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

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.

Fig. 1

Therapeutic regimen using oral and intravenous l-arginine for patients with MELAS. a Diagram showing the bidirectionality of the therapeutic regimen using oral and intravenous l-arginine for patients with interictal or acute MELAS. b Diagram showing the scheme of pharmacotherapy with intravenous l-arginine for patients with acute MELAS. tid, ter in die; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

Fig. 2

Kaplan–Meyer curve indicating the 9-year survival of patients who were treated with oral and intravenous l-arginine

Fig. 3

Relationships between plasma arginine concentrations and the ictuses of stroke-like episodes assessed by MRI. The red broken line indicates the maximal plasma arginine concentration (167 µmol/L) at which an ictus of stroke-like episodes developed. The black solid line indicates the plasma arginine concentration that is required for the normalization of endothelial function. MRI magnetic resonance imaging