Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) is one of the highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates in its chemical structure and by the fact that the commonly used antidotes (atropine in combination with an oxime) are not able to sufficiently eliminate its acute toxic effects.
The neuroprotective effects of the newly developed oximes (K027, K048) or trimedoxime in combination with atropine (atropine, K027/atropine, K048/atropine and trimedoxime/atropine mixtures) on rats poisoned with tabun at a lethal dose (270 micro g/kg i.m.; 120% of LD50 value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automaticmeasurement of motor activity. The neurotoxicity of tabun was monitored at 24 hours and 7 days following tabun challenge. The results indicate that atropine alone is not able to protect rats from the lethal effects of tabun. Five non-treated tabun-poisoned rats and five tabun-poisoned rat treated with atropine alone died within 24 hours. On the other hand, atropine combined with all tested oximes allows most tabun-poisoned rats to survive within 7 days following tabun challenge. All three oximes tested combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of lethal poisonings, although they are not able to eliminate tabun-induced neurotoxicity completely. Due to their neuroprotective effects, all the tested oximes appear to be more suitable oximes for the antidotal treatment of acute tabun exposure than the currently used oximes (pralidoxime, obidoxime, HI-6).
neuroprotective; neurotoxicity; oxime; rat; tabun
Bajgar J: The Use of Chemical Weapons and Negotiations on their Ban: from History to the Present Time (in Czech). Nukleus Hradec Kralove, Czech Republic, 2006.
Cabal J, Bajgar J: Tabun - reappearance 50 years later (in Czech). Chem Listy 93:27-31, 1999.
Cabal J, Kuca K, Kassa J: Specification of the structure of oximes able to reactivate tabuninhibited acetylcholinesterase. Pharmacol Toxicol 95:81-86, 2004.
Cassel G, Karlsson L, Waara L et al.: Pharmacokinetics and effects of HI-6 in blood and brain of soman-intoxicated rats: A microdialysis study. Eur J Pharmacol 332:43-52, 1997.
Dawson RM: Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol 14:317-331, 1994.
Dohnal V, Kuca K, Jun D: Prediction of a new broad-spectrum reactivator capable of reactivating acetylcholinesterase inhibited by nerve agents. J Appl Biomed 3:139-145, 2005.
Eto M: Organophosphorus Pesticides: Organic and Biological Chemistry. CRC Press Inc., Cleveland, USA, 1976.
Frantik E, Hornychova M: Clustering of neurobehavioral measures of toxicity. Homeostasis 36:19-25, 1995.
Hornychova M, Frantik E, Kubat J, Formanek J: Neurotoxicity profile of supermethrin, a new pyrethroid insecticide. Cent Eur J Publ Health 3:210-218, 1995.
Jokanovic M: Anticholinesterase activity and delayed neurotoxic effects of tabun in hens. Vojvosanit Pregl 50:451-456, 1993.
Jokanovic M, Maksimovic M, Kilibarda V et al.: Oxime-induced reactivation of acetycholinesterase inhibited by phosphoramidates. Toxicol Lett 85:35-39, 1996.
Kassa J: Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J Toxicol Clin Toxicol 40:803-816, 2002.
Kassa J, Cabal J: A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with currently available oximes and H oximes against soman by in vitro and in vivo methods. Toxicology 132:111-118, 1999a.
Kassa J, Cabal J: A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods. Pharmacol Toxicol 84:41-45, 1999b.
Kassa J, Cabal J, Kuca K: A comparison of the efficacy of currently available oximes against tabun in rats. Biologia 60, Suppl. 17:77-79, 2005.
Kassa J, Koupilova M: The importance of anticholinergic drug selection for the neuroprotective effects of antidotes in somanpoisoned rats. Homeostasis 12:52-53, 2000.
Kassa J, Krejcova G: Neuroprotective effects of currently used antidotes in tabun-poisoned rats. Pharmacol Toxicol 92:258-264, 2003.
