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

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.