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Time course, safety, and efficacy of reversible acetylcholinesterase inhibitors in cynomolgus macaques
Author(s) -
Hamilton Lindsey,
Bonvillain Andrew,
Myers Todd
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.617.1
Subject(s) - acetylcholinesterase , aché , nerve agent , pharmacology , soman , pyridostigmine , acetylcholinesterase inhibitor , chemistry , pyridostigmine bromide , huperzine a , toxicity , toxicology , medicine , enzyme , biochemistry , biology , myasthenia gravis
Galantamine (GAL) and huperzine (HUP), reversible acetylcholinesterase (AChE) inhibitors, are potentially superior to the current standard, pyridostigmine, as a pretreatment for nerve agent intoxication. GAL and HUP were compared for time course of AChE inhibition in 12 cynomolgus macaques. Both drugs are rapidly absorbed following intramuscular injection. Peak AChE inhibition occurred at about 14 minutes and the elimination half‐time approximated 165 minutes for both drugs. The dose at which AChE inhibition was 50% of baseline was calculated to be 4.1 ug/kg for HUP and 362 ug/kg for GAL. Thus, HUP is 88 times more potent than GAL in this species. To address safety, HUP (5 – 40 ug/kg) and GAL (125 – 1000 ug/kg) were examined using an operant time estimation task. HUP was completely devoid of behavioral toxicity at all doses studied, despite producing peak AChE inhibition of about 92% at the highest dose (40 ug/kg). In contrast, GAL was behaviorally toxic at doses of 500 ug/kg and higher, and the calculated dose for 50% behavioral disruption compared to baseline performance was about 552 ug/kg. The safety ratio of HUP exceeded 9.5 whereas the safety ratio for GAL was 1.52. Next, we will determine the efficacy of GAL and HUP against challenge with the median lethal dose of the warfare nerve agent soman, an irreversible AChE inhibitor. This research was supported by the Defense Threat Reduction Agency, Medical S&T Division.