CN103945858A - 用于治疗糖尿病和相关病症的方法和组合物 - Google Patents
用于治疗糖尿病和相关病症的方法和组合物 Download PDFInfo
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- CN103945858A CN103945858A CN201280056939.9A CN201280056939A CN103945858A CN 103945858 A CN103945858 A CN 103945858A CN 201280056939 A CN201280056939 A CN 201280056939A CN 103945858 A CN103945858 A CN 103945858A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及用于治疗糖尿病和相关病症的方法和组合物。更具体地，本发明涉及包含左旋谷氨酰胺、其盐或其衍生物的组合物，以及该组合物在治疗糖尿病和相关病症中的应用。在方法方面，本发明提供一种治疗糖尿病的方法。该方法包括患有糖尿病的人每天摄取0.05g/kg体重至10.0g/kg体重的左旋谷氨酰胺、左旋谷氨酰胺盐或左旋谷氨酰胺衍生物。
Description
本申请主张申请号为No.61/629633、申请日为2011年11月21日的美国临时专利申请的优先权。现将其全部内容整体引入本申请作为参考。
技术领域
本发明涉及用于治疗糖尿病和相关病症的方法和组合物。更具体地，本发明涉及包含左旋谷氨酰胺、其盐或其衍生物的组合物，以及该组合物在治疗糖尿病和相关病症中的应用。
背景技术
糖尿病(diabetes mellitus)也被称为糖尿病(diabetes)，是一组新陈代谢疾病，其中患者具有高血糖水平。患有糖尿病的人或者不能产生足够的胰岛素来调节血糖水平，或者该人的细胞不能恰当地对产生的胰岛素做出响应。
存在三种基本类型的糖尿病：1型；2型；和妊娠糖尿病。1型糖尿病由身体不能产生胰岛素引起。2型糖尿病由胰岛素抗性引起；人的细胞不能恰当地使用胰岛素。妊娠糖尿病是处于怀孕中的某些孕妇所经历的，其中，没有2型糖尿病的早期史。
糖尿病是通过由一次或多次的血液测试所获得的测量值来诊断。例如，以下测试和相关值是典型的糖尿病征兆：空腹血糖水平≥7.0mmol/L(126mg/dL)；口服75g葡萄糖(例如，葡萄糖耐量测试)两小时后，血糖水平≥11.1mmol/L(200mg/dL)；联合高血糖症，偶然血糖水平≥11.1mmol/L(200mg/dL)；糖化血红蛋白(即Hb A1C)水平≥6.5％。
高血糖症的症状能够包含过度口渴、疲劳、尿频、饥饿、体重降低和高甘油三酯血症，但不局限于此。如果某人的血甘油三酯水平超过200mg/dL，则他就患有高甘油三酯血症；认为超过500mg/dL的任何值是极高的水平。正常的甘油三酯水平通常小于150mg/dL。
在本技术领域中需要一种能够用于治疗糖尿病和其相关病症的其它组合物和方法。这是本发明的目的。
附图说明
图1表示左旋谷氨酰胺(1)以及左旋谷氨酰胺盐和衍生物(2)。
发明内容
本发明涉及用于治疗糖尿病和相关病症的方法和组合物。更具体地，本发明涉及包含左旋谷氨酰胺、其盐或其衍生物的组合物，以及该组合物在治疗糖尿病和相关病症中的应用。
在方法方面，本发明提供了一种治疗糖尿病的方法。该方法包括患有糖尿病的人每天摄取0.05g/kg体重至10.0g/kg体重的左旋谷氨酰胺、左旋谷氨酰胺盐或左旋谷氨酰胺衍生物。
在另一方法方面，本发明提供了一种治疗高甘油三酯血症的方法。该方法包括患有高甘油三酯血症的人每天摄取0.05g/kg体重至10.0g/kg体重的左旋谷氨酰胺、左旋谷氨酰胺盐或左旋谷氨酰胺衍生物。
具体实施方式
本发明涉及用于治疗糖尿病和相关病症的方法和组合物。更具体地，本发明涉及包含左旋谷氨酰胺、其盐或其衍生物的组合物，以及该组合物在治疗糖尿病和相关病症中的应用。
图1表示谷左旋氨酰胺的结构，其为化合物1。左旋谷氨酰胺盐及其衍生物作为化合物2表示于图2中。非限制性的左旋谷氨酰胺盐及其衍生物具有以下涉及化合物2的取代基：
R1是NH2；
R2是NH2、NH3 +、NH3Br、NH3OPO3H、NH3OC(O)CH3(即，乙酸盐)、
NH3OC(O)CHCHCO2H(即，富马酸盐-反式烯烃)、
NH3OC(O)CH(OH)CH(OH)CO2H(即，酒石酸盐)、
NH3OC(O)CHCHCO2H(即，马来酸盐-顺式烯烃)、
NH3OC(O)CH2-C(OH)(CO2H)CH2CO2H(即，柠檬酸盐)、
NH3OC(O)CO2H(即，草酸盐)、
NH3OS(O)2OH(即，甲磺酸盐)、
NH3OS(O)2C6H4CH3(即，对甲苯磺酸盐)、和
NH3OC(O)C(O)CH2CH2CO2H(即，α-酮戊二酸盐)。
R3是OH、O-、ONa、OK、OCa、OLi、
ONH2(CH2C6H5)CH2CH2NHCH2C6H6(即，苄星盐)、
