ABSTRACT
I. Introduction.......................................................................................................................... 219 II. Galantamine ......................................................................................................................... 220
A. History.......................................................................................................................... 220 B. Use in Alzheimer’s Disease ......................................................................................... 221 C. Mechanisms of Action ................................................................................................. 222
III. Galantamine in Organophosphorus Poisoning .................................................................... 222 A. Existing Treatments ..................................................................................................... 222 B. Promise of Galantamine............................................................................................... 223 C. Pretreatment with Galantamine.................................................................................... 223 D. Posttreatment with Galantamine .................................................................................. 226 E. Protection Against Brain Damage ............................................................................... 227
IV. Conclusions.......................................................................................................................... 228 Acknowledgments......................................................................................................................... 229 References ..................................................................................................................................... 229
Since their development just before World War II, the organophosphorus (OP) nerve agents have been potential and actual threats to soldiers on the battlefield (Wiener and Hoffman, 2004; Geoghegan and Tong, 2006). Their more recent use in 1994-1995 terrorism incidents in Japan (Tokuda et al., 2006) has added a threat to the general civilian population as well, which was already present for farm workers or exterminators using OP insecticides (Karalliedde and Senanayake, 1989). These agents’ acute toxic effects are primarily due to irreversible inhibition of acetylcholinesterase (AChE), the enzyme that breaks down the neurotransmitter acetylcholine at the neuromuscular junction and elsewhere (Maxwell et al., 2006). Other mechanisms, particularly in the brain, have also received
some support (Duysen et al., 2001). Symptoms vary according to the OP and route and the extent of exposure, but usually include a nicotinic cholinergic syndrome characterized by skeletal muscle fasciculations followed by desensitizing neuromuscular blockade, and a variety of other effects resulting from overstimulation of muscarinic receptors. A more complete clinical list of symptoms includes miosis, excess sweating, headache, tightness in the chest, labored breathing, dizziness, excess salivation, muscle cramps, difficulty in walking, convulsions, diarrhea, wheezing, abdominal cramps, muscle fasciculations, unconsciousness, coma, respiratory failure, and death. As suggested by this list, death is usually due to respiratory failure, resulting from both diaphragm paralysis and failure of central respiratory drive (Rickett et al., 1986). Currently used treatments for OP poisoning are far from satisfactory. They consist of atropine to block muscarinic effects, oximes to reactivate the inhibited AChE before ‘‘aging’’ of the phosphorylated enzyme occurs, and benzodiazepines to control seizures (Marrs, 2004). More recently, the Food and Drug Administration approved the use of pyridostigmine, a reversible inhibitor of AChE and butyrylcholinesterase (BuChE), as a pretreatment for military personal under threat of exposure to nerve agents (Layish et al., 2005). The intent was to protect a portion of the AChE molecules against irreversible blockade by the nerve agent by occupying them with the reversible inhibitor. This is particularly important for exposure to soman, because the soman-inhibited AChE ages rather rapidly.
