4‐Methylpyrazole: A Controlled Study of Safety in Healthy Human Subjects after Single, Ascending Doses

Abstract

4-Methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, is a possible future drug for the treatment of methanol and ethylene glycol intoxications and the severe ethanol-disulfiram reaction. Therefore a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase I study" was performed in healthy volunteers in order to determine the tolerance of 4-MP at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4), and 100 mg/kg (n = 3). Along with each dose group, there were two placebos except with the 100 mg/kg group where there was only one placebo. In the 10 and 20 mg/kg group there were no side-effects in any subject. At the 50 mg/kg level, three out of four subjects experienced slight to moderate nausea and dizziness from 0 to 2.5 h after dosing. In the 100 mg/kg group all three subjects reported side-effects like nausea, dizziness, and vertigo, that were short-lived in two subjects, but lasted up to 30 h in one subject. The study was stopped after evaluation of the latter subject, so fewer subjects were completed in this last group. Despite these subjective side-effects, there were no significant changes in objective clinical parameters like pulse, blood pressure, body temperature, or blood and urine chemistries. We conclude that at a single dose of 4-MP (10-20 mg/kg) producing plasma levels within a probable therapeutic range, no side-effects were attributed to 4-MP.

Fomepizole as a therapeutic strategy in paediatric methanol poisoning. A case report and review of the literature

“…Side-effects of classical ethanol therapy such as hypoglycaemia and [17]. Commonly reported adverse events in clinical trials are headache, nausea and dizziness [12]. Less frequent sideeffects are phlebitis, dyspepsia, agitation, anxiety, hiccup, rash, transient tachycardia, seizures, headache and bradycardia [5,6].…”

Treatment of acute methanol poisoning with fomepizole

“…Fomepizole was well tolerated, in spite of prolonged administration (up to 8 days) in three patients. Jacobsen and colleagues [30] have shown that fomepizole is well tolerated in healthy human subjects in therapeutic doses, with no significant changes in clinical or laboratory, including liver function tests.…”

Bradycardia and hypotension associated with fomepizole infusion during hemodialysis

“…administered fomepizole to healthy human volunteers in single oral doses ranging from 10 to 100 mg/kg. At doses of 50 and 100 mg/kg, subjects experienced nausea and vertigo but there were no alterations in pulse or blood pressure (9). The methylpyrazole for toxic alcohols (META) study group conducted carefully monitored, unblinded clinical trials evaluating intravenous fomepizole (10-15 mg/kg/ dose) in 19 patients with ethylene glycol poisoning and 11 patients with methanol poisoning (10-11).…”