Objective L-arginine may enhance radiotherapy efficacy through nitric oxide (NO) -mediated glycolysis inhibition; however, its real-time metabolic effects in brain metastases remain undefined. This proof-of-concept study aimed to characterize, for the first time in vivo, the rapid pharmacodynamic profile of intravenous L-arginine on lactate metabolism in brain metastases and generate hypotheses for future trials. Methods Twenty patients with solid tumor brain metastases were randomized 1: 1: 1: 1 to receive normal saline or 10 g, 20 g, or 30 g intravenous L-arginine. Serial magnetic resonance spectroscopy (MRS) was performed at baseline and multiple post-infusion timepoints (approximately 19–36 minutes) to quantify lactate dynamics. The primary endpoint was lactate reduction at T3 (approximately 30 minutes). Results All patients completed the study. The pooled L-arginine group showed significantly greater lactate reduction at T3 compared with controls (median ΔLacT3: −1. 09 vs. 0. 00, p = 0. 0012). Lactate reduction was most prominent and consistent in the 30 g group, with a peak reduction of 63. 5% at 30 minutes (ρ = −0. 753, p 0. 001). No treatment-related adverse events were observed up to 24 hours post-infusion. Conclusion This proof-of-concept study demonstrates that intravenous L-arginine rapidly and safely suppresses lactate metabolism in brain metastases, with a peak effect at approximately 30 minutes. The 30 g dose yielded the most robust metabolic suppression within the 10–30 g range. The “30 g L-arginine followed by radiotherapy within 30 minutes” regimen is proposed as a priority candidate for validation in future phase II trials. Clinical benefits require further confirmation in larger randomized controlled trials. Clinical Trial Registration https: //www. chictr. org. cn/, identifier ChiCTR2400080841.
Liu et al. (Thu,) studied this question.