米屈肼

米屈肼
临床资料
其他名称	Mildronate；THP，MET-8 Mildronāts，或 Quaterine
识别信息
	IUPAC命名法 2-(2-Carboxylato-ethyl)-1,1,1-trimethylhydrazinium; ;
CAS号	86426-17-7
PubChem CID	123868;
ChemSpider	110405 ;
UNII	73H7UDN6EC;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID10997497 ;
ECHA InfoCard	100.110.108
化学信息
化学式	C6H15N2O2+
摩尔质量	147.19 g/mol
3D模型（JSmol（英语：JSmol））	交互式图像;
水溶性	>40 mg/mL mg/mL (20 °C)
	SMILES C[N+](C)(C)NCCC(=O)[O-];
	InChI InChI=1S/C6H14N2O2/c1-8(2,3)7-5-4-6(9)10/h7H,4-5H2,1-3H3; Key:PVBQYTCFVWZSJK-UHFFFAOYSA-N;

米屈肼（Meldonium，亦有译作米曲肼，商品名为Mildronate，又名MET-88、Mildronāts、Quaterine^[1]）或按其化学名称缩写作THP^[2]，一种受管制药物，目前主要由位于拉脱维亚的Grindeks（英语：Grindeks）公司及另外数家替代药物生产商所生产。现时这种药物在东欧国家用作抗缺血药物^[3]。

Quick Facts 临床资料, 其他名称 ...

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从2016年1月1日起，本药被世界反运动禁药机构（WADA）列为运动比赛的禁药^[4]^[5]，因为米屈肼被认为是左旋肉碱的先导物质，具有提升服用者的体能耐久度的效果^[6]。然而，目前已知有运动员在此药被列为禁药之前就已在使用^[7]。

医疗用途

米屈肼在临床上用于治疗心绞痛（angina）和心肌梗塞（英语：myocardial infarction）^[8]^[9]^[10]等冠状动脉疾病(英语：Coronary artery disease, CAD)。米屈肼的功效的首次临床试验在2005年进行，当时米屈肼与赖诺普利（lisinopril，一种血管仅肽I转化酶抑制剂）一起使用，以治疗慢性心脏衰竭。这次测试的结论是米屈肼与赖诺普利一并使用可改善生活质素、运动耐力^[11]，及慢性心脏衰竭患者的末梢循环机制。^[12]2008年的进一步研究报告认为，米曲肼和赖诺普利的并用可以改善慢性心脏衰竭患者的颈动脉压力感受器反射(Baroreceptor)机制。^[13]2010年2月，一次进一步的临床试验、测试心绞痛患者对于米曲肼与标准运动耐受疗法(Exercise intolerance)的并合疗法下之效能及安全性(Pharmacovigilance)，结果认为候选药物可以显著地改善稳定型心绞痛患者的运动耐受力(Exercise intolerance)。^[14]^[15]^[16]

中国陕西西安第四军医大学的研究小组于2013年8月完成II期的临床试验，有227位患者参与。这次试验是有关于米屈肼对于急性缺血性中风的疗效、及药物警戒性(Pharmacovigilance)方面的运作机能。得出的结论认为米屈肼作为桂哌齐特（英语：Cinepazide）(Cinepazide)的注射剂是有效的及安全的。^[17]^[18]

使用许可

截至2016年3月，尽管本药已在东欧广泛使用，但在美国尚未被美国食品药药品监督管理局(FDA)许可^[19]。

上市剂型

米屈肼的服用剂型、以250毫克及500毫克的胶囊剂包装；注射剂型、则为含有10％剂量溶液的注射剂^[20]。

物理和化学性质

米屈肼的化学名称为“3-(2,2,2-trimethylhydraziniumyl)propionate”，即“3-(2,2,2-三甲基肼基)丙酸酯”^[2]^[21]。其化学结构类似于γ-丁基甜菜碱（英语：Gamma-butyrobetaine）化合物，所分别的只是在γ-丁基甜菜碱的第四个碳亚甲基以氨基来替换。 γ-丁基甜菜碱是肉碱合成的前驱^[22]。

于1970年代中期由当时为前苏联占领的拉脱维亚的拉脱维亚苏维埃社会主义共和国科学院（即今日拉脱维亚有机合成研究所的前身）科学家Ivars Kalviņš（英语：Ivars Kalviņš）于1970年研制。

