Camille A Boulet

Comparison of several oximes against poisining by soman, tabun and GF

Three oximes currently being evaluated for adoption as replacement nerve agent therapy by various countries were compared for therapeutic efficacy against the toxic organophosphate inhibitors soman and tabun under a standard set of conditions. These oximes together with PAM-Cl and toxogonin, were also compared for efficacy against GF, an agent weaponized by Iraq. The order of effectiveness against soman was HI-6 greater than HLö-7 greater than pyrimidoxime. HLö-7 was very effective against tabun poisoning while HI-6 and pyrimidoxime were of moderate value. Against GF, HI-6 and HLö-7 were extremely effective, toxogonin was moderately effective, and PAM-Cl and pyrimidoxime were the least effective. HI-6 provided a high level of protection against all of the agents tested as did HLö-7 to a slightly lesser degree. The other oximes suffered from their lack of effects against one or more of the organophosphates.

Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice

The toxicity and efficacy of two oximes, HLö-7 and pyrimidoxime, were evaluated in mice and compared to those obtained with HI-6. HLö-7 and pyrimidoxime produced 24 h LD50 values of 356 and 291 mg/kg (i.p.), respectively. In combination with atropine (17.4 mg/kg, i.p.), HLö-7 was a very efficient therapy against poisoning by 3×LD50 dose of soman, sarin and GF and 2×LD50 dose of tabun with ED50 values of 12.4, 0.31, 0.32 and 25.2 mg/kg, respectively. In contrast, pyrimidoxime was a relatively poor therapy which resulted in ED50 values of >150, 5.88, 100 and 71 mg/kg against poisoning by soman, sarin, GF and tabun, respectively. HLö-7 produced significant (p <0.05) reactivation of phosphorylated acetylcholinesterase, in vivo, resulting in 47, 38, 27 and 10% reactivation of sarin, GF, soman and tabun inhibited mouse diaphragm acetylcholinesterase, respectively. HLö-7 also antagonized sarin-induced hypothermia in mice suggesting that it reactivated central acetylcholinesterase. The potential of HLö-7 as a replacement oxime for the treatment of nerve agent poisoning is discussed.

Elevated frequency of sister chromatid exchanges in lymphocytes of victims of the Tokyo sarin disaster and in experiments exposing lymphocytes to by-products of sarin synthesis

More than 5000 passengers of Tokyo subway trains were injured with toxic chemicals including the nerve gas sarin. Most of the victims examined had marked miosis and decreased serum cholinesterase activity. To monitor the genetic aftereffects of sarin exposure, we measured sister chromatid exchanges (SCEs) of the victims using peripheral blood lymphocytes. The frequency of SCEs was significantly higher in the victims than in the control group. Analyzing results using samples of urine from the victims suggested that the victims were exposed to not only sarin per se, but by-products of sarin synthesis, i.e. diisopropyl methylphosphonate (DIMP), diethyl methylphosphonate (DEMP) and ethyl isopropyl methylphosphonate (EIMP). Thus, the in vitro SCE-inducing effect of DIMP, DEMP and EIMP was examined using human lymphocytes and we obtained positive results.

SYNTHESIS AND STRUCTURE OF SOME PHOSPHONYLATED OXIMES RELATED TO ORGANOPHOSPHATE NERVE AGENTS

Abstract Oximes, and in particular oximate salts, can be useful nucleophiles for the treatment of organophosphate nerve agent poisoning and decontamination of chemical warfare agents. In this paper, the reactions of phosphonochloridate analogues of the chemical warfare nerve agents VX, GB, and GA and the oximes 2-butanone oxime, 2,3-butanedione monoxime, and its potassium salt (KD), are examined. Under controlled conditions. (0°C, 1 molar eq. KD), the major product is the O-(O-alkyl phosphonyl)oxime; with excess oximate KD, the intermediate phosphonylated oximes containing an α-carbonyl undergo a “second-order” Beckmann rearrangement to give (E)-mono(O-acetyloxime)-2,3-butanedione.

ANALYSIS OF DIMETHYLPYROPHOSPHONATE DECOMPOSITION PRODUCTS OF VX BY GC-MS/MS AND 31P NMR

Abstract The detection and identification of decomposition products of chemical warfare agents can be used to investigate allegations of chemical warfare agent use, identify synthetic routes and trace sources of chemical warfare agents and their precursors. Compounds which contain a P-CH3 bond are particularly important as these compounds can provide evidence for the presence or decomposition of organo-phosphorus nerve agents. Capillary column GC-MS analysis of a distillation fraction of O-ethyl S-[2-diisopropylamino)ethyl] methylphosphonothiolate (VX), a major phosphonothiolate nerve agent, indicated the presence of two additional components comprising about 10% of the total volatile organic content. These compounds were characterized and identified by GC-MS, GC-MS/MS and 31P NMR as O,O-diethyl dimethylpyrophosphonate and O,O-diethyl dimethylmonothionopyrophosphonate. O,O-Diethyl dimethylmonothionopyrophosphonate presented a structural isomerism ambiguity whereby the position of the sulfur atom could not...

Electrospray Mass Spectrometric Characterization of Six Therapeutic Oximes: HI-6, HS-6, Obidoxime, 2-PAM, TMB-4 and HLö-7

Pyridinium and bis-pyridinium oxime salts are currently in use or under development for treatment of patients exposed to organophosphorus nerve agents. The low volatility and thermal lability of these compounds limits the number of mass spectrometric approaches that may be used to characterize them. Electrospray mass spectrometry (ESI-MS), a relatively new ionization approach, was investigated as a possible technique for the characterization and identification of these oximes and their degradation products. Six therapeutic oxime salts, the bis-pyridinium oximes, HI-6, HS-6, obidoxime, TMB-4 and HLo-7, and the pyridinium oxime, 2-PAM, were analysed by ESI-MS, making use of collisionally-activated dissociation (CAD) in the ESI interface. The CAD mass spectrum of each oxime was acquired with two different sampling cone voltage settings and the quadrupole mass analyser associated with a hybrid tandem mass spectrometer was utilized for tandem mass spectrometry (MS/MS) and CAD-MS/MS applications including the reliable differentiation of similar bis-pyridinium oximes and the identification of a HI-6 decomposition product.

Use of 2D NMR for the assignment of structure of 1,3,2-oxazaphospholidin-2-ones

Reaction of a chiral amino alcohol with an alkyl phosphorodichloridate gives a mixture of diastereomeric 1,3,2-oxazaphospholidin-2-ones which are epimeric at phosphorus. Analysis by 1D and 2D nmr has shown that it is possible to establish the absolute configuration at phosphorus by nmr techniques. Specifically, stereospecific differences in chemical shifts and NOESY spectra for each isomer are used to establish the absolute stereochemistry at phosphorus for (4R,5S)-2-ethoxy-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidin-2-one diastereomers