Therapeutic efficacy of HI-6 in soman-poisoned marmoset monkeys.
The therapeutic efficacy of the oxime HI-6 against intoxication with the irreversible cholinesterase (ChE) inhibitor soman was tested in marmoset monkeys. Five out of six marmosets, intoxicated with 5 x LD50 soman and treated immediately with diazepam (0.2 mg.kg-1 iv) and 15 sec later with atropine (0.5 mg.kg-1 im) and HI-6 (50 mg.kg-1 im), survived for more than 24 hr. One of these animals died after 4 days. In the HI-6-treated marmosets blood ChE activity was inhibited at a rate slower than that in three animals treated similarly but with saline instead of HI-6. The latter marmosets died within 8 min after soman. HI-6 achieved its plasma peak 5 min after injection and was eliminated with a t1/2 of about 40 min. In a second experiment similarly treated marmosets were euthanized at 5 min (three saline-treated animals) or at 10 min (three HI-6-treated animals) after the soman intoxication to enable the determination of acetylcholinesterase (AChE) activities in diaphragm and brain tissue. In addition, in these animals blood AChE and butyrylcholine esterase (BuChE) activities were determined. Low AChE activities were encountered in diaphragms and brains. These levels were not significantly different between saline- and HI-6-treated marmosets. In vitro treatment with HI-6 at 40 min after soman still led to an increase of the AChE activity, which was significant in diaphragm, suggesting that postmortem AChE inhibition had occurred. The ratio of AChE to BuChE in blood was significantly enhanced in HI-6-treated animals, indicating that HI-6 preferentially reactivated AChE. It is concluded that (i) HI-6 is an effective treatment against soman poisoning in marmosets and (ii) AChE reactivation or protection by HI-6 contributed to the survival of the animals.
van Helden
H P
HP
Medical Biological Laboratory TNO, Rijswijk, The Netherlands.
van der Wiel
H J
HJ
de Lange
J
J
Busker
R W
RW
Melchers
B P
BP
Wolthuis
O L
OL
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood; D002144:Callithrix; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002802:Cholinesterases / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003964:Diaphragm / Q000201:enzymology; D003975:Diazepam / Q000627:therapeutic use; D004789:Enzyme Activation; D010091:Oximes; D011041:Poisoning / Q000188:drug therapy; D011726:Pyridinium Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012999:Soman / Q000506:poisoning*
D002800:Cholinesterase Inhibitors; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases; C022870:asoxime chloride; D003975:Diazepam