Bottoncetti_1987_Br.J.Pharmacol_91_299

The prophylactic action of meptazinol against physostigmine- and neostigmine-induced lethality was evaluated in mice. Meptazinol proved to be effective against physostigmine (1 mg kg-1 i.p.), but not against neostigmine (0.5 mg kg-1 i.p.). The antagonism by meptazinol of physostigmine-induced poisoning was maximal when the drug was administered 15 min before physostigmine. Under these conditions the ED50 (95% confidence limits) of meptazinol was 24 (22.0-26.1) mg kg-1 s.c. A 30 mg kg-1 dose of the drug prevented lethality in 89% of the animals. The action of meptazinol was not antagonized by naloxone hydrochloride (2 mg kg-1 i.p.), injected 10 min before meptazinol. Pretreatment of mice with 30 mg kg-1 meptazinol 15 min before physostigmine (1 mg kg-1) poisoning increased brain acetylcholinesterase (AChE) activity on average, from 8 to 31% of control values. The protection of cholinesterases against physostigmine- and neostigmine-induced inactivation was demonstrated in vitro directly on purified preparations of the enzymes using a dilution method. The ED50 values (95% confidence limits) for the protective effect of meptazinol of electric eel AChE against 1 and 3 microM physostigmine and 1 microM neostigmine were 2.6 (1.4-4.9), 9.5 (5-18) and 3 (1.6-5.7) microM, respectively, while for protection of horse serum butyrylcholinesterase (BCHE) against the same inhibitors, the ED50 values were 12 (5.4-26.4), 42 (27-65.1) and 8 (3.6-17.6) microM, respectively. It is suggested that prevention of physostigmine-induced lethality by meptazinol is a consequence of its protective action on AChE in the central nervous system.