制脱瘾综合症(如震颤、出汗、反射亢进、恶心、焦虑和惊厥)和对酒精的欲望的用途。
至今所用的治疗酒精中毒的药物均表现出较大的缺点。
通常用于治疗酒精脱瘾综合症的大量药物的药理学作用是相似的。实际上，对于惯用的药物中最有用的一些，酒精已产生了交叉耐受性。SNC抑制剂可能适用于所有治疗脱瘾综合症的病人，虽然并不是所有的人都需要它。
曾在治疗中广泛应用的三聚乙醛，由于其讨厌的气味和一系列使用后突然、莫名其妙的死亡而完全被废弃。
现在很少使用快速作用的巴比妥酸盐(戊巴比妥和司可巴比妥)。
可选择的药物是苯并二氮卓类如氯化二氮卓(Chlorodiazepoxide)和安定。然而它们表现出一个严重的缺点，即酗酒者服用氯化二氮卓(Chlorodiazepoxide)和安定后可能中毒并甚至产生身体的成瘾性和脱瘾综合症。
由于不能控制剧烈的震颤性谵妄并且会降低癫痫发作的阈值，所以不建议使用吩噻嗪类。
最近，围绕双硫仑的治疗用途存在一些争论，这种物质干扰乙醛代谢(醇氧化的中间产物)并产生其蓄积，因此引起毒性症状和严重的不适。服用双硫仑12小时内饮酒在5-15分钟内产生面部潮红，随后伴以面部和颈部强烈的血管舒张，并且结膜混浊、搏动性头病、心动过速、呼吸过度和出汗。在30-60分钟内出现恶心和呕吐，并可能会严重到导致血压过高、头晕，有时产生晕厥或虚脱。此反应持续1-3小时。不适的感觉如此强烈以致很少有病人在服用双硫仑时冒险饮酒。有时此药物也引起惊厥、心率失常和心肌梗塞。
肉碱在降低实验动物的脱瘾综合症方面的功效已见报道。
Abu Murad等[英国病理学杂志(Brit.J.Pathol.)58卷第6期，1977年12月]报道对小鼠“在给予乙醇期间的饮食中加入DL-肉碱…显著降低了酒精脱瘾综合症的强度。”
Corbett等(神经药理学，23卷第2B期，269-271页，1984)提出这样的假设：服用肉碱可以“通过阻止酒精诱发的钙/镁ATP酶活性的变化”而抵抗“长时间服用酒精和酒精脱瘾的至少一部分影响……”。
对于乙酰L-肉碱，Tempesta等(国际临床药理学研究杂志X(1/2)101-107，1990)报告了由多通道双盲安慰剂对照研究得出的初步数据，其提示乙酰L-肉碱在降低至少禁酒一个月的长期酗酒者的某些感知性缺陷方面可能有功效。
还未提出和验证其它链烷酰基L-肉碱，尤其是丙酰L-肉碱，在治疗酗酒方面的功效。
现在已经发现一种含有L-肉碱、乙酰L-肉碱、丙酰L-肉碱或其药理学上可接受的盐的联合组合物不仅能够抑制酗酒者的脱瘾综合症(如震颤、出汗、反射亢进、恶心、焦虑和惊厥)和对酒精的欲望，也能作为一种预防手段，有效地用于基本上健康但偶尔非连续地过度摄入酒精饮料的人。
值得注意的是本发明组合物的使用者也可以是实质上健康的个体，尤其是年轻人，虽然在临床上不能将其认定为酒精成瘾者，但他们偶尔也沉溺于过度摄入烈性酒精饮料，由于在一个较短的时间里生活方式发生了深刻的变化，尤其是对于年轻人，这种情况越来越频繁。这种现象会影响家庭生活及社会和个人关系的重要方面，并产生甚而影响社会经济状况的令人担忧的后果。
本发明的联合组合物不仅可以作为药物组合物，也可以作为饮食的补充物、健康食品、医疗食品(medical food)或营养品(nutraceutical)或作为上述产品中的成分使用。那么，所述组合物除含有L-肉碱和上述链烷酰基L-肉碱的混合物外，也可以含有其它活性成分，如饮食补充物、维生素、辅酶、矿物质等。
L-肉碱/乙酰L-肉碱/丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。优选此比例为5∶4∶1。
在单位剂量的剂型中，此组合物含有0.44-0.66g L-肉碱内盐；0.44-0.66g乙酰L-肉碱内盐；和0.12-0.18g丙酰L-肉碱内盐或等摩尔的其药理学可以接受的盐。
L-肉碱、乙酰L-肉碱和丙酰L-肉碱的药理学可接受的盐指这些活性成分与不具有有害毒性或副作用的酸形成的任意一种盐。这些酸是药学专家熟知的。
