Characterization and treatment of the toxicity of O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate, a structural isomer of VX, in guinea pigs

被引:0
|
作者
Maxwell, DM
Brecht, KM
Koplovitz, I
机构
来源
JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY | 1996年 / 15卷
关键词
VX; isomer; V-agent; acetylcholinesterase; organophosphorus; chemical warfare;
D O I
暂无
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
O-isobutyl S-[2-(diethylamino)ethyl]methyIphosphonothioate (VR), a structural isomer of the chemical warfare agent O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate (VX) was characterized with respect to its toxicity, acetylcholinesterase (AChE) inhibition, oxime reactivation, and antidotal treatment. VR was highly toxic in guinea pigs, with an s.c. LD(50) of 11.3 mu g/g. The bimolecular rate constant for inhibition of AChE by VR was 1.4 x 10(8) M(-1) min(-1), which is similar to the AChE inhibition rate constants of VX and of other chemical warfare agents whose toxicity is attributed to their inhibition of AChE. Complete in vitro reactivation of VR-inhibited AChE was produced by oximes, but reactivation with the bispyridinium oximes 1-(((4-(aminocarbonyl)pyridino)methoxy methyl)-2-((hydroximino)methyl)pyridinium dichloride (HI-6), 1-(((4-(aminocarbonyl)pyridino)methoxy)methyl)-2,4-bis(hydroxyimino)methyl)pyridinium dimethanesulfonate (HL delta 7), and toxogonin dichloride (TOXO) occurred at a much higher rate than with the monopyridinium oxime 2-pyridine aldoxime methylchloride (2-PAM). The reactivation rates with HL delta 7, HI-6, and TOXO were, respectively, 21-, 5-, and 3-fold greater than with 2-PAM. The aging of VR-inhibited AChE to an oxime-resistant state occurred slowly with a half-life of 43 h. Treatment of guinea pigs with equimolar (145 mu mol/kg) amounts of HI-6 (55 mg/kg) or 2-PAM (25 mg/kg) in combination with atropine (16 mg/kg) i.m. 1 min after VR exposure produced protective ratios of 43.9 for HI-6 and 6.5 for 2-PAM. Carbamate pretreatment prior to these oxime/atropine treatments caused no increase in their protective ratios against VR. These observations suggest that VR is a highly toxic anticholinesterase agent that can be effectively treated with an appropriate oxime/atropine regimen.
引用
收藏
页码:S78 / S88
页数:11
相关论文
共 31 条
  • [1] Cardiorespiratory effects of O-isobutyl S-[2-(diethylamino)-ethyl]methylphosphonothioate - A structural isomer of VX
    Chang, FCT
    Gouty, SC
    Eder, LC
    Hoffman, BE
    Maxwell, DM
    Brecht, KM
    JOURNAL OF APPLIED TOXICOLOGY, 1998, 18 (05) : 337 - 347
  • [2] A comparative survey of pathophysiology induced by soman, VX and a structural isomer of VX, O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate.
    Hoffman, B
    Gouty, SC
    Eder, LC
    Chang, FCT
    FASEB JOURNAL, 1998, 12 (05): : A699 - A699
  • [3] Pharmacological antagonism of lethal effects induced by O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate
    Chang, FCT
    Hoffman, BE
    DeBus, S
    DRUG AND CHEMICAL TOXICOLOGY, 2002, 25 (03) : 321 - 337
  • [4] Scopolamine antagonizes the lethal effects of O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate.
    DeBus, S
    Hoffman, B
    Chang, FCT
    FASEB JOURNAL, 2000, 14 (04): : A548 - A548
  • [5] Combined atropine and scopolamine optimizes the therapeutic outcome in guinea pigs intoxicated by O-isobutyl S-[2(diethylamino)ethyl]methylphosphonothioate.
    DeBus, SJ
    Krzysiak, A
    Sherman, N
    Chang, FCT
    FASEB JOURNAL, 2001, 15 (04): : A557 - A557
  • [6] Parmacological antagonism of lethal effects induced by O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonthionate.
    Hoffman, BE
    Gouty, SC
    Chang, FCT
    FASEB JOURNAL, 1999, 13 (05): : A1101 - A1101
  • [7] Cardiorespiratory and neuromuscular effects of O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) in rats
    Dube, SN
    Mazumder, PK
    Kumar, D
    Purnanand
    BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY, 1997, 59 (02) : 246 - 253
  • [8] Cardiorespiratory and Neuromuscular Effects of O-Ethyl S-[2- (Diisopropylamino) Ethyl] Methylphosphonothioate (VX) in Rats
    S. N. Dube
    P. K. Mazumder
    D. Kumar
    Bulletin of Environmental Contamination and Toxicology, 1997, 59 : 246 - 253
  • [9] Gas-chromatographic determination of sarin, soman, and O-isobutyl S-2-(N,N-diethylamino)ethyl methylphosphonothioate (VX-like compound) traces in water
    Stan'kov, I.N.
    Sergeeva, A.A.
    Derevyagina, I.D.
    Konovalov, K.V.
    Zhurnal Analiticheskoj Khimii, 2003, 58 (02): : 182 - 187
  • [10] Gas-chromatographic determination of sarin, soman, and O-isobutyl S-2-(N,N-diethylamino)ethyl methylphosphonothioate (a VX-like compound) traces in water
    Stan'kov, IN
    Sergeeva, AA
    Derevyagina, ID
    Konovalov, KV
    JOURNAL OF ANALYTICAL CHEMISTRY, 2003, 58 (02) : 160 - 164