CN109106717A - 一种用于治疗中重度急性酒精中毒的组合物 - Google Patents
一种用于治疗中重度急性酒精中毒的组合物 Download PDFInfo
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Abstract
本发明公开了一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物主要成分为:维生素B1、维生素B2、维生素B6、维生素C和烟酰胺。本发明组合物为可制备成口服制剂、注射剂。本发明组合物可制备成药品、保健食品。本发明组合物具有加快酒精在体内代谢、消除酒精中毒症状和减轻酒精对人体各脏器的延续损害尤其是肝脏损害的功能,且无毒副作用。
Description
技术领域
本发明涉及药品、保健食品领域,具体涉及了一种防治中重度急性酒精中毒的组合物。
技术背景
《急性酒精中毒诊治共识》一文定义急性酒精中毒(acute alcoholintoxication)是指由于短时间摄人大量酒精或含酒精饮料后出现的中枢神经系统功能紊乱状态,多表现行为和意识异常,严重者损伤脏器功能,导致呼吸循环衰竭,进而危及生命,也称为急性乙醇中毒(acute ethanol intoxication)。文中指出急性酒精中毒已成为急诊科最常见的中毒之一,无论国内还是国外,发病均呈上升趋势,有研究甚至认为,酒精的危害超过海洛因。
共识文中指出轻度急性酒精中毒轻度中毒患者不需要治疗,能自然转归,中重度急性酒精中毒患者则需要进行药物治疗。
共识一文指出具备下列之一者为中度酒精中毒:①.处于昏睡或昏迷状态或Glasgow昏迷评分大于5分小于等于8分;②.具有经语言或心理疏导不能缓解的躁狂或攻击行为;③.意识不清伴神经反射减弱的严重共济失调状态;④.具有错幻觉或惊厥发作;⑤.血液生化检测有以下代谢紊乱的表现之一者如酸中毒、低血钾、低血糖;⑥.在轻度中毒基础上并发脏器功能明显受损表现如与酒精中毒有关的心律失常(频发早搏、心房纤颤或房扑等),心肌损伤表现(ST-T异常、心肌酶学2倍以上升高)或上消化道出血、胰腺炎等。
共识一文指出具备下列之一者为重度酒精中毒:①.处于昏迷状态Glasgow评分等于小于5分;②.出现微循环灌注不足表现,如脸色苍白,皮肤湿冷,口唇微紫,心率加快,脉搏细弱或不能触及,血压代偿性升高或下降(低于90/60 mmHg或收缩压较基础血压下降30mmHg以上,1 mmHg=0.133 kPa),昏迷伴有失代偿期临床表现的休克时也称为极重度;③.出现代谢紊乱的严重表现如酸中毒(pH≤7.2)、低血钾(血清钾≤2.5 mmol/L)、低血糖(血糖≤2.5 mmoL/L)之一者;④.出现重要脏器如心、肝、肾、肺等急性功能不全表现。
《急性酒精中毒诊治共识》规范中推荐的治疗急性酒精中毒的药物大多为促醒、促进酒精代谢、镇静药物和营养补充剂。其中药品说明书中适应症有酒精中毒的只有维生素B1、维生素B6,均为单一配方制剂。其中维生素B1药理作用为参与体内辅酶的形成,能维持正常糖代谢及神经、消化系统功能。维生素B6在红细胞内转化为磷酸吡哆醛,作用辅酶对蛋白质、碳水化合物、脂类的各种代谢起作用,同时还参与色氨酸转化成烟酸或5-羟色胺。
维生素C参与机体内抗体及胶原形成,组织修补(包括某些氧化还原作用),苯丙氨酸、酪氨酸、叶酸的代谢,铁、碳水化合物的利用,脂肪、蛋白质的合成,以及维持免疫功能,羟化5-羟色胺,保持血管的完整,并促进非血红素铁的吸收。烟酸在组织呼吸过程中,作为催化重要的氧化还原反应的多种酶中的辅酶发挥作用。它可以成为基质脱下来的氧离子的受体被还原,然后经黄素蛋白的作用被再氧化,恢复到原来的状态。烟酸具有扩张血管、降低血脂、减少胆固醇合成,溶解纤维蛋白,防止血栓形成的作用。维生素B2是辅酶的组成成份,参与糖、蛋白质、脂肪的代谢,维持正常的视觉功能和促进生长,参与细胞的生长代谢,是肌体组织代谢和修复的必须营养素,同时还可以强化肝功能、调节肾上腺素的分泌。
经过调研,现阶段,临床上缺乏可用于治疗中重度急性酒精中毒的特效药。
我们经过多年开发,以维生素B1、维生素B2、维生素B6、维生素C和烟酰胺为主要原料开发出一种组合物配方制剂,所有主要原料成分每日用量均在国家药品规定的安全用量范围内。且药效试验表明组合物配方较临床使用的单一配方制剂效果更佳。
发明内容
