A pharmacodynamic study of rapid lactate metabolic modulation by intravenous L-arginine in brain metastases

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.

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).

All patients completed the study. The pooled L-arginine group showed significantly greater lactate reduction at T3 compared with controls (median ΔLac_T3: -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.

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.

https://www.chictr.org.cn/, identifier ChiCTR2400080841.