适宜的盐的非限定性的例子如下：氯化物、溴化物、碘化物、天冬氨酸盐，尤其是酸性天冬氨酸盐；柠檬酸盐，尤其是酸性柠檬酸盐；酒石酸盐；磷酸盐，尤其是酸性磷酸盐；富马酸盐，尤其是酸性富马酸盐；甘油磷酸盐；葡萄糖磷酸盐；乳酸盐；马来酸盐，尤其是酸性马来酸盐；乳清酸盐；草酸盐，尤其是酸性草酸盐；硫酸盐，尤其是酸性硫酸盐；三氯乙酸盐；三氟乙酸盐和甲磺酸盐。
国际药理学杂志33(1986)，201-217列出了FDA批准的药理学可接受的盐，将此出版物结合于此作为参考。
由于L-肉碱及上述链烷酰基L-肉碱几乎是无毒的，因此本发明的联合组合物不引起任何上述提及的有害的毒性或副作用。
以下报告的是一些将本发明的联合组合物与分别服用L-肉碱及乙酰L-肉碱的活性进行比较的体内药理学研究的详细资料。
在下文中，“COMP”代表联合组合物，“LC”代表L-肉碱，“ALC”代表乙酰L-肉碱，“PLC”代表丙酰L-肉碱。
按照Vogel试验法测定的COMP对乙醇依赖性大鼠的镇静作用
使用Wistar雄性大鼠(每笼5只分组)，将其置于21℃连续的亮-暗变换的条件下，喂以标准的实验室饲料。长期给这些动物没有限制地服用10％乙醇达6个月。
使用Keppler D.等在实验分子病理学(Exp.Mol.Path.)9，279(1968)记载的一种Vogel试验的修改方案，测定COMP是否对在寻找乙醇的强迫性行为中包括的焦虑因素具有活性及其强度。
试验开始前，动物禁水48小时。乙醇处置停止时，将动物分为4组，腹膜内给药：第一组(A)接受盐溶液(15ml/kg)，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，第三组(C)接受LC(20mg/kg)，第四组(D)接受ALC(20mg/kg)。
试验当天，给动物2个饮水瓶，一只盛水，另一只盛水和乙醇的混合物(90∶10v/v)，后一饮水瓶的金属喷嘴与电源相连，动物每舔饮水瓶5次后，传送电击(1mA)10分钟，迫使动物退缩，克服其饮用水-乙醇溶液的欲望。动物拒绝饮用水-乙醇溶液，将它们的注意力仅限于只盛水的饮水瓶，作为有效的指标。将10分钟测定周期内治疗组动物舔瓶的次数与对照组比较，从而对结果进行评定。结果示于表1。
表1
治疗组动物在10分钟测定周期内的舔瓶次数
| 动物组 | 舔瓶次数 |
| A(盐水)B(COMP)C(LC)D(ALC) | 39.8±7.54.9±1.14*10±6.4*32.2±6.4 |
*相比于A，P＜0.01 相比于B，P＜0.05
用Hunt-Maichrowicz法测定COMP时大鼠脱瘾综合症的影响
使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料，进行实验。长期给这些动物没有限制地服用10％乙醇达6个月。
停止给动物服用乙醇8小时后，将动物分为4组，每组5只大鼠。
第一组(A)接受盐溶液(15ml/kg)腹膜内给药，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，也是腹膜内给药，第三组(C)接受LC(20mg/kg)，第四组(D)给以ALC(20mg/kg)。测定大鼠的震颤，以评价上述治疗酒精脱瘾综合症产生的效果，如同在人体，震颤是脱瘾综合症最具特征性的信号。用Hunt和Majchrowicz描述的方法测定震颤的次数[见Hunt W.A.和Majchrowicz E.，药理学与实验治疗学杂志，213，9-12(1980)]。结果见表2。
表2
| 动物组 | 30分钟 | 60分钟 | 90分钟 | 120分钟 |
| A(盐水)B(COMP)C(LC)D(ALC) | 6±1.50±0.252±0.54±2 | 9±2.50±01±0.55±2 | 8±2.50±0.652±15±1.5 | 9±1.50±0.253±16±2 |
通过观察长期用酒精处理的大鼠受到声音刺激后的行为测定COMP对大鼠脱瘾综合症的影响
使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料，进行实验。长期给这些动物没有限制地服用10％乙醇达6个月。
停止给动物服用乙醇8小时后，将动物分为4组，每组10只大鼠。
