ABSTRACT
I. Introduction.......................................................................................................................... 146 II. Enzyme-Based Bioscavengers ............................................................................................. 146
A. Plasma-Derived Human Butyrylcholinesterase ........................................................... 147 1. Isolation and Purification...................................................................................... 147 2. Characterization .................................................................................................... 148 3. Pharmacokinetics and Toxicity............................................................................. 148 4. Behavioral and Physiological Safety .................................................................... 149 5. In Vitro and In Vivo Stability ............................................................................... 150 6. Efficacy ................................................................................................................. 150 7. Immunoreactivity .................................................................................................. 152
B. Recombinant Human Butyrylcholinesterase ................................................................ 153 1. Sources.................................................................................................................. 153 2. Characterization .................................................................................................... 154 3. Efficacy ................................................................................................................. 154 4. Improving Efficacy by Mutagenesis..................................................................... 155 5. Gene Therapy........................................................................................................ 156
C. Catalytic Bioscavengers ............................................................................................... 156 1. Enhancing Activity of Stoichiometric Bioscavengers .......................................... 156 2. Sources of OP Hydrolases .................................................................................... 157 3. Evolving Mammalian Paraoxonases..................................................................... 158
D. Extrapolation of Animal Data to Humans ................................................................... 158 III. Oxime-Based Therapy ......................................................................................................... 159
A. In Vitro Evaluation of Oxime Reactivation................................................................. 159 B. In Vivo Evaluation of Oximes...................................................................................... 161 C. Design and Development of the Next Generation of Oximes..................................... 162
IV. Centrally Acting Pretreatment Drugs .................................................................................. 164 V. Summary .............................................................................................................................. 165 References ..................................................................................................................................... 166
Nerve agents are organophosphorus (OP) compounds that are among the most toxic substances known to mankind (Dacre, 1984). Originally, OPs were developed for use as insecticides (Ballantyne and Marrs, 1992), but their extreme toxicity toward higher vertebrates led to their adoption as weapons of warfare (Maynard and Beswick, 1992). The most likely route of exposure to these agents is through inhalation or by absorption through the skin. All OPs produce their acute toxic effects by irreversibly inhibiting acetylcholinesterase (AChE, E.C. 3.1.1.7), the enzyme that breaks down the neurotransmitter acetylcholine (ACh) (Koelle, 1963; Taylor, 1990). The accumulation of ACh in response to OP exposure causes an overstimulation of cholinergic receptors at the neuromuscular junctions (Stewart, 1959; Stewart and Anderson, 1968; Heffron and Hobbinger, 1979), which can lead to muscle weakness, increased secretions, respiratory depression, seizures, coma, and ultimately death resulting from respiratory or cardiovascular failure or convulsion consequences (de Candole, 1953).
