Synergism of the toxicity of physostigmine and neostigmine by lithium or by a reserpine-like agent (Ro4-1284).

Abstract

A single sublethal i.p. dose of lithium chloride (300 mg/kg or 7.1 meq/kg) followed 12 h later by an otherwise sublethal s.c. dose of physostigmine sulfate (1.0 mg/kg) resulted in 90% mortality among male rats following a pronounced cholinergic syndrome, including convulsions. This confirms a previous report of a lethal synergism of physostigmine after subacute dosing with lithium. Mortality could be completely prevented by 1.0 mg/kg of atropine sulfate given 30 min before physostigmine, but was incompletely, if at all, reduced by selective peripheral cholinergic blockers, methylatropine bromide (0.5, 1.5 mg/kg) or glycopyrrolate (1 mg/kg). This suggested a predominantly central site for the toxic interaction. However, a similar synergism of lethality caused by neostigmine methylsulfate (0.3 mg/kg, s.c.) after treatment with lithium, which could be eliminated by methylatropine or glycopyrrolate, indicates that lithium may also produce lethal synergism of a cholinesterase (ChE) inhibitor that does not act centrally. Ro4-1284, an agent that has reserpine-like actions, was tested in combination with physostigmine or neostigmine; it showed synergism of toxicity nearly the same as in the case of lithium plus the cholinergic agents. These findings support the hypothesis that lithium causes the toxic synergism via a reduction of adrenergic activity, leading to an imbalance between adrenergic and cholinergic influences and a consequent failure to tolerate the effects of the ChE inhibitors. A potential hazard for the clinical use of physostigmine and neostigmine, concurrently with lithium or reserpine-like agents, it suggested.

• Authors: W M Davis, N S Hatoum
• Journal: Toxicology (Toxicology) Vol. 17 Issue 1 Pg. 1-7 ( 1980) ISSN: 0300-483X [Print] Ireland
• PMID: 6904065 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Quinolizines
• 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-
• Neostigmine
• Lithium
• Physostigmine

Topics

• 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- (toxicity)
• Adrenergic Fibers (drug effects)
• Animals
• Central Nervous System (drug effects)
• Cholinergic Fibers (drug effects)
• Drug Synergism
• Lethal Dose 50
• Lithium (toxicity)
• Male
• Neostigmine (toxicity)
• Physostigmine (toxicity)
• Quinolizines (toxicity)
• Rats