Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research

J Neurol. 2018 Dec;265(12):2861-2874. doi: 10.1007/s00415-018-9057-7. Epub 2018 Sep 29.

Abstract

Objective: To examine the efficacy and safety of the therapeutic regimen using oral and intravenous L-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

Methods: In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous L-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral L-arginine was the MELAS scale, while that for intravenous L-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.

Results: Oral L-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous L-arginine improved the rates of four major symptoms-headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of L-arginine were well tolerated.

Conclusions: The systematic administration of oral and intravenous L-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.

Keywords: Ictus; L-Arginine; MELAS; Mitochondrial disease; Stroke-like episodes.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adolescent
  • Adult
  • Arginine / administration & dosage*
  • Arginine / adverse effects
  • Arginine / blood
  • Central Nervous System Agents / administration & dosage*
  • Central Nervous System Agents / adverse effects
  • Central Nervous System Agents / blood
  • Female
  • Follow-Up Studies
  • Humans
  • MELAS Syndrome / blood
  • MELAS Syndrome / drug therapy*
  • Male
  • Prospective Studies
  • Treatment Outcome
  • Young Adult

Substances

  • Central Nervous System Agents
  • Arginine