参考资料

[1]
Patent Number: 1429753.. [2012-08-16]. （原始内容存档于2013-11-05）（英语）.
[2]
Pubchem. Mildronate. nih.gov. [2016-03-09]. （原始内容存档于2020-08-11）（英语）.
[3]
Grindeks: We Believe that Meldonium Should not be Included in the List of Banned Substances in Sport. Grindeks. 2016-03-09 [2016-03-09]. （原始内容存档于2016-03-12）（英语）.
[4]
Prohibited List. World Anti-Doping Agency. [2016-03-09]. （原始内容存档于2017-07-12）（英语）.
[5]
莎拉波娃宣佈未通過興奮劑檢測. 文汇报. 2016-03-08 [2016-03-08]. （原始内容存档于2016-03-12）（中文）.
[6]
科普莎娃藥物：今年一月進入禁藥名單能提升耐久性. 2016-03-08 [2016-03-08]. （原始内容存档于2016年3月8日）（中文（繁体））.
[7]
All About Meldonium, the Banned Drug Used by Sharapova. New York Times. Associated Press. 2016-03-08 [2016-03-08]. （原始内容存档于2020-05-23）（英语）.
[8]
Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. Journal of Cardiovascular Pharmacology. March 2006, 47 (3): 493–9. PMID 16633095. doi:10.1097/01.fjc.0000211732.76668.d2.
[9]
Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. Journal of Cardiovascular Pharmacology. December 2006, 48 (6): 314–9. PMID 17204911. doi:10.1097/01.fjc.0000250077.07702.23.
[10]
Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N. Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. European Journal of Pharmacology. May 2000, 395 (3): 217–24. PMID 10812052. doi:10.1016/S0014-2999(00)00098-4.
[11]
方进隆. 心肺耐力和有氧運動訓練: 7. （原始内容存档于2013-01-29）（中文（繁体））.
[12]
Dzerve V, Matisone D, Kukulis I, Romanova J, Putane L, Grabauskiene˙V, Skarda I, Berzina D, Strautmanis J. Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the ﬁrst report) (PDF). Seminars in Cardiology. 2005, 11 (2): 56–64. ISSN 1648-7966. （原始内容 (PDF)存档于2012-03-28）.
[13]
Vitols A, Voita D, Dzerve V. Mildronate improves carotid baroreceptor reﬂex function in patients with chronic heart failure (PDF). Seminars in Cardiovascular Medicine. 2008, 13: 6. （原始内容 (PDF)存档于2013-09-21）.
[14]
Dzerve V, Matisone D, Pozdnyakov Y, Oganov R. Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial (PDF). Seminars in Cardiovascular Medicine. 2010, 16: 3. （原始内容 (PDF)存档于2013-09-21）.
[15]
Stock news / For investors / Leading pharmaceutical company in the Baltic - «Grindeks» JSC. grindeks.lv. [9 March 2016]. （原始内容存档于2016年3月8日）.
[16]
Dzerve V, MILSS I Study Group. A Dose-Dependent Improvement in Exercise Tolerance in Patients With Stable Angina Treated With Mildronate: A Clinical Trial "MILSS I" (PDF). Medicina (Kaunas). 2011, 47 (10): 544–51. PMID 22186118. （原始内容 (PDF)存档于2013年9月21日）.
[17]
Zhu Y, Zhang G, Zhao J, Li D, Yan X, Liu J, Liu X, Zhao H, Xia J, Zhang X, Li Z, Zhang B, Guo Z, Feng L, Zhang Z, Qu F, Zhao, G. Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial. Clinical Drug Investigation. 2013. doi:10.1007/s40261-013-0121-x.
[18]
Mildronate for Acute Ischemic Stroke. clinicaltrials.gov. [9 March 2016]. （原始内容存档于2018-02-25）.
[19]
Görgens Christian, Guddat Sven, Dib Josef, Geyer Hans, Schänzer Wilhelm, Thevis Mario. Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry.. Drug Testing and Analysis. November–December 2015, 7: 973–979 [2016-03-08]. doi:10.1002/dta.1788. （原始内容存档于2018-02-26）.
[20]
Mildronate. Grindeks.lv. [2016-03-09]. （原始内容存档于2016-03-12）.
[21]
Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochemical Pharmacology. January 1988, 37 (2): 195–202. PMID 3342076. doi:10.1016/0006-2952(88)90717-4.
[22]
Fraenkel G, Friedman S. Carnitine. Vitamins Hormones. 1957, 15: 73–118. PMID 13530702. doi:10.1016/s0083-6729(08)60508-7.

延伸阅读

Rose, N.R.; McDonough, M.A.; King, O.N.; Kawamura, A. & Schofield, C.J. Inhibition of 2-Oxoglutarate Dependent Oxygenases (print, online review). Chemical Society Reviews. 2011, 40 (8; August): 4364–4397 [9 March 2011]. PMID 21390379. doi:10.1039/c0cs00203h. （原始内容存档于2020-08-04）.
Kalvinsh; Ivars (Ikshkile, LV), Birmans; Anatolijs: Meldonium salts, method of their preparation and pharmaceutical composition on their basis （页面存档备份，存于互联网档案馆）

[1] [1]
Patent Number: 1429753.. [2012-08-16]. （原始内容存档于2013-11-05）（英语）.

