Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Paediatr Drugs. 2020 Jun;22(3):279-293. doi: 10.1007/s40272-020-00384-5.
Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.
补充精氨酸已被证明是一种安全的治疗选择，可以改善与内皮功能障碍相关的心血管疾病中内源性一氧化氮（NO）的调节。在成人的临床研究中，内源性氨基酸 L-精氨酸被报道可改善高血压、肺动脉高压、子痫前期、心绞痛和 MELAS（线粒体脑肌病、乳酸酸中毒和卒中样发作）综合征中的心血管功能。L-瓜氨酸是 L-精氨酸的天然前体，比 L-精氨酸更具生物利用度，因为它避免了肝脏首过代谢，并且循环时间更长。尽管尚未得到充分研究，但精氨酸/瓜氨酸在儿童的一些危及生命的疾病中具有巨大的治疗潜力。然而，要在儿童中优化精氨酸或瓜氨酸的临床开发，需要更多关于在适当年龄和相关疾病状态下的药代动力学和暴露-反应关系的信息。本文总结了精氨酸/瓜氨酸在成人和儿童中的临床前和临床研究，包括目前可用的药代动力学信息。精氨酸/瓜氨酸的药理学受到几个患者特定因素的影响，例如由于发育年龄和疾病状态导致的基础精氨酸/瓜氨酸的变化。目前可用的药代动力学研究不足以为临床研究的最佳设计提供信息，尤其是在儿童中。精氨酸补充的成功从实验室到病床的临床转化还需要来自精心设计的药代动力学/药效学研究以及药代动力学方法的信息。
