MET‐88: SR Ca²⁺‐Uptake Stimulator for Treating Chronic Heart Failure

Meldonium: Pharmacological, toxicological, and analytical aspects

“…Thus, the non-lethal dose in female rats may be four times lower compared to male rats, a result that suggests females may have greater susceptibility to toxicity. 44 A hypothesis for this particular behavior may be the excretion rate. Forsdahl et al 22 demonstrated differences between women and men volunteers, although it is not the purpose of the study.…”

“…41,42 Two weeks of meldonium treatment reduced L-carnitine by 60% in rat heart (100 mg/kg orally daily). 44 However, humans treated with the therapeutic dose for 4 weeks exhibited only an 18% decrease in plasma L-carnitine. 50 Another study conducted by Liepinsh et al 40 administered 200 mg/kg meldonium intraperitoneally in mice once a day for 20 days.…”

“…23,29,41,43 Peroxisome-mediated fatty acid metabolism increases the AMP/ATP ratio, which activates AMPK, an enzyme responsible for restoring ATP levels, and increases cellular glucose oxidation. 44 In the blood-brain barrier, OCTN2 is apparently the main mechanism that allows meldonium entry into the central nervous system (CNS). 29,45 Meldonium in the brain improves hemodynamics, electrolyte balance, and oxygenation in cerebrovascular disorders.…”

“…A chronic toxicity study in Beagles performed over 52 weeks (daily oral dose of 400 mg/kg) indicated that the nontoxic dose is 25 mg/kg/day. 44 For acute toxicity, Kirimoto et al 44 reported an approximate lethal single meldonium dose of over 5000 mg/kg for rats and male dogs; both species presented similar behavior, and there were no sex-related differences. However, the number of animals and administration route were not described in this communication.…”

“…However, the number of animals and administration route were not described in this communication. 44 According to TOXNET, 17 the responsible dose in which 50% of the animals must die (median lethal dose) was 7850 and 4430 mg/kg by intraperitoneal and intravenous administration in mice, respectively; 18,500 mg/kg by oral application in rats; and 8000 mg/kg by intravenous administration in rabbits. 17…”