Kassa J, Kuca K, Cabal J, Paar M: A comparison of the efficacy of new asymmetric bispyridinium oximes (K027, K048) with currently available oximes against tabun by in vivo methods. J Toxicol Environ Health 69, 2006, in press.
Kassa J, Kunesova G: A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabuninduced neurotoxicity in rats. J Appl Toxicol 26, published online 21. March 2006.
Kuca K, Bielavsky J, Cabal J, Bielavska M: Synthesis of a potential reactivator of acetylcholinesterase 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium)-propane dibromide. Tetrahedron Lett 44:3123-3125, 2003a.
Kuca K, Bielavsky J, Cabal J, Kassa J: Synthesis of a new reactivator of tabun inhibited acetylcholinesterase. Bioorg Med Chem Lett 13:3545-3547, 2003b.
Kuca K, Kassa J: A comparison of the ability of a new bispyridinium oxime-1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods. J Enzyme Inhib Med Chem 18:529-535, 2003.
Kuca K, Kassa J: In vitro reactivation of acetylcholinesterase using the oxime K027. Vet Hum Toxicol 46:15-18, 2004.
Marrs TC: Organophosphate poisoning. Pharmacol Ther 58:51-66, 1993.
McDonough JH Jr., Zoeffel LD, McMonagle J et al.: Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea-pigs. Epilepsy Res 38:1-14, 2000.
Moser VC, Tilson H, McPhail RC et al.: The IPCS collaborative study on neurobehavioral screening methods: II. Protocol design and testing procedures. Neurotoxicology 18:929-938, 1997.
Ohtomi S, Takase M, Kumagai F: Sarin poisoning in Japan. A clinical experience in Japan Self Defense Force (JSDF) Central Hospital Int Rev Arm Ser 69:97-102, 1996.
Patocka J, Cabal J, Kuca K, Jun D: Oxime reactivation of acetylcholinesterase inhibited by toxic phosphorus esters: in vitro kinetics and thermodynamics. J Appl Biomed 3:91-99, 2005.
Poziomek EJ, Hackley BE, Steinberg GM: Pyridinium aldoximes. J Org Chem 23:714-717, 1958.
Puu G, Artursson E, Bucht G: Reactivation of nerve agent inhibited acetylcholinesterase by HI-6 and obidoxime. Biochem Pharmacol 35:1505-1510, 1986.
Roth Z, Josifko M, Maly V, Trcka V: Statistical Methods in Experimental Medicine (in Czech) SZN, Czechoslovakia, 1962.
Sakurada K, Matsubara K, Shimizu K et al.: Pralidoxime iodide (2-PAM) penetrates across the blood-brain barrier. Neurochem Res 28:1401-1407, 2003.
Taylor P: Anticholinesterase agents. In: Hardman JG and Limbird LE (eds.): The pharmacological basis of therapeutics, McGraw Hill, NewYork, USA 1996, pp. 161-176.
Worek F, Widmann R, Knopff O, Szinicz L: Reactivating potency of obidoxime, pralidoxime, HI-6 and HLo-7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds. Arch Toxicol 72:237-243, 1998.
Kassa J, Karasova JZ, Musilek K, Kuca K, Jung YS: A comparison of the neuroprotective efficacy of newly developed oximes (K117, K127) and currently available oxime (obidoxime) in tabun-poisoned rats. Toxicol Mechanisms Methods 19:232-238, 2009.
Gupta AK, Greenway FL, Cornelissen G, Pan W, Halberg F: Prediabetes is associated with abnormal circadian blood pressure variability. J Human Hypetrens 22:627-633, 2008.
Kassa J, Karasova J: The evaluation of the neuroprotective effects of bispyridinium oximes in Tabun-poisoned rats. J Toxicol Env Health-Part-A-Curr Iss 70:1556-1567, 2007.
Cornelissen G, Halberg F, Otsuka K, Singh RB, Chen CH: Chronobiology predicts actual and proxy outcomes when dipping fails. Hypertension 49:237-239, 2007.