CN114377113A - 用于预防、治疗和/或缓解宿醉及其相关症状的双酶组合物 - Google Patents
用于预防、治疗和/或缓解宿醉及其相关症状的双酶组合物 Download PDFInfo
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- CN114377113A CN114377113A CN202210141233.8A CN202210141233A CN114377113A CN 114377113 A CN114377113 A CN 114377113A CN 202210141233 A CN202210141233 A CN 202210141233A CN 114377113 A CN114377113 A CN 114377113A
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- enzyme
- hangover
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Abstract
提供了用于预防、治疗和/或缓解宿醉及其相关症状的双酶组合物,即包括两种来自动物的外源酶的组合物,其供人类在消耗酒精之前和/或之后消耗以通过基于双酶的过量酒精分解来预防、治疗和/或缓解由酒精过度消耗引起或造成的宿醉和/或其相关症状,其中所述两种外源酶中的第一种酶能够将酒精转化成第一种代谢物,而其第二种酶能够将第一种代谢物转化成第二种代谢物,所述第二种代谢物在所述两种外源酶和NAD+/NADH存在的情况下在酒精的氧化反应之后可排泄至全身循环;第一种酶与第二种酶的摩尔比维持人类中第一种和第二种代谢物之间的比率,从而避免在过量酒精消耗之后人类中第一种代谢物的局部升高。
Description
技术领域:
本发明涉及用于预防、治疗和/或缓解宿醉及其相关症状的双酶组合物,且更具体地,涉及在人体内基于辅助酶的酒精分解。
背景技术:
酒精中毒或酒精使用障碍(“AUD”)是一种慢性复发性脑部疾病,其特征在于,尽管存在不利的社会、职业和健康后果,但停止或控制酒精使用的能力受损。AUD使人们面临许多不良健康后果(包括酒精性肝病、急性酒精中毒和各种癌症)的风险。根据WHO在2018年全球酒精和健康状况报告,在2016年,酒精的有害使用导致全球约300万人死亡(占所有死亡的5.3%)。由酒精消耗造成的死亡率高于由疾病诸如结核病、HIV/AIDS和糖尿病造成的死亡率。
摄入的饮料酒精(乙醇)对人体内的不同器官(包括脑/中枢神经系统、肝脏和胰腺)的影响取决于乙醇浓度摄入和暴露的持续时间。这两个变量都受到乙醇吸收至血流和组织中以及乙醇代谢的影响5。人体内参与乙醇代谢的主要酶是醇脱氢酶(“ADH”)和醛脱氢酶(“ALDH”)。乙醇代谢的主要途径涉及将其氧化为乙醛,即一种由ADH和辅酶NAD+催化的反应。在由ALDH和辅酶NAD+催化的第二种反应中,乙醛被氧化成乙酸。其如图1中所举例说明。ADH和ALDH影响酒精中毒风险的机制被认为涉及乙醛水平的局部升高,其由更快的乙醇氧化或更慢的乙醛氧化所导致。乙醛是一种有毒物质,其累积导致高度不良的反应,包括面部潮红、恶心、心率加快和宿醉及其相关症状(图1)。
最近,许多人使用非处方的疼痛缓解剂如阿司匹林或对乙酰氨基酚来缓解宿醉及其相关症状。重要的是认识到,酒精和对乙酰氨基酚的组合可能对肝脏有毒。此外,没有治疗急性酒精中毒的药物。血液透析是紧急情况下的唯一选项,特别是在美国,药物美他多辛尚未获得FDA批准。因此,可以有效最小化由饮酒所带来的潜在健康危害风险的创新预防措施的开发已成为减轻对整体经济负担的一项非常重要的策略。在健康护理市场上,关于有效、安全和方便的日常用作偶尔和频繁饮酒者和AUD患者的预防措施的产品,存在巨大的空白。
如从与酒精摄入相关的各种情况来看,本领域需要增强人体中的酒精分解。增强的酒精和酒精代谢产物的分解将减少酒精的长期有害影响(诸如肝损伤)以及短期影响(诸如宿醉和酒精中毒)。因此,本领域需要低成本且具有最小副作用的可以增强在人体内的酒精分解的组合物。
发明内容:
