Randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and tolerability of metrifonate in patients with probable Alzheimer disease

A randomized, double-blind, placebo-controlled, parallel-group study was un dertaken to evaluate the safety and tolerability of a once-daily oral admin istration of metrifonate in patients with probable mild to moderate Alzheim er disease. Metrifonate was given as a loading dose of 125-225 mg based on weight (2.5 mg/kg) for 2 weeks, followed by a maintenance dose of 50-90 mg based on weight (1.0 mg/kg) for 4 weeks. Twenty-nine patients received metr ifonate, and 10 patients received placebo. Metrifonate produced a mean eryt hrocyte acetylcholinesterase inhibition at the end of treatment of 86.3%. T he proportion of patients who experienced at least one adverse event was co mparable between the metrifonate (76%) and placebo (80%) groups. Selected a dverse events in disfavor of metrifonate (defined as those for which the in cidence in the metrifonate and placebo groups differed by at least 10%) wer e diarrhea, nausea, leg cramps, and accidental injury. Adverse events were predominantly mild in intensity and transient. No severe adverse events wer e experienced by any patient. The most notable hemodynamic change observed during metrifonate treatment was a clinically insignificant mean decrease i n the heart rate (by electrocardiogram) of approximately 9 beats/min, compa red with an approximate 3-beats/min decrease for the placebo group. No musc le weakness was observed in this study. No clinically relevant laboratory a bnormalities, such as liver toxicity, or changes in exercise tolerance or p ulmonary function tests were found with metrifonate treatment. This metrifo nate dose provided a high level of acetylcholinesterase inhibition, which w as associated in these patients with a favorable safety and tolerability pr ofile. Indeed, the magnitude of the peripheral acetylcholinesterase inhibit ion is the highest tolerable inhibition level yet observed.