Antagonism of sarin poisoning in rats and guinea pigs by atropine, oximes, and mecamylamine

Fleisher, Joseph H.; Harris, Larrel W.; Miller, Gail R.; Thomas, Norman; Cliff, William J.

doi:10.1016/0041-008x(70)90160-2

Cited by 53 publications

(7 citation statements)

References 10 publications

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“…These criteria in these species as the probit slope for soman in guinea resulted in the addition of the supplemental oxime pigs presented in Table 1. These observations demon-PR data shown in Table 2 from Fleisher et al (1970), strated that highly toxic OP compounds produce sim- Lundy et al (1992) and Inns and Leadbeater (1983). ilar steep probit slopes regardless of the OP compound In vitro oxime reactivation constants (kR) were taken or the mammalian species in which the toxicity of the from Worek et al (2002), which contained an OP compounds is determined, extensive study of oxime reactivation of OP-inhibited Evaluation of the hypothesis that AChE inhibition is AChE from guinea pigs.…”

Section: Sponsoring I Monitoring Agency Name(s) and Address(es) 10 Smentioning

confidence: 75%

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

Maxwell¹,

Brecht²,

Koplovitz³

et al. 2006

Arch Toxicol

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Section: Sponsoring I Monitoring Agency Name(s) and Address(es) 10 Smentioning

confidence: 75%

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

Maxwell¹,

Brecht²,

Koplovitz³

et al. 2006

Arch Toxicol

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“…A reference for obidoxime Cl 2 indicated a relatively low LD 50 = 78.9 mg/kg by the IM route in guinea pigs but lacked other details (Fleisher et al, 1970). In our laboratory, the LD 50 (and LD 01 , 95% fiducial limits, probit slope) determined were 179 (142, 157-191 mg/kg, 23) for 2-PAM Cl, 314 (277, 300-354 mg/kg, 43) for HLö-7 DMS, and 679 (528, 635-944 mg/kg, 21) for MMB4 DMS.…”

Section: Resultsmentioning

confidence: 99%

Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig

et al. 2016

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-Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD 50 /oxime ED 50 ) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl 2 . The 24-hr median lethal dose (LD 50 ) for the four by intramuscular (IM) injection and the median effective dose (ED 50 ) were determined. In the ED 50 study, male guinea pigs clipped of hair received 2x LD 50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED 90 ) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 μmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl 2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl 2 . Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED 90 < 149 μmol/kg against all three topical OPs tested.

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“…HI-6 DMS, MMB4 DMS, RS194B and MINA were evaluated at an additional dose level equal to the median lethal dose (LD50) for the oxime divided by the Therapeutic Index (TI) for 2-PAM Cl (Table 2c). Specifically, TI 2-PAM Cl is the ratio of the 24-hr LD 50 (168 mg/kg; Fleisher et al 1970) to the FDA-approved human therapeutic dose (i.e., median effective dose, ED 50 = 25.7 mg/kg; Koplovitz et al 1992) or…”

Section: Methodsmentioning

confidence: 99%

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

Wilhelm

Snider

Babin

et al. 2014

Toxicology and Applied Pharmacology

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The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.

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Antagonism of sarin poisoning in rats and guinea pigs by atropine, oximes, and mecamylamine

Cited by 53 publications

References 10 publications

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

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