Sarin AChE activity

Very high levels of MPA and /-PrMPA were detected as their TBDMS derivatives by GC/FPD in the urine of a Matsumoto casualty rendered unconscious and with low-blood AChE activity (42). Urine was collected over a 7-day period. Concentrations of i-PrMPA and MPA respectively were day 1, 760 ng/ml and 140 ng/ml day 3, 80 ng/ml and 20 ng/ml day 7, 10 ng/ml, MPA not detected (no standard of i -PrMPA was available and quantitation was based on detector response to MPA). The exposure was estimated as 2.79 mg of sarin, making crude assumptions on the percentage that would be excreted, i -PrMPA was detected as the... 

GA, a unitary chemical munition, inhibits AChE, the enzyme responsible for the breakdown of the neurotransmitter ACh. When inhaled, its toxicity is half that of sarin. It depresses plasma and RBC-AChE activities significantly in the blood. At 20-25% of red blood cell AChE baseline, the effect of the nerve agent becomes noticeable. There is no evidence of systemic toxicity other than the cholinesterase activity (Parker et al, 1990 Munro et al, 1994). GA has not been shown to produce OPIDN except at extremely high doses. The cardiac effect of GA conforms to OP-caused arrhythmias and AV block. 

A. Relationship Between Regenerated Sarin and AChE Activity and its Use as a Dose Surrogate... 

Regenerated sarin Sr from red blood cells is experimentally related to AChE activity H in Figure 51.3. It is apparent that the relationship can be adequately described in terms of a Michaelis-Menten equation as follows ... 

Correlation of Regenerated Sarin With AChE Activity... 

FIGURE 62.4. RBC AChE inhibition in rhesus monkey following administration of sarin [0.75 LD50 (15 pg/kg) i.v.] and with 2-PAM (25.8mg/kg) administered IM at 9 min postsarin i.v. administration. Atropine was administered (0.4 mg/kg) IM 15 min prior to sarin administration. The filled circles indicate experimental data (Woodard et al, 1994) the curves show our PBPK model simulations of AChE activity after sarin, both with (upper curve) and without (lower curve) 2-PAM administration. 

There are only a few reports in the open literature on the effect of oximes in nerve agent-exposed humans. Pralidoxime chloride was very effective in reactivating erythrocyte AChE in individuals exposed to sublethal intravenous or oral VX while this oxime was substantially less effective in humans exposed to IV sarin (Sidell and Groff, 1974). Accidental sarin exposure by inhalation resulted in an initial progressive deterioration (coma, apnea) of the patient despite atropine and 2-PAM treatmentand substantial recovery of erythrocyte AChE activity (Sidell, 1974). It took several hours until the patient s condition improved. Sidell also reported an accidental oral soman exposure. A lethal dose of diluted soman splashed into and around the mouth of an individual, resulting in coma, bronchoconstriction and respiratory depression, which was successfully treated with repeated atropine injections. 2-PAM (2 g IV) had no effect on inhibited erythrocyte AChE. 

Figure 8. Calculated human AChE activities (left-hand side) after intravenous cyclosarin and simultaneous intramuscular oxime injection. The changes in AChE activity were calculated by using the toxicokinetic data of (-)-sarin (Spruit et al., 2000) and human pharmacokinetic data of the oximes (Worek et al., 2005) for 1, 2 and 3 autoinjector equivalents (AIs) of obidoxime (1 AI = 250 mg), 2-PAM (1 AI = 600 mg) and HI 6 (1 AI = 500 mg) and exposure to 0.8 x LD50 cyclosarin ((—), 1...

The inhibition of AChE activity in nerve tissues of animals at different times after exposure to low-dose nerve agents are depicted in Table 3.3. In most studies, subcutaneous, intravenous, inhalation, and oral routes of exposure were used. AChE activity in whole brain, spinal cord, and brain regions such as cerebral cortex, corpus striatum, meduUa, and cerebellum was significantly decreased in rats, " " mice, and hens, ° hours, days, and weeks after low-dose exposure to nerve agents such as soman, sarin, and tabun. 

FIGURE 6.6B In vivo detoxification of sarin by FBS AChE in mice. Mice received i.v. FBS AChE (9 nmol) followed by sarin (14 nmol) and 1 mg HI-6. Sarin/HI-6 injections ( ) or sarin alone injections (i.v.) were then repeated at 15-min intervals. AChE activity was determined 5 min prior to each sarin injection. All mice survived. 

Husain and Somani (2003) Mouse Sarin. PB, exercise Exercise augmented synergistic effects of chemical exposures on AChE activity and NTE activity in various tissues... 

There is no correlation between AChE inhibition and the disposition of [ H]-soman, H)-DFP, and [ H]-sarin in brain (Kadar cf a/, 1985 Little etal., 1988). For example, the hypothalamus binds two to five times more OP compared to the striatum, but the striatum has more AChE activity than the hypothalamus. This suggests that in the hypothalamus, targets other than cholinesterase bind OP (Little et al., 1988). In a related experiment, binding of pH]-DFP to whole brain homogenate was decreased only 15% by preincubation with 1 pM eserine (a specific inhibitor of AChE and BChE), suggesting that only 15% of the DFP-Iabeled proteins are cholinesterases (Richards etal., 1999). 

Inhibition of the brain AChE by G compounds (sarin and soman) is very fast, reaching 50% activity within minutes. For VX, there is a delay and a decrease in AChE activity was observed after more than 20 minutes, probably caused by a more difficult absorption in comparison with sarin and soman. The half-lives are very dependent on the dose of the agent... 

Following an acute exposine to sarin (llOpg/kg, s.c.), AChE activity in skeletal muscles was reduced to 23% in SOL and 48% in diaphragm within Ih, w hile EDL AChE was significantly unaffected. By 24 h, however, a still-greater inhibition was seen for these muscles, and in EDL, AChE activity was reduced to 43%. In an early phase, recovery of AChE was rapid, but still not complete... 

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