Protective effects of S+ ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs.
Soman poisoning is known to induce full-blown tonic-clonic seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Previous studies in guinea-pigs have shown that racemic ketamine (KET), with atropine sulfate (AS), is very effective in preventing death, stopping seizures and protecting sensitive brain areas when given up to 1h after a supra-lethal challenge of soman. The active ketamine isomer, S(+) ketamine (S-KET), is more potent than the racemic mixture and it also induces less side-effects. To confirm the efficacy of KET and to evaluate the potential of S-KET for delayed medical treatment of soman-induced SE, we studied different S-KET dose regimens using the same paradigm used with KET. Guinea-pigs received pyridostigmine (26 microg/kg, IM) 30min before soman (62 microg/kg, 2 LD(50), IM), followed by therapy consisting of atropine methyl nitrate (AMN) (4 mg/kg, IM) 1min following soman exposure. S-KET, with AS (10mg/kg), was then administered IM at different times after the onset of seizures, starting at 1h post-soman exposure. The protective efficacy of S-KET proved to be comparable to KET against lethality and SRBD, but at doses two to three times lower. As with KET, delaying treatment by 2h post-poisoning greatly reduced efficacy. Conditions that may have led to an increased S-KET brain concentration (increased doses or number of injections, adjunct treatment with the oxime HI-6) did not prove to be beneficial. In summary, these observations confirm that ketamine, either racemic or S-KET, in association with AS and possibly other drugs, could be highly effective in the delayed treatment of severe soman intoxication.
Dorandeu
Frederic
F
Département de Toxicologie/CRSSA, 24 avenue des Maquis du Grésivaudan, La Tronche, France. fdorandeu@crssa.net
Baille
Valerie
V
Mikler
John
J
Testylier
Guy
G
Lallement
Guy
G
Sawyer
Thomas
T
Carpentier
Pierre
P
D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001925:Brain Damage, Chronic / Q000139:chemically induced* / Q000517:prevention & control*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D007649:Ketamine / Q000494:pharmacology*; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010091:Oximes; D011726:Pyridinium Compounds / Q000494:pharmacology; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*; D013237:Stereoisomerism
D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D010091:Oximes; D011726:Pyridinium Compounds; D007649:Ketamine; D001285:Atropine; D012999:Soman; C022870:asoxime chloride