ON(CH2CH3)2CH2CH2OC(O)C6H3ClNH2(即，氯普鲁卡因盐)、
ON(CH3)3CH2CH2OH(即，胆碱盐)、
ONH2(CH2CH2OH)2(即，二乙醇胺盐)、
ONH3CH2CH2OH(即，乙醇胺盐)、
ONH3CH2CH2NH2(即，乙二胺盐)、
ONH2(CH3)CH2CH(OH)CH(OH)CH(OH)CH(OH)CH2OH(即，葡甲胺盐)、
ONH3C(CH2OH)3(即，氨丁三醇盐)、
ONH3C(CH3)3(即，叔丁胺盐)、
ON(CH2CH3)2CH2CH2OC(O)C6H4NH2(即，普鲁卡因盐)、
NHCH(CH3)CO2H、NHCH(CH(CH3)2)CO2H、
NHCH(CH(CH3)(CH2CH3))CO2H、NHCH(CH2CH(CH3)2)CO2H、
NHCH(CH2CH2SCH3)CO2H、NHCH(CH2C6H5)CO2H、
NHCH(CH2C6H5OH)CO2H、NHCH(CH2C8H6N)CO2H、NHCH2CO2H、
NHCH(CH2CH2C(O)NH2)CO2H、NHCH(CH2C(O)NH2)CO2H、
NHCH(CH(OH)CH3)CO2H、NHCH(CH2OH)CO2H、
NHCH(CH2CH2CO2H)CO2H,NHCH(CH2CO2H)CO2H。
通常，将单一化合物(即，左旋谷氨酰胺)给药于寻求治疗糖尿病或其病症的人。然而，在某些情况中，可以给药两种或更多种化合物的混合物。例如，可以将左旋谷氨酰胺与一种或多种左旋谷氨酰胺盐或衍生物一起给药。
左旋谷氨酰胺、其盐、其衍生物或混合物可以以任意合适的方式给药。例如，在某些情况中，其以水溶液方式给药。该溶液可以只将左旋谷氨酰胺、其盐或衍生物作为溶解成分，或其可以包含其他药学上可接受的化合物。该化合物的非限制性例子包含缓冲液和香料。
另外，可以给药左旋谷氨酰胺、其盐、衍生物或混合物的方式的非限制性例子包括：作为液体中的悬浮液(例如，水或果汁)；作为固体，或者作为粉末或以其他形式(例如，丸剂或胶囊剂)；作为与食物的混合物(例如，酸奶)。如同以水溶液方式给药，上述施用形式可以包含其他药学上可接受的成分。
根据本发明给药的左旋谷氨酰胺、其盐或衍生物的量通常是在0.05g/kg体重至10.0g/kg体重的范围内。时常地，该量是在0.10g/kg体重至8.0g/kg体重的范围内。在某些情况中，该量是在0.15g/kg体重至7.0g/kg体重的范围内。
通常，左旋谷氨酰胺、其盐或衍生物每天向人给药一次。然而，根据说明该化合物可以每天给药多于一次。
根据本发明的组合物可以用于治疗糖尿病，该糖尿病由测量血糖水平的大量不同测试来确定。在施用左旋谷氨酰胺、其盐或衍生物至少一个月、两个月或三个月后，先前测试的空腹血糖水平为≥7.0mmol/L的人通常降至≤6.9mmol/L。时常地，其降至≤6.8mmol/L或≤6.7mmol/L。
先前测试的血糖水平为≥11.1mmol/L的人在口服75g葡萄糖后两小时的血糖水平通常降至≤11.0mmol/L。时常地，该水平降至≤10.9mmol/L或≤10.8mmol/L。在某些情况中，其降至≤10.7mmol/L。
先前测试的糖化血红蛋白水平为≥6.5％的人的糖化血红蛋白水平通常降至≤6.4％。时常地，该水平降至≤6.3％或≤6.2％。在某些情况中，其降至≤6.1％。
根据本发明的组合物也可以用于治疗某些糖尿病病症，包含高甘油三酯血症。在给药左旋谷氨酰胺、其盐或衍生物至少一个月、两个月或三个月后，先前测试的血液水平超过500mg/dL的人的甘油三酯水平通常降至小于200mg/dL。在某些情况中，甘油三酯血液水平降至小于180mg/dL或160mg/dL。先前测试的血液水平超过200mg/dL的人的甘油三酯水平通常降至小于200mg/dL或小于190mg/dL。时常地，甘油三酯水平降至小于180mg/dL、170mg/dL、160mg/dL或150mg/dL。
当将本发明的组合物用于治疗糖尿病时，该组合物可以结合其他用于治疗糖尿病的方法。例如，该组合物可以与胰岛素增敏剂、促分泌素和/或α-葡糖苷酶抑制剂一起给药。胰岛素增敏剂的非限制性例子包含：双胍类(例如，甲福明二甲双胍(Glucophage))、噻唑烷二酮类(例如，罗格列酮(Avandia)，匹格列酮(Actos))。促分泌素的非限制性例子包含：磺脲类(例如，甲磺丁脲(Orinase)，乙酰苯磺酰环己脲(Dymelor)，甲磺吖庚脲(Tolinase)，氯磺丙脲(Diabinese)，格列吡嗪(Glucotrol)，格列苯脲(Diabeta，Micronase，Glynase)，格列美脲(Amaryl)和格列齐特(Diamicron))；和非磺脲类(例如，瑞格列奈(Prandin)和那格列奈(Starlix))。α-葡糖苷酶抑制剂的非限制性例子包含：米格列醇(Glyset)；和阿卡波糖(Precose/Glucobay)。