第一组(A)通过腹膜内给药服用盐溶液(15ml/kg)，第二组(B)接受COMP(20mg LC+20mg ALC+4mg PLC/kg)，也是腹膜内给药，第三组(C)接受LC(20mg/kg)，第四组(D)接受ALC(20mg/kg)。观察由一只电铃(100dB)发出声音1分钟而导致大鼠产生行为反应(惊厥)的敏感度，从而评价各种治疗方法对酒精脱瘾综合症的影响。在各组大鼠用药1小时后进行该试验，结果示于表3。
表3
| 动物分组 | 惊厥动物/治疗动物总数 |
| A(盐水)B(COMP)C(LC)D(ALC) | 8/101/105/106/10 |
COMP对长期接受乙醇处理的大鼠的中枢神经系统(CNS)中脂过氧化作用(lipoperoxidation)的影响
进行本研究以测定在服用COMP后丙醛(malonaldehyde，MDA)发生何种变化，MDA是一种表示由于乙醇的有害影响而使中枢神经系统对于自由基伤害的易受损性的可靠而可定量的指标。
试验使用每笼5只分组的Wistar雄性大鼠，将其置于21℃连续亮-暗变换的条件下，喂以标准的实验室饲料。两组大鼠，每组5只，在试验的过程中始终给予10％的乙醇水溶液。第3组动物给予标准的实验室饲料而不接受任何治疗。经过乙醇两个月的处理后，给第一组动物以单次腹膜内注射的剂量服用COMP(20mg LC+20mgALC+4mg PLC/kg)。服药后几小时，将动物处死，迅速取出大脑。用Slater和Sawyer(Slater T.F.和Sawyer B.C.，1971，生物化学杂志，东京8：2180)描述的改良的微量法测定MDA。将组织在0℃于Tris-HCl 0.05M(pH 7.4)缓冲液中保持10分钟，然后匀浆。用20％(w/v)三氯醋酸提取部分(0.05ml)脑组织匀浆物。离心后，将0.9ml上清液加到于0.026M Tris-HCl(pH7.0)缓冲液中的0.67％硫代巴比妥酸溶液1ml中。样品置于沸水中10分钟，冷却后用分光光度计测定在532nm的吸光度。以nmol/mg蛋白质表示MDA。用Smith法(Smith等，1985，分析生物化学27：502)，用二辛可宁酸(bicinchoninic acid)作为试剂测定蛋白质。以下的表4显示了MDA在对照组动物、服用乙醇后的动物和服用乙醇+COMP的动物体内的含量。
表4
| 动物分组 | MDAnmol/mg蛋白质 |
| 对照组乙醇组乙醇+COMP | 0.543±0.191.12±0.130.385±0.15 |
本发明的组合物可以用按本领域技术人员已知的常规方法制备成的任何一种常规剂型口服或胃肠外给药。这些剂型包括口服单位剂量的形式，可以为液体或固体，如片剂、胶囊、溶液、糖浆剂等，还可以是可注射的剂型，如小瓶或安瓿装无菌溶液。
这些药物剂型中使用常规的溶剂、稀释剂和赋形剂。可以选择性地加入防腐剂、甜味剂和调味剂。这些物质的非限定性的例子是羧甲基纤维素钠、多山梨醇酯(polysorbate)、山梨醇、微晶淀粉、滑石和其它对于制药技术人员显而易见的物质。
Claims (10)
1.一种可口服或胃肠外给药的组合物，其中含有L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的混合物，其含量是单位剂型中含有0.44-0.66g L-肉碱；0.44-0.66g 乙酰L-肉碱；0.12-0.18g丙酰L-肉碱，或者等摩尔量的其药理学可接受的盐。
2.根据权利要求1所述的组合物，其中L-肉碱∶乙酰L-肉碱∶丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。
3.根据权利要求2所述的组合物，其中所述的比例为5∶4∶1。
4.根据权利要求1所述的组合物，其中L-肉碱、乙酰L-肉碱和丙酰L-肉碱的药理学可接受的盐选自以下物质：氯化物；溴化物；碘化物；天冬氨酸盐；柠檬酸盐；酒石酸盐；磷酸盐；富马酸盐；甘油磷酸盐；葡萄糖磷酸盐；乳酸盐；马来酸盐；乳清酸盐；草酸盐；硫酸盐；三氯乙酸盐；三氟乙酸盐和甲磺酸盐。
5.根据权利要求1所述的组合物，其中L-肉碱、乙酰L-肉碱和丙酰L-肉碱的药理学可接受的盐选自以下物质：酸性天冬氨酸盐；酸性柠檬酸盐；酸性磷酸盐；酸性富马酸盐；酸性马来酸盐；酸性草酸盐；酸性硫酸盐。
