Potent organophosphorous (OP) agents, such as
VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, human
butyrylcholinesterase (huBuChE), in the plasma more closely matches that of
VX than do the residence times of conventional
therapy drugs (
oxime, anti-
muscarinic,
anticonvulsant). Intramuscular (i.m.) huBuChE afforded almost complete protection when administered prior to the onset of observable
cholinergic signs of
VX poisoning, but once signs of
poisoning became evident the efficacy of i.m. huBuChE decreased. A combination of
nerve agent therapy drugs (
oxime, anti-
muscarinic,
anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of
VX (0.74 mg/kg) to 48 h, even when administered on signs of
poisoning. Survival was presumed to be due to immediate alleviation of the
cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered
atropine,
diazepam and
HI-6 reached a peak within 15 min and were eliminated rapidly within 4h. Plasma concentrations of huBuChE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological
therapy rapidly treated the initial signs of
poisoning, whilst the bioscavenger provided prolonged protection by neutralising further
nerve agent entering the bloodstream and preventing it from reaching the target organs.