当将本发明的组合物用于治疗高甘油三酯血症时，该组合物可以结合其他用于治疗高甘油三酯血症的方法。例如，该组合物可以与他汀类、贝特类、烟酸、鱼油和处方Ω-3酸乙酯一起给药。他汀类的非限制性例子包含：阿托伐他汀(Lipitor)；氟伐他汀(Lescol)；洛伐他汀(Mevacor)；普伐他汀(Pravachol)；罗素伐他汀(Crestor)；和辛伐他汀(Zocor)。贝特类的非限制性例子包含：非诺贝特(Tricor)；和吉非罗齐(Lopid)。处方Ω-3酸乙酯的非限制性例子包含复方Ω-3不饱和脂肪酸(O macor)。
实验结果
HA1C降低
某人具有6.9％测量的糖化血红蛋白水平(即，Hb A1C水平)。该人以水溶液的方式每天摄取30g的左旋谷氨酰胺。在给药三个月的左旋谷氨酰胺后，测量该人的Hb A1C水平为6.1％。
甘油三酯降低
某人具有500mg/dL测量的甘油三酯血液水平。该人以水溶液的方式每天摄取30g的左旋谷氨酰胺。在给药三个月的左旋谷氨酰胺后，测量该人的甘油三酯血液水平为150mg/dL。
Claims (12)
1.一种治疗糖尿病的方法，其中，所述方法包括患有糖尿病的人每天摄取0.05g/kg体重至10.0g/kg体重的左旋谷氨酰胺、左旋谷氨酰胺盐或左旋谷氨酰胺衍生物。
2.如权利要求1所述的方法，其中，所摄取的化合物是左旋谷氨酰胺。
3.如权利要求2所述的方法，其中，所述左旋谷氨酰胺作为水溶液的一部分被摄取。
4.如权利要求3所述的方法，其中，所述左旋谷氨酰胺被摄取至少一个月。
5.如权利要求4所述的方法，其中，在开始所述方法之前，所述患有糖尿病的人具有≥6.5％测量的Hb A1C水平，并且在摄取左旋谷氨酰胺至少一个月后，具有≤6.4％测量的Hb A1C水平。
6.如权利要求5所述的方法，其中，在摄取左旋谷氨酰胺至少一个月后，所述测量的Hb A1C水平为≤6.3％。
7.一种治疗高甘油三酯血症的方法，其中，所述方法包括患有糖尿病的人每天摄取0.05g/kg体重至10.0g/kg体重的左旋谷氨酰胺、左旋谷氨酰胺盐或左旋谷氨酰胺衍生物。
8.如权利要求11所述的方法，其中，所摄取的化合物是左旋谷氨酰胺。
9.如权利要求12所述的方法，其中，所述左旋谷氨酰胺作为水溶液的一部分被摄取。
10.如权利要求13所述的方法，其中，所述谷氨酰胺被摄取至少一个月。
11.如权利要求14所述的方法，其中，在开始所述方法之前，患有高甘油三酯血症的人具有≥200mg/dL测量的血甘油三酯水平，并且在摄取左旋谷氨酰胺至少一个月后，所述测量的血甘油三酯水平为≤190mg/dL。
12.如权利要求15所述的方法，其中，在摄取左旋谷氨酰胺至少一个月后，所述测量的甘油三酯血液水平为≤6.3％170mg/dL。
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| CN201810135122.XA CN108478551A (zh) | 2011-11-21 | 2012-11-17 | 用于治疗糖尿病和相关病症的方法和组合物 |
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| CN201810134012.1A Division CN108354916A (zh) | 2011-11-21 | 2012-11-17 | 用于治疗糖尿病和相关病症的方法和组合物 |
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| CN1649617A (zh) * | 2002-03-01 | 2005-08-03 | 日清药业股份有限公司 | 肝病、高血脂症和糖尿病治疗剂 |
| WO2010107307A1 (en) * | 2009-03-20 | 2010-09-23 | Glnp (Generic Life Quality Enhancing Niche Products) Holding B.V. | Kit of parts comprising l-glutamine and egcg |
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| US6031000A (en) * | 1998-06-23 | 2000-02-29 | Iowa State University Research Foundation, Inc. | Composition comprising β-hydroxy-β-methylbutyric acid and at least one amino acid and methods of use |
| AU2002321135B2 (en) * | 2001-06-27 | 2007-11-08 | Probiodrug Ag | Dipepitdyl peptidase IV inhibitors and their uses as anti-cancer agents |
| SE0201713D0 (sv) * | 2001-11-23 | 2002-06-06 | Gramineer Internat Ab | New methods and use III |