本发明的目的是提供一种用于治疗中重度急性酒精中毒的组合物,具有加快酒精在体内代谢、消除酒精中毒症状和减轻酒精对人体各脏器的延续损害尤其是肝脏损害的功能,且无毒副作用。
本发明提供的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物包括主要成分维生素B1、维生素B2、维生素B6、维生素C、烟酰胺和药用辅料。
本发明提供的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物主要成分每日用量为:维生素B1为10-500mg,维生素B2为4-30 mg、维生素B6为5-100 mg、维生素C为100-1000 mg、烟酰胺为13-400 mg。
本发明提供的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物所述药用辅料为淀粉、糊精、微晶纤维素、硬脂酸镁、滑石粉、注射用水。
本发明提供的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物可制备成口服制剂、注射剂。
本发明提供的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物可制备成药品、保健食品。
具体实施方式
以下结合具体实施例,对本发明的技术方案作进一步地详细介绍,但本发明的保护范围并不局限于此。
实施例1
以重量计,主要成分配比维生素B1为20g,维生素B2为20g、维生素B6为12.5g、维生素C为300g、烟酰胺为20g,另以淀粉、糊精、微晶纤维素、硬脂酸镁、滑石粉为药用辅料,按照传统片剂制备工艺制成片剂2000片。
用法用量:口服,一次1片,一日2次。
动物药效试验
1、试验样品以及阳性对照药
以实施例1制备的片剂为试验样品。成人用法用量:口服,一次1片,一日2次。(每日用量:2片,其中含维生素B1为20mg,维生素B2为20mg、维生素B6为12.5mg、维生素C为300mg、烟酰胺为20mg。)
以市售维生素B1片、维生素B6片为阳性对照药。
维生素B1片,规格:10mg。成人用法用量:口服,一次1片,一日3次。(每日用量:3片,30mg。)
维生素B6片,规格:10mg。成人用法用量:口服,一日1-2片。(说明书每日用量:10mg~20mg,此次试验选取每日用量为:2片,20mg。)
2、剂量换算以及试验用法
试验采用SD大鼠,大鼠与成人临床等效剂量以6为换算系数,成人体重以60kg计算,每日用量一次性灌胃给予。例如阳性对照药维生素B1片,成人临床等效剂量为:3片,30mg,则换算成大鼠1倍等效剂量为:3片÷60 kg×6=0.3片/kg。
试验用法:按大鼠与成人临床等效剂量的1倍进行灌胃给药,每日用量一次性灌胃给予,给药体积用量为5mL/kg。试验样品和阳性对照药均采用灭菌注射用水溶解成给药需要的浓度。具体设计如下:
试验样品:成人每日用量为2片(其中含维生素B1为20mg,维生素B2为20mg、维生素B6为12.5mg、维生素C为300mg、烟酰胺为20mg),换算成大鼠为:2片÷60 kg×6=0.2片/kg,给药体积用量为5mL/kg,则试验样品给药需要的浓度为:0.2片/kg÷5mL/kg=0.04片/ml。因此试验样品样品溶液制备方法为取4片试验样品加灭菌注射液用水溶解并定容至100ml,即得,浓度为0.04片/ml。
维生素B1片:成人每日用量为3片(含维生素B1为30mg), 换算成大鼠为:3片÷60kg×6=0.3片/kg,给药体积用量为5mL/kg,则阳性对照药维生素B1片给药需要的浓度为:0.3片/kg÷5mL/kg=0.06片/ml。因此维生素B1片样品溶液制备方法为取6片维生素B1片加灭菌注射液用水溶解并定容至100ml,即得,浓度为0.06片/ml。
维生素B6片:成人每日用量为2片(含维生素B6为20mg),换算成大鼠为:2片÷60kg×6=0.2片/kg,给药体积用量为5mL/kg,则阳性对照药维生素B6片给药需要的浓度为:0.2片/kg÷5mL/kg=0.04片/ml。因此维生素B6片样品溶液制备方法为取4片维生素B6片加灭菌注射液用水溶解并定容至100ml,即得,浓度为0.04片/ml。
3、试验方法
3.1分组
264只大鼠(雄性)严格禁食16.5h,不禁水。使用excel软件按体重大小分层,随机分为正常组(24只)、模型组(60只)、试验样品组(60只)、维生素B1片组(60只)、维生素B6片组(60只)。