在一个方面,提供了包括两种来自动物的外源酶的组合物,其供人类在消耗酒精之前和/或之后消耗以通过基于双酶的过量酒精分解来预防、治疗和/或缓解由酒精过度消耗引起或造成的宿醉和/或其相关症状,其中所述两种外源酶中的第一种酶能够将酒精转化成第一种代谢物,而其第二种酶能够将第一种代谢物转化成第二种代谢物,所述第二种代谢物在所述两种外源酶和NAD+/NADH存在的情况下在酒精的氧化反应之后可排泄至全身循环,且其中所述组合物中第一种酶与第二种酶的摩尔比为1:15-60,以便维持人类中第一种和第二种代谢物之间的比率,从而避免在过量酒精消耗之后人类中第一种代谢物的局部升高。
在一个实施方案中,所述第一种酶是醇脱氢酶且所述第二种酶是醛脱氢酶。
在另一个实施方案中,所述组合物中第一种酶与第二种酶的摩尔比为1:40。
在其它实施方案中,第一种代谢物的局部升高导致宿醉症状。
在另一个实施方案中,所述第一种代谢物是乙醛。
在其它实施方案中,所述第二种代谢物是乙酸盐。
在还另一个实施方案中,与宿醉相关的症状包括疲劳、情感淡漠、专心问题、笨拙、意识错乱、口渴、出汗、战栗、胃痛、恶心、头晕和心脏狂跳。
在一个实施方案中,所述醛脱氢酶由SEQ ID NO:1的氨基酸序列表示。
在一个实施方案中,所述两种外源酶的来源动物包括牛和羊。
在其它实施方案中,所述外源酶来自牛和羊的肝脏。
附图简要说明:
图1示意地说明了ADH和ALDH2如何在人体内代谢酒精的一般机制。
图2显示了根据酒精及其副产物或代谢物的浓度随时间的变化,本组合物的体外酶促活性的结果。
图3显示了在提取物的加热过程中ADH和ALDH的含量的体外酶促活性的结果。
图4显示了通过使用酒精宿醉严重程度量表(AHSS)调查本发明的组合物对宿醉严重程度的影响的基本标准。
定义:
下述缩写和它们的相应长表达在本文中可互换地使用:
ADH-醇脱氢酶
AHSS-酒精宿醉严重程度量表
ALDH-醛脱氢酶
AUD-酒精使用障碍
FDA-食品和药品管理局
I.M.-肌肉内的
I.V.-静脉内的
US-美国
WHO-世界卫生组织
具体实施方式:
1.本发明的机制:
酶是大分子生物催化剂,其可以加速人体内的化学反应。细胞中几乎所有的代谢过程都需要酶催化才能以足够快的速率发生以维持生命。已知酶催化超过5,000种生化反应。大多数酶是蛋白,且特异性来自其独特的三维结构。由于许多酶由人体自然产生,因此它们安全地用作可摄入的补充剂。
本发明聚焦于用于酒精代谢的两种酶,即醇脱氢酶(“ADH”)和醛脱氢酶(“ALDH”)。ADH是一种主要存在于肝脏和胃中的酶,它将乙醇转化为乙醛,所述乙醛是然后由ALDH进一步分解为乙酸的毒素,所述乙酸可以转化为二氧化碳和水。这两种酶使用体外测定进行研究,证明相应的酶促活性是非常有效的,并可能用于增强频繁饮酒者体内酒精的降解,以预防、治疗和/或缓解宿醉及其相关症状。这些酶也可以用于治疗其有缺陷的微生物组从非基于酒精的食品和饮料过度产生乙醇的那些人。
在一个方面,在体外测试了ADH和ALDH以确定对乙醇底物的活性。ADH和ALDH来源于哺乳动物肝脏,这是可以促进低成本口服补充剂生产的起始材料的丰富天然来源。
牛或羊的肝脏源自澳大利亚。测试的酶使用在1:15-60且更优选1:40的范围内的ADH和ALDH的理想比率,以使酶促酒精降解过程的第二步成为优势酶促反应。开发这种制剂的基本原理是防止乙醛的积累,所述乙醛是宿醉及其相关症状的主要原因。使用这种制剂,乙醛(即在酶促过程的第一步中来自乙醇的分解产物)被有效地降解为乙酸,并最终降解为水和二氧化碳。这种特殊制剂的体外酶促活性如图2中所举例说明。
2.在本发明中使用的制剂
在一个方面,本发明生产了呈肠溶胶囊形式的高质量治疗性酶制剂,以增强在人体内的酒精降解,以便缓解偶尔和频繁饮酒者的宿醉及其相关症状。它是通过专有提取和分离方法从牛或羊肝脏中提取的冷冻干燥粉末,所述方法产生的产品对人类消耗而言是安全的且对酒精降解是有效的。
使用专有的提取和分离方法,成功地从不同来源(包括牛和羊)的肝脏中提取ADH和ALDH酶。将提取物冷冻干燥并作为干粉储存。来自不同动物来源的提取物/冷冻干燥粉末与在ADH和ALDH的理想摩尔比下的ADH和ALDH酶含量非常一致。来自牛和羊的肝脏(当肝脏提取物的浓度为约50mg/ml时)的ADH的体外酶促活性结果分别为平均0.843单位和0.808单位,且ALDH的体外酶促活性结果分别为平均30.453单位和29.322单位。
