Sjakste Nikolajs, Gutcaits Aleksandrs, Kalvinsh Ivars
Faculty of Medicine, University of Latvia, Riga.
CNS Drug Rev. 2005 Summer;11(2):151-68. doi: 10.1111/j.1527-3458.2005.tb00267.x.
Mildronate (3-(2,2,2-trimethylhydrazinium)propionate; MET-88; meldonium, quaterine) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. Mildronate was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Mildronate is efficient in the treatment of heart ischemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non-carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the gamma-butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the gamma-butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via acetylcholine receptors or specific gamma-butyrobetaine ester receptors. This article summarizes known pharmacological effects of mildronate, its pharmacokinetics, toxicology, as well as the proposed mechanisms of action.
米屈肼（3-(2,2,2-三甲基肼基)丙酸酯；MET-88；米多君、四甲铵）是拉脱维亚有机合成研究所研发的一种抗缺血药物。米屈肼旨在抑制肉碱的生物合成，以防止缺血组织中脂肪酸β氧化的细胞毒性中间产物积累，并阻断这一高耗氧过程。米屈肼在治疗心脏缺血及其后果方面疗效显著。对米屈肼药理活性的广泛评估显示，它对脑循环障碍和中枢神经系统（CNS）功能具有有益作用。该药物在神经科诊所用于治疗脑循环障碍。它似乎能改善患者情绪；患者变得更加活跃，运动功能障碍减轻，乏力、头晕和恶心症状也不那么明显。由于大脑不以脂肪酸作为燃料，因此应考虑米屈肼在中枢神经系统中的其他作用机制。一些报告表明，米屈肼可能存在一种替代的、不依赖肉碱的作用机制。我们最近的研究结果表明，米屈肼对中枢神经系统的作用可能是通过修饰γ-丁酰甜菜碱及其酯类库，刺激血管内皮细胞产生一氧化氮来介导的。据推测，米屈肼可能会增加γ-丁酰甜菜碱酯的形成。后者是强效拟胆碱药，可能通过乙酰胆碱受体或特定的γ-丁酰甜菜碱酯受体激活内皮型一氧化氮合酶（eNOS）。本文总结了米屈肼已知的药理作用、药代动力学、毒理学以及提出的作用机制。
