Protection and inflammatory markers following exposure of guinea pigs to sarin vapour: comparative efficacy of three oximes.
The purpose of the present study was to compare the antidotal efficacy and the combined effects on inflammatory markers of three oximes--toxogonine, TMB4 and 2-PAM--in combination with anticholinergic drugs following exposure to sarin vapour by inhalation. Guinea pigs restrained in plethysmographs were exposed to various doses of sarin vapour (in the range of 1.4-4.4LD50). The antidotal mixture was injected immediately (5-20 s) following exposure (3 mg kg(-1) atropine and 1 mg kg(-1) benactyzine in combination with 6 mg kg(-1) toxogonine, 2 mg kg(-1) TMB4 or 12 mg kg(-1) 2-PAM). Bronchoalveolar lavage (BAL) samples were taken from surviving animals 24 h after exposure to determine the levels of inflammatory markers. A differential cell count was performed in BAL samples on Giemsa-stained slides. The inflammatory markers--histamine and prostaglandins (PGE)--were measured in BAL using radioimmunoassay (RIA) techniques. The survival rate in the various treatment groups and analysis of BAL samples showed that: (i) Toxogonine, TMB4 and 2-PAM, without pyridostigmine pretreatment, at doses that were proportional to their doses in the respective auto-injectors, exhibited similar antidotal efficacy against sarin exposure. (ii) The results demonstrated that a centrally acting anticholinergic drug is essential in the antidotal mixture to ensure survival. (iii) Histamine release and eosinophilia following sarin inhalation might require additional intervention, aimed at reducing the symptoms of allergic reaction and possibly expediting recovery.
Levy
A
A
Israel Institute for Biological Research, Department of Pharmacology, PO Box 19, Ness Ziona 74100, Israel. RonLevy@iibr.gov.il
Chapman
S
S
Cohen
G
G
Raveh
L
L
Rabinovitz
I
I
Manistersky
E
E
Kapon
Y
Y
Allon
N
N
Gilat
E
E
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D018893:Bronchoalveolar Lavage; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000032:analysis; D007249:Inflammation; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008297:Male; D009768:Obidoxime Chloride / Q000494:pharmacology*; D011041:Poisoning / Q000517:prevention & control; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D011453:Prostaglandins / Q000032:analysis; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011863:Radioimmunoassay; D012524:Sarin / Q000008:administration & dosage / Q000633:toxicity*; D014835:Volatilization
D015415:Biomarkers; D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; D011453:Prostaglandins; D011726:Pyridinium Compounds; C106320:trimethylene-bis(4-hydroxyiminomethylpyridinium); D009768:Obidoxime Chloride; D006632:Histamine; D012524:Sarin; C028797:pralidoxime