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首页> 外文期刊>CNS drug reviews >Lacosamide: a review of preclinical properties.
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Lacosamide: a review of preclinical properties.

机译：Lacosamide：临床前特性综述。

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摘要

Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for otherindications have been initiated.
机译：Lacosamide（LCM），（SPM 927，（R）-2-乙酰氨基-N-苄基-3-甲氧基丙酰胺，以前称为harkoseride或ADD 234037）是一系列功能化氨基酸的成员，这些氨基酸被专门合成为抗惊厥药候选药物。 LCM在不同的啮齿动物癫痫发作模型中显示出抗癫痫功效，在实验动物模型中显示出不同的神经病性和慢性炎症性疼痛类型和症状，具有抗伤害感受性。最近的结果表明，LCM具有双重作用模式，是其抗惊厥和止痛活性的基础。已经发现，LCM选择性地增强了电压门控钠通道的缓慢灭活而不影响快速灭活。此外，采用蛋白质组亲和标记技术，将胶原蛋白反应介导蛋白2（CRMP-2别名DRP-2）鉴定为结合伴侣。后续实验证实了LCM与CRMP-2的体外功能相互作用。 LCM在治疗浓度下不抑制或诱导多种细胞色素P450酶。在对小鼠，大鼠，兔子和狗进行的安全药理学和毒理学研究中，LCM的耐受性良好。在涉及中枢神经，呼吸系统，胃肠道和肾系统的安全性研究中，没有观察到或只有轻微的副作用，并且没有滥用责任的迹象。重复的剂量毒性研究表明，静脉内或口服LCM后，不良事件是可逆的，并且主要包括对CNS的夸大药效作用。在体内未观察到遗传毒性或致癌作用，LCM在生殖和发育动物研究中显示出良好的特征。目前，LCM处于临床发展的后期，是对部分发作性癫痫发作无法控制的患者的辅助治疗，目前正被评估为患有糖尿病性神经病的单药治疗。已经启动了进一步的试验来确定LCM在疼痛和其他适应症方面的潜力。

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