从冷冻干燥粉末的内部稳定性测试来看,当在室温和干燥湿度下储存超过12个月时,它显示非常好的稳定性。
本发明使用专有的提取方法。专有的提取意味着精确控制来自哺乳动物肝脏的提取物的加热和冷却过程。发现当将肝脏提取物加热到40℃时,可获得ADH含量最高的提取物,同时ADH和ALDH酶含量大致在1:40的理想摩尔比。图3中举例说明了在该加热过程中ADH和ALDH的含量的体外酶促活性。
本发明的治疗性酶不能从猪肝产生。根据本发明的体外研究,猪肝提取物中不存在ALDH,其中ALDH是本组合物中的主要组分之一。
任选地,提取的酶可以与抗氧化剂一起包装在肠溶胶囊中。抗氧化剂以及其它任选的赋形剂可以保护酶不被降解,以维持更长的贮存期限和最大的效力。
根据本发明的口服补充剂可用于以下方面:
1.增强人体内的酒精代谢,以缓解宿醉及其相关症状。
2.降解酒精以预防酒精性肝病(“ALD”)。
实施例:
通过选择符合图4中所示的基本标准的受试者进行了调查,以通过使用酒精宿醉严重程度量表(AHSS)评价本发明的组合物对宿醉严重程度的影响。
成功招募了25名受试者,并要求他们在1个月测试时段期间完成两次相同的问卷调查。受试者在晚餐中饮用150ml至550ml酒精饮料,酒精含量范围为15%至55%。在酒精消耗后第二天8-12小时完成问卷调查,其中每名受试者的一份问卷调查在其正常酒精摄入实践下完成,且另一份在酒精消耗前服用本发明的组合物完成。使用包括疲劳、情感淡漠、专心问题、笨拙、意识错乱、口渴、出汗、战栗、胃痛、恶心、头晕和心脏狂跳在内的12种症状来评价所有受试者的宿醉的严重程度。
要求受试者指明当他们醒来时经历上述12种症状的程度。可以看出,2名受试者在测试时段期间未出现宿醉和/或与其相关的任何症状,无论是否服用本组合物;22名受试者在没有本组合物的情况下出现宿醉和/或其相关症状,但服用本组合物后宿醉或相关症状缓解;1名受试者出现宿醉和相关症状,无论是否服用本组合物。根据AHSS调查,约88%的受试者对本组合物有阳性应答,其中在酒精消耗后其宿醉和相关症状显著缓解。
在较高剂量,本发明的酶组合物可用作口服或注射药物,其可以在急性酒精中毒的紧急情况下快速除去酒精。通过在身体组织和器官(例如肝脏)从血液中摄取有害水平的酒精之前将酒精高效地转化为无害物质,本组合物可以降低和预防急性酒精中毒的严重程度。
对于可注射制剂和任选地对于口服制剂,可以采用通过将携带人h-ADH和h-ALDH基因的哺乳动物表达载体引入安全且研究充分的哺乳动物细胞系中的重组DNA技术。通过色谱技术进一步分离和纯化这些哺乳动物细胞表达的靶酶。本发明可用于生产临床级h-ADH和h-ALDH,用于医院和诊所中紧急使用的治疗性酶药物的有效静脉内(“I.V.”)或肌肉内(“I.M.”)输注。
人类基因组包括19个ALDH基因。ALDH1主要存在于肝脏中,并且可以用在本发明的酶提取物版本中。另一种ALDH是在线粒体中发现的ALDH2。可以选择ALDH2作为在本发明中使用的ALDH;其序列由SEQ ID NO:1表示:
重组ALDH诸如ALDH2可商购得自供应商诸如Sigma Aldrich。生产ALD和ALDH的重组技术的例子描述于2017年1月5日出版的Nene等人,J.Biomed.Sci.2017,24:3,其公开内容通过引用并入本文。
本发明的制剂中的活性成分可以并入口服制剂中,所述口服制剂可作为饮食补充产品施用。该产品的一个潜在健康益处是缓解偶尔和频繁饮酒者的宿醉以及相关症状。该产品应在消耗酒精前服用。
参考文献:
以下参考文献中的每一篇的公开内容都通过引用并入本文。
1.Thomas D.Hurley,Howard J.Edenberg,Ting-Kai Li.Pharmacogenomics ofAlcoholism.见:Pharmacogenomics:The Search for Individualized Therapies,Germany Wiley-VCH,Weinheim,第21章,第417-441页.
2.Nene等人,J.Aldehyde dehydrogenase 2activation and coevolution ofitsεPKC-mediated phosphorylation sites.Biomed.Sci.2017,24:3.