| US20070025953A1 (en) * | 2005-07-27 | 2007-02-01 | Jones Michael R | Co-therapy for diabetic conditions |
| CN101472579B (zh) * | 2006-04-22 | 2013-07-03 | 霍利斯-伊登医药公司 | 药物和用途 |
| WO2008038771A1 (fr) * | 2006-09-29 | 2008-04-03 | Ajinomoto Co., Inc. | Composition contenant de la glutamine destinée à augmenter le flux sanguin |
| US20080221074A1 (en) * | 2006-11-17 | 2008-09-11 | Jaime Flores-Riveros | Drug Screen and Treatment Method |
| EP2057905A1 (en) * | 2007-11-12 | 2009-05-13 | TIMA Foundation | Composition for moderating Triglyceride and Cholesterol Levels |
| HUE034551T2 (en) * | 2009-01-12 | 2018-02-28 | Biokier Inc | Preparation and method of treating diabetes |
| US9301938B2 (en) | 2009-09-23 | 2016-04-05 | Biokier, Inc. | Composition and method for treatment of diabetes |
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2012
- 2012-11-17 CN CN201280056939.9A patent/CN103945858A/zh active Pending
- 2012-11-17 US US13/694,301 patent/US20130143968A1/en not_active Abandoned
- 2012-11-17 WO PCT/US2012/000557 patent/WO2013077893A1/en active Application Filing
- 2012-11-17 JP JP2014542296A patent/JP6089042B2/ja active Active
- 2012-11-17 EP EP18196395.0A patent/EP3437649A1/en active Pending
- 2012-11-17 BR BR112014011898A patent/BR112014011898A2/pt not_active Application Discontinuation
- 2012-11-17 CN CN201810135122.XA patent/CN108478551A/zh active Pending
- 2012-11-17 CN CN201810134012.1A patent/CN108354916A/zh active Pending
- 2012-11-17 EP EP12850971.8A patent/EP2782588B1/en not_active Revoked
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2014
- 2014-05-15 IN IN1037/KOLNP/2014A patent/IN2014KN01037A/en unknown
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2016
- 2016-10-24 JP JP2016207931A patent/JP6389495B2/ja active Active
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2018
- 2018-03-08 JP JP2018041934A patent/JP6550160B2/ja active Active
- 2018-08-17 JP JP2018153440A patent/JP2018199692A/ja active Pending
- 2018-12-26 HK HK18116609.9A patent/HK1257401A1/zh unknown
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2019
- 2019-01-15 US US16/350,812 patent/US20190192463A1/en not_active Abandoned
