4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses.
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.
Jacobsen
D
D
Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932.
Sebastian
C S
CS
Blomstrand
R
R
McMartin
K E
KE
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D004341:Drug Evaluation; D004361:Drug Tolerance; D019855:Ethylene Glycol; D005026:Ethylene Glycols / Q000506:poisoning; D000077604:Fomepizole; D006801:Humans; D008297:Male; D000432:Methanol / Q000506:poisoning; D009325:Nausea / Q000139:chemically induced; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D012449:Safety
D005026:Ethylene Glycols; D011720:Pyrazoles; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D019855:Ethylene Glycol; D000432:Methanol