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Claims (10)
1.包含两种来自动物的外源酶的组合物,所述组合物供人类在消耗酒精之前和/或之后消耗以通过基于双酶的过量酒精分解来预防、治疗和/或缓解由酒精过度消耗引起或造成的宿醉和/或其相关症状,其中所述两种外源酶中的第一种酶能够将酒精转化成第一种代谢物,而其第二种酶能够将第一种代谢物转化成第二种代谢物,所述第二种代谢物在所述两种外源酶和NAD+/NADH存在的情况下在酒精的氧化反应之后可排泄至全身循环,且其中所述组合物中第一种酶与第二种酶的摩尔比为1:15-60,以便维持人类中第一种和第二种代谢物之间的比率,从而避免在过量酒精消耗之后人类中第一种代谢物的局部升高。
2.根据权利要求1所述的组合物,其中所述第一种酶是醇脱氢酶且所述第二种酶是醛脱氢酶。
3.根据权利要求2所述的组合物,其中所述组合物中的第一种和第二种酶的摩尔比为1:40。
4.根据权利要求1所述的组合物,其中所述第一种代谢物的局部升高导致宿醉症状。
5.根据权利要求1所述的组合物,其中所述第一种代谢物是乙醛。
6.根据权利要求1所述的组合物,其中所述第二种代谢物是乙酸盐。
7.根据权利要求1所述的组合物,其中所述与宿醉相关的症状包括疲劳、情感淡漠、专心问题、笨拙、意识错乱、口渴、出汗、战栗、胃痛、恶心、头晕和心脏狂跳。
8.根据权利要求2所述的组合物,其中所述醛脱氢酶由SEQ ID NO:1的氨基酸序列表示。
9.根据权利要求1所述的组合物,其中所述两种外源酶的来源动物包括牛和羊。
10.根据权利要求9所述的组合物,其中所述外源酶来自牛和羊的肝脏。
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US11795441B2 (en) | 2021-05-05 | 2023-10-24 | Alcolear Limited | Dual-enzyme composition for preventing, treating and/or alleviating veisalgia and symptoms associated therewith |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109718255A (zh) * | 2018-05-02 | 2019-05-07 | 艾美科健株式会社 | 一种消除宿醉酶粉末的制备方法和含有该成分的消除宿醉用组合物 |
CN112426519A (zh) * | 2020-11-29 | 2021-03-02 | 长沙晶易医药科技有限公司 | 一种含乙醇脱氢酶和乙醛脱氢酶的胃滞留缓释制剂及其制备方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5759539A (en) | 1995-06-06 | 1998-06-02 | Georgia Research Foundation, Inc. | Method for rapid enzymatic alcohol removal |
US20050271739A1 (en) | 2004-06-08 | 2005-12-08 | Wang Xiang H | Methods and compositions for accelerating alcohol metabolism |
US10245288B2 (en) | 2011-02-04 | 2019-04-02 | Joseph E. Kovarik | Method and system for reducing the likelihood of developing NASH in an individual diagnosed with non-alcoholic fatty liver disease |
CN103911335B (zh) | 2014-04-18 | 2016-04-13 | 四川农业大学 | 约氏乳酸杆菌bs15及其在预防和治疗非酒精性脂肪肝中的应用 |
KR102011979B1 (ko) | 2017-10-16 | 2019-08-19 | (주)케어젠 | 세사몰과 펩타이드의 결합체를 유효성분으로 함유하는 숙취 해소용 조성물 |
-
2021
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-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109718255A (zh) * | 2018-05-02 | 2019-05-07 | 艾美科健株式会社 | 一种消除宿醉酶粉末的制备方法和含有该成分的消除宿醉用组合物 |
CN112426519A (zh) * | 2020-11-29 | 2021-03-02 | 长沙晶易医药科技有限公司 | 一种含乙醇脱氢酶和乙醛脱氢酶的胃滞留缓释制剂及其制备方法 |
Non-Patent Citations (3)
Title |
---|
KALNINE,N.等: ""AAP36614.1"", 《GENBANK》 * |
傅婷等: "猪肝乙醇脱氢酶的分离纯化及部分性质", 《食品科学》 * |
毛跟年等: "乙醛脱氢酶及其医疗领域研究进展", 《天然产物研究与开发》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11471514B1 (en) | 2021-05-05 | 2022-10-18 | Alcolear Limited | Dual-enzyme composition for preventing, treating and/or alleviating veisalgia and symptoms associated therewith |
WO2022233288A1 (en) * | 2021-05-05 | 2022-11-10 | Alcolear Limited | Dual-enzyme composition for preventing, treating and/or alleviating veisalgia and symptoms associated therewith |
US11795441B2 (en) | 2021-05-05 | 2023-10-24 | Alcolear Limited | Dual-enzyme composition for preventing, treating and/or alleviating veisalgia and symptoms associated therewith |
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