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Patent Citations (2)
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| CN1649617A (zh) * | 2002-03-01 | 2005-08-03 | 日清药业股份有限公司 | 肝病、高血脂症和糖尿病治疗剂 |
| WO2010107307A1 (en) * | 2009-03-20 | 2010-09-23 | Glnp (Generic Life Quality Enhancing Niche Products) Holding B.V. | Kit of parts comprising l-glutamine and egcg |
Non-Patent Citations (4)
| Title |
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| DORIT SAMOCHA-BONET等: "Glutamine Reduces Postprandial Glycemia and Augments the Glucagon-Like Peptide-1 Response in Type 2 Diabetes Patients", 《THE JOURNAL OF NUTRITION》, 18 May 2011 (2011-05-18) * |
| EMMANUEL C. OPARA等: "L-Glutamine Supplementation of a High Fat Diet Reduces Body Weight and Attenuates Hyperglycemia and Hyperinsulinemia in C57BL/6J Mice", 《NUTRIENT METABOLISM》, 31 December 1996 (1996-12-31) * |
| JERRY R GREENFIELD等: "Oral glutamine increases circulating glucagon-like peptide 1,glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects", 《AM J CLIN NUTR》, vol. 89, 3 December 2008 (2008-12-03), pages 106 - 113, XP002679635, DOI: 10.3945/ajcn.2008.26362 * |
| 吴亚谋等: "谷氨酰胺对2型糖尿病大鼠血糖和胰岛素抵抗的影响", 《国际麻醉学与复苏杂志》, vol. 32, no. 5, 31 October 2011 (2011-10-31) * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6550160B2 (ja) | 2019-07-24 |
| JP2018199692A (ja) | 2018-12-20 |
| EP2782588A1 (en) | 2014-10-01 |
| HK1257401A1 (zh) | 2019-10-18 |
| EP3437649A1 (en) | 2019-02-06 |
| CN108354916A (zh) | 2018-08-03 |
| JP6089042B2 (ja) | 2017-03-01 |
| JP2018115175A (ja) | 2018-07-26 |
| EP2782588B1 (en) | 2020-04-15 |
| JP6389495B2 (ja) | 2018-09-12 |
| EP2782588A4 (en) | 2015-05-20 |
| JP2017052766A (ja) | 2017-03-16 |
| BR112014011898A2 (pt) | 2017-05-16 |
| WO2013077893A1 (en) | 2013-05-30 |
| JP2014533689A (ja) | 2014-12-15 |
| CN108478551A (zh) | 2018-09-04 |
| US20130143968A1 (en) | 2013-06-06 |
| PH12020550726A1 (en) | 2021-06-14 |
| IN2014KN01037A (en) | 2015-10-09 |
| US20190192463A1 (en) | 2019-06-27 |
| ES2785094T3 (es) | 2020-10-05 |
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Application publication date: 20140723 |