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首页> 外文期刊>CNS drug reviews >KTX 0101: A Potential Metabolic Approach to Cytoprotection in Major Surgery and Neurological Disorders.
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KTX 0101: A Potential Metabolic Approach to Cytoprotection in Major Surgery and Neurological Disorders.

机译：KTX 0101：大手术和神经系统疾病中细胞保护的潜在代谢方法。

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KTX 0101 is the sodium salt of the physiological ketone, D-beta-hydroxybutyrate (betaOHB). This neuroprotectant, which has recently successfully completed clinical Phase IA evaluation, is being developed as an intravenous infusion fluid to prevent the cognitive deficits caused by ischemic foci in the brain during cardiopulmonary bypass (CPB) surgery. KTX 0101 maintains cellular viability under conditions of physiological stress by acting as a "superfuel" for efficient ATP production in the brain and peripheral tissues. Unlike glucose, this ketone does not require phosphorylation before entering the TCA cycle, thereby sparing vital ATP stores. Although no reliable models of CPB-induced ischemia exist, KTX 0101 is powerfully cytoprotectant under the more severe ischemic conditions of global and focal cerebral ischemia, cardiac ischemia and lung hemorrhage. Neuroprotection has been demonstrated by reductions in infarct volume, edema, markers of apoptosis and functional impairment. One significant difference between KTX 0101 and other potential neuroprotectants in development is that betaOHB is a component of human metabolic physiology which exploits the body's own neuroprotective mechanisms. KTX 0101 also protects hippocampal organotypic cultures against early and delayed cell death in an in vitro model of status epilepticus, indicating that acute KTX 0101 intervention in this condition could help prevent the development of epileptiform foci, a key mechanism in the etiology of intractable epilepsy. In models of chronic neurodegenerative disorders, KTX 0101 protects neurons against damage caused by dopaminergic neurotoxins and by the fragment of beta-amyloid, Abeta(1-42), implying possible therapeutic applications for ketogenic strategies in treating Parkinson's and Alzheimer's diseases. Major obstacles to the use of KTX 0101 for long term therapy in chronic disorders, e.g., Parkinson's and Alzheimer's diseases, are the sodium loading problem and the need to administer it in relatively large amounts because of its rapid mitochondrial metabolism. These issues are being addressed by designing and synthesizing orally bioavailable multimers of betaOHB with improved pharmacokinetics.
机译：KTX 0101是生理酮D-β-羟基丁酸酯（betaOHB）的钠盐。这种神经保护剂最近已成功完成了IA期临床评估，目前正在开发为静脉输注液，以防止在心肺分流（CPB）手术期间由大脑局部缺血灶引起的认知缺陷。 KTX 0101充当“超级燃料”，在大脑和周围组织中高效产生ATP，从而在生理应激条件下维持细胞活力。与葡萄糖不同，这种酮在进入TCA循环之前不需要磷酸化，因此可以节省重要的ATP储备。尽管尚无可靠的CPB诱导的缺血模型，但KTX 0101在全脑和局灶性脑缺血，心脏缺血和肺出血等更严重的缺血条件下具有强大的细胞保护作用。通过减少梗塞体积，水肿，凋亡标志物和功能障碍，证明了神经保护作用。 KTX 0101与正在开发的其他潜在神经保护剂之间的一个重要区别是，βOHB是人类新陈代谢生理学的组成部分，它利用了人体自身的神经保护机制。在癫痫持续状态的体外模型中，KTX 0101还可以保护海马器官型培养物免受早期和延迟的细胞死亡，这表明在这种情况下进行急性KTX 0101干预可以帮助预防癫痫样病灶的发展，这是顽固性癫痫病因的关键机制。在慢性神经退行性疾病模型中，KTX 0101保护神经元免受多巴胺能神经毒素和β-淀粉样蛋白Abeta（1-42）片段造成的损害，这暗示了生酮策略在治疗帕金森氏和阿尔茨海默氏病中的可能治疗应用。在慢性疾病例如帕金森氏症和阿尔茨海默氏病中，长期使用KTX 0101的主要障碍是钠负荷问题，由于其线粒体代谢迅速，因此需要大量施用。这些问题正在通过设计和合成具有改善的药代动力学的口服生物利用度的βOHB多聚体来解决。

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