[PubChem-2] [2]
Pubchem. Mildronate. nih.gov. [2016-03-09]. （原始内容存档于2020-08-11）（英语）.

[3] [3]
Grindeks: We Believe that Meldonium Should not be Included in the List of Banned Substances in Sport. Grindeks. 2016-03-09 [2016-03-09]. （原始内容存档于2016-03-12）（英语）.

[2016list-4] [4]
Prohibited List. World Anti-Doping Agency. [2016-03-09]. （原始内容存档于2017-07-12）（英语）.

[5] [5]
莎拉波娃宣佈未通過興奮劑檢測. 文汇报. 2016-03-08 [2016-03-08]. （原始内容存档于2016-03-12）（中文）.

[6] [6]
科普莎娃藥物：今年一月進入禁藥名單能提升耐久性. 2016-03-08 [2016-03-08]. （原始内容存档于2016年3月8日）（中文（繁体））.

[7] [7]
All About Meldonium, the Banned Drug Used by Sharapova. New York Times. Associated Press. 2016-03-08 [2016-03-08]. （原始内容存档于2020-05-23）（英语）.

[pmid16633095-8] [8]
Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. Journal of Cardiovascular Pharmacology. March 2006, 47 (3): 493–9. PMID 16633095. doi:10.1097/01.fjc.0000211732.76668.d2.

[pmid17204911-9] [9]
Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. Journal of Cardiovascular Pharmacology. December 2006, 48 (6): 314–9. PMID 17204911. doi:10.1097/01.fjc.0000250077.07702.23.

[pmid10812052-10] [10]
Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N. Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. European Journal of Pharmacology. May 2000, 395 (3): 217–24. PMID 10812052. doi:10.1016/S0014-2999(00)00098-4.

[11] [11]
方进隆. 心肺耐力和有氧運動訓練: 7. （原始内容存档于2013-01-29）（中文（繁体））.

[trial2005-12] [12]
Dzerve V, Matisone D, Kukulis I, Romanova J, Putane L, Grabauskiene˙V, Skarda I, Berzina D, Strautmanis J. Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the ﬁrst report) (PDF). Seminars in Cardiology. 2005, 11 (2): 56–64. ISSN 1648-7966. （原始内容 (PDF)存档于2012-03-28）.

[trial2008-13] [13]
Vitols A, Voita D, Dzerve V. Mildronate improves carotid baroreceptor reﬂex function in patients with chronic heart failure (PDF). Seminars in Cardiovascular Medicine. 2008, 13: 6. （原始内容 (PDF)存档于2013-09-21）.

[trial1b-14] [14]
Dzerve V, Matisone D, Pozdnyakov Y, Oganov R. Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial (PDF). Seminars in Cardiovascular Medicine. 2010, 16: 3. （原始内容 (PDF)存档于2013-09-21）.

[trial1a-15] [15]
Stock news / For investors / Leading pharmaceutical company in the Baltic - «Grindeks» JSC. grindeks.lv. [9 March 2016]. （原始内容存档于2016年3月8日）.

[pmid22186118-16] [16]
Dzerve V, MILSS I Study Group. A Dose-Dependent Improvement in Exercise Tolerance in Patients With Stable Angina Treated With Mildronate: A Clinical Trial "MILSS I" (PDF). Medicina (Kaunas). 2011, 47 (10): 544–51. PMID 22186118. （原始内容 (PDF)存档于2013年9月21日）.

[trial2a-17] [17]
Zhu Y, Zhang G, Zhao J, Li D, Yan X, Liu J, Liu X, Zhao H, Xia J, Zhang X, Li Z, Zhang B, Guo Z, Feng L, Zhang Z, Qu F, Zhao, G. Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial. Clinical Drug Investigation. 2013. doi:10.1007/s40261-013-0121-x.

[trial2b-18] [18]
Mildronate for Acute Ischemic Stroke. clinicaltrials.gov. [9 March 2016]. （原始内容存档于2018-02-25）.

[19] [19]
Görgens Christian, Guddat Sven, Dib Josef, Geyer Hans, Schänzer Wilhelm, Thevis Mario. Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry.. Drug Testing and Analysis. November–December 2015, 7: 973–979 [2016-03-08]. doi:10.1002/dta.1788. （原始内容存档于2018-02-26）.

[20] [20]
Mildronate. Grindeks.lv. [2016-03-09]. （原始内容存档于2016-03-12）.

[21] [21]
Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochemical Pharmacology. January 1988, 37 (2): 195–202. PMID 3342076. doi:10.1016/0006-2952(88)90717-4.

[22] [22]
Fraenkel G, Friedman S. Carnitine. Vitamins Hormones. 1957, 15: 73–118. PMID 13530702. doi:10.1016/s0083-6729(08)60508-7.

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