3.2造模
通过灌胃二锅头白酒,建立大鼠急性酒精中毒模型;所有大鼠灌胃3次,每次间隔24h;正常组大鼠灌胃灭菌注射用水,其余大鼠灌胃二锅头白酒(56度,牛栏山),造模体积用量均为15.6mL/kg。乙醇造模剂量=造模体积用量×体积分数×密度,其中体积分数为56%,密度为0.8g/mL。详见表1。
表1 造模剂量表
3.3造模后给药
第2次造模后0.5h, 进行第1次给药;第3次造模后0.5h, 进行第2次给药。详见表2。
表2 给药剂量表
3.4观测指标
①.中毒症状:记录大鼠灌酒后的中毒症状至少1次。
②.肝功能血清生化指标:第2次给药后24h取血,分离出血清,测定血清中ALT、AST水平。
③.肝脏病理组织学观察:取血完成后立即断头处死大鼠,解剖并任取部分肝脏,用10%中性甲醛溶液固定后,送检。
3.5全血的采集及处理
大鼠眼眶取血1~1.5mL,室温静置约1~2h后,2500r/min 离心10min,取上清,2500r/min再离心10min,再取上清约200~400μL,-20℃保存。
3.6试验数据统计学处理方法
运用SPSS 13.0 for windows软件,进行统计学分析,以P<0.05,确定组间差异具有统计学意义。计量资料(ALT、AST)先检验数据是否服从正态分布,再选用t检验或非参数检验(Nonparametric Tests),检验组间差异的显著性。若数据服从正态分布或经对数转换后服从正态分布,可采用单因素方差分析(ONE-WAY ANOVA,其中方差相齐采用LSD 检验,方差不齐则采用Tamhane’s T2 检验),也可采用成组样本t检验;若数据始终不服从正态分布,采用非参数检验中的两样本秩和检验方法(Mann-Whitney )。分类资料(如肝脏脂肪变性等级)直接采用非参数检验中的两样本秩和检验方法。
4、试验结果
4.1中毒症状
除正常组外,其余各组大鼠灌酒后出现了侧躺、俯卧、屈足、伸腿、蹬足前行、闭眼、翻正反射消失(背部向下,保持30s不动)症状,且有部分大鼠死亡。
4.2血清中ALT水平
见表3。模型组、维生素B1片组、维生素B6片组分别与正常组比较,ALT均升高,均P<0.01;试验样品组正常组比较,ALT升高,P<0.05;维生素B1片组、维生素B6片组分别与模型组比较,ALT均降低,P<0.05;试验样品组与模型组比较,ALT降低,P<0.01。
表3 各试验组间血清中ALT水平差异
组别 | 样本量<i>n</i>(个) | ALT(U/L) |
正常组 | 24 | 31.52±7.16<sup>▽▽</sup> |
模型组 | 37 | 63.86±28.60<sup>△△</sup> |
试验样品组 | 42 | 40.12±10.32<sup>△▽▽</sup> |
维生素B1片组 | 40 | 51.57±13.16<sup>△△▽</sup> |
维生素B6片组 | 39 | 53.46±12.78<sup>△△▽</sup> |
注:1、各试验组的血清中ALT水平均以“平均值±标准差”表示。
2、同一时间点下,血清中ALT水平组间比较,符号上标:与正常组比较,△代表
P<0.05,△△代表P<0.01;与模型组比较,▽代表P<0.05,▽▽代表P<0.01。
4.3血清中AST水平
见表4。模型组与正常组比较,AST值增高,P<0.01;试验样品组与正常组比较,P>0.05;维生素B1片组、维生素B6片组分别与正常组比较,AST值均增高,P<0.05;试验样品组与模型组比较,AST值降低,P<0.01;维生素B1片组、维生素B6片组分别与模型组比较,AST值均降低,P<0.05。
表4 各试验组间血清中AST水平差异
组别 | 样本量<i>n</i>(个) | AST(U/L) |
正常组 | 24 | 245.4±70.3 |
模型组 | 37 | 321.6±137.5<sup>△△</sup> |
试验样品组 | 42 | 250.6±69.7<sup>▽▽</sup> |
维生素B1片组 | 40 | 283.6±76.2<sup>△▽</sup> |
维生素B6片组 | 39 | 287.9±78.5<sup>△▽</sup> |
注:1、各试验组的血清中AST水平均以“平均值±标准差”表示。
2、同一时间点下,血清中AST水平组间比较,符号上标:与正常组比较,△代表