6.根据上述任一权利要求所述的组合物，其中含有维生素、辅酶和/或矿物质。
7.L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的联合制剂在制备用于抑制酗酒者的脱瘾综合症和饮酒欲望的药物方面的应用。
8.L-肉碱、乙酰L-肉碱和丙酰L-肉碱或其药理学可接受的盐的联合制剂在制备用于预防健康个体滥用酒精的健康食品、医疗食品或营养品方面的应用。
9.根据权利要求7或8的用途，其中L-肉碱∶乙酰L-肉碱∶丙酰L-肉碱或其药理学可接受的盐的摩尔比为6∶4∶1至3∶2∶1。
10.根据权利要求9所述的用途，其中所述摩尔比为5∶4∶1。
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| CN101766715B (zh) * | 2008-12-31 | 2012-08-29 | 克科 | 解酒醒酒组合物 |
| CN101766635B (zh) * | 2008-12-31 | 2012-10-10 | 克科 | 解酒醒酒组合物 |
| CN106176756A (zh) * | 2015-04-30 | 2016-12-07 | 刘力 | 包含手性异构化合物的赖氨酸五维药物组合物及其用途 |
| WO2021211540A1 (en) * | 2020-04-14 | 2021-10-21 | The Regents Of The University Of California | Diagnosis and treatment of addiction |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0776604A1 (en) * | 1995-12-01 | 1997-06-04 | Unilever N.V. | Microwavable crispy bread-rolls |
| EP0793962A1 (en) * | 1996-03-04 | 1997-09-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Medicament containing a carnitine derivative for treating arteriosclerosis obliterans |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1245869B (it) * | 1991-06-05 | 1994-10-25 | Sigma Tau Ind Farmaceuti | Impiego di propionil l-carnitina per il recupero del tono muscolare in soggetti immobilizzati |
| DE19527281A1 (de) * | 1995-07-26 | 1997-01-30 | Hans Guenter Berner Gmbh | Nahrungsergänzungsmittel |
-
1997
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0776604A1 (en) * | 1995-12-01 | 1997-06-04 | Unilever N.V. | Microwavable crispy bread-rolls |
| EP0793962A1 (en) * | 1996-03-04 | 1997-09-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Medicament containing a carnitine derivative for treating arteriosclerosis obliterans |
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