P<0.05,△△代表P<0.01;与模型组比较,▽代表P<0.05,▽▽代表P<0.01。
4.4肝脏病理组织学观察
4.4.1病变描述
①.正常组:
肝小叶结构完整,分界清晰、未见增生及假小叶形成,肝细胞内及细小胆管内无胆汁淤积,未见各类细胞浸润,汇管区无明显扩大及纤维结缔组织增生。小叶间胆管无扩张及增生,被膜完整,未见增厚及渗出。1例( 1/24)例动物可见轻度炎细胞浸润及点状坏死,可能与动物质量及环境因素有关,多考虑为自发性病变。
②.模型组:
28例动物(28/37)肝脏细胞可见不同程度的脂肪变性,30例动物(30/37)肝脏可见不同程度的炎细胞浸润及坏死。其余动物肝小叶结构完整,分界清晰、未见增生及假小叶形成,肝细胞内及细小胆管内无胆汁淤积,未见各类细胞浸润,汇管区无明显扩大及纤维结缔组织增生。小叶间胆管无扩张及增生,被膜完整,未见增厚及渗出。
③.试验样品组:
23例动物(23/42)肝脏细胞可见不同程度的脂肪变性,23例动物(23/42)肝脏可见不同程度的炎细胞浸润及坏死。其余动物肝小叶结构完整,分界清晰、未见增生及假小叶形成,肝细胞内及细小胆管内无胆汁淤积,未见各类细胞浸润,汇管区无明显扩大及纤维结缔组织增生。小叶间胆管无扩张及增生,被膜完整,未见增厚及渗出。
④.维生素B1片组:
25例动物(25/40)肝脏细胞可见不同程度的脂肪变性,26例动物(26/40)肝脏可见不同程度的炎细胞浸润及坏死。其余动物肝小叶结构完整,分界清晰、未见增生及假小叶形成,肝细胞内及细小胆管内无胆汁淤积,未见各类细胞浸润,汇管区无明显扩大及纤维结缔组织增生。小叶间胆管无扩张及增生,被膜完整,未见增厚及渗出。
⑤.维生素B6片组:
25例动物(25/39)肝脏细胞可见不同程度的脂肪变性,25例动物(25/39)肝脏可见不同程度的炎细胞浸润及坏死。其余动物肝小叶结构完整,分界清晰、未见增生及假小叶形成,肝细胞内及细小胆管内无胆汁淤积,未见各类细胞浸润,汇管区无明显扩大及纤维结缔组织增生。小叶间胆管无扩张及增生,被膜完整,未见增厚及渗出。
4.4.2病变程度及分布
见表5。
脂肪变性:模型组、试验样品组与正常组比较,均P<0.01;试验样品组与模型组比较,P<0.05;维生素B1片组、维生素B6片组分别与模型组比较,脂肪变性程度均较模型组轻,但P>0.05。
炎症病变:模型组、试验样品组分别与正常组比较,均P<0.01;试验样品组、维生素B1片组、维生素B6片组分别与模型组比较,炎症病变程度均较模型组轻,但P>0.05。
表5 各试验组肝脏病变程度及分布情况
5、结论
实施例1试验样品灌胃给药2次(1次/日,主要成分每日用量为:维生素B1为20mg,维生素B2为20 mg、维生素B6为12.5 mg、维生素C为300 mg、烟酰胺为20 mg),对急性酒精中毒模型大鼠肝损伤有一定的治疗效果,主要体现为可减轻肝脂肪变性程度,可降低血清中ALT水平。并且试验样品治疗效果优于市售阳性对照药维生素B1片(1次/日,灌胃2次,每日用量含维生素B1为30mg)、维生素B6片(1次/日,灌胃2次,每日用量含维生素B6为20mg)。
Claims (4)
1.一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物包括主要成分维生素B1、维生素B2、维生素B6、维生素C、烟酰胺和药用辅料。
2. 根据权利要求1所述的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物所含主要成分每日用量为:维生素B1为10-500mg,维生素B2为4-30 mg、维生素B6为5-100 mg、维生素C为100-1000 mg、烟酰胺为13-400 mg。
3.根据权利要求1-2所述的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物可制备成口服制剂、注射剂。
4.根据权利要求1-3所述的一种用于治疗中重度急性酒精中毒的组合物,其特征在于该组合物可制备成药品、保健食品。
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"健康大讲堂"编委会: "《降低血压的100条原则》", 31 March 2017, 福建科学技术出版社 * |
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