Behavioral toxicity of anticholinesterases in primates: Effects of daily repeated soman exposure

Blick, Dennis W.; Weathersby, Frank R.; Brown, G. Carroll; Murphy, Michael R.

doi:10.1016/0091-3057(94)90326-3

Cited by 13 publications

(3 citation statements)

References 21 publications

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“…Animal studies have demonstrated that repeated exposures to some organophosphate ChE inhibitors can result in increased tolerance to the action of these agents (reviewed in Ho and Hoskins, 1987;Hoskins and Ho, 1992;Blick et al, 1994). At least one published study documents evidence for tolerance in humans.…”

Section: Development Of Tolerancementioning

confidence: 96%

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

Young

Opresko

Watson

et al. 1999

Human and Ecological Risk Assessment: An International Journal

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During the process of deriving oral Reference Dose (RfDs) values for chemical warfare agents, several issues arose regarding the identification of adverse effect levels and the application of uncertainty factors. For those agents that function as cholinesterase inhibitors (e.g., agents VX, GA, GB, and GD), these issues included the following: (1) Is the endpoint of blood cholinesterase inhibition an indicator of toxicity or a biomarker of exposure? (2) Can an experimental animal species be more sensitive than humans, thereby eliminating the need for an animal-to-human uncertainty factor? (3) Can the uncertainty factor that is used to extrapolate from a lowest-observed adverseeffect-level (LOAEL) to a no-observed-adverse-effect-level (NOAEL) be less than the default value of 10? (4) Can an oral RfD be derived from non-oral toxicity data? (5) Can an uncertainty factor of less than 10 be used to extrapolate from subchronic to chronic exposure (i.e., is the critical effect adequately described by the subchronic exposure data)? (6) What constitutes an adequate data base for organophosphate cholinesterase inhibitors, and what uncertainty factor should be used for an incomplete data base? Young, et al.Analysis of relevant data resulted in the following selection and justifications of uncertainty factors. For uncertainty associated with intraspecies extrapolation (UF H ), physiologic and pathologic conditions affecting cholinesterase activity levels justified maintaining a UF H of 10 for all of the nerve agents. Because available data indicated that humans tended to be more sensitive than rats regarding anticholinesterase effects, an interspecies variability (UF A ) factor of 10 was retained for agents GA, GB, and GD. For agent VX, however, the available data revealed that the domestic sheep test species exhibited sensitivity equivalent to or greater than that of humans thereby justifying a UF A of 1. For uncertainties regarding extrapolation from subchronic-to-chronic exposure data, consideration of information on the physiology of cholinergic systems and the available toxicity data for the nerve agents and other cholinesterase inhibitors indicated that a UF S of 3 was justified for all four of the nerve agents. For uncertainties regarding LOAEL-to-NOAEL extrapolation (UF L ), the selection of agent GB, GD, and VX doses resulting in cholinesterase inhibition in the absence of clinical signs of toxicity (biomarker of exposure) justified this endpoint as a minimal LOAEL and a UF L of 3. For agent GA, a NOAEL was used, and therefore no UF L was required. The uncertainty factor for data base completeness (UF D ), was based upon several considerations. Of primary concern was the fact that chronic toxicity studies are not considered an essential component of the data base requirements for cholinesterase inhibitors because of the unlikelihood that the endpoint will change with an increase in exposure time beyond that defined as a subchronic exposure. Additionally, limited data regarding reproductive and developmental toxicity ...

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Section: Development Of Tolerancementioning

confidence: 96%

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

Young

Opresko

Watson

et al. 1999

Human and Ecological Risk Assessment: An International Journal

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“…)-2-oxo-1,1-diphenylethoxy)-2-oxo-1,1-diphenylethyl 4-Aminobutanoate dihydrochloride (22). Compound 22 was obtained from 20 in quantitative yield using procedure 2.…”

Section: -(2-(2-(diethylamino)ethoxymentioning

confidence: 99%

Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote

Weitman

Eisenkraft

Tashma

et al. 2022

Sci Rep

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Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood–brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.

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“…In the great majority of the available literature on repeated low-dose exposure to CWNAs, soman is the OP studied most often. Repeated low-dose soman exposure has been investigated in mice (Sterri et al, 1981), rats (Sterri et al, 1980;Dulaney et al, 1985;Hymowitz et al, 1985;Kerenyi et al, 1990;Shih et al, 1990;Howerton et al, 1991), guinea pigs (Sterri et al, 1981(Sterri et al, , 1982, and primates (Gause et al, 1985;Blick et al, 1991Blick et al, , 1994. The effects of the repeated soman exposures, cited above, ranged from performance decrements on a well-learned compensatory tracking task (Blick et al, 1994) to development of attention deficits (Gause et al, 1985) to hyper-reactive responses to handling (Shih et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

The effects of repeated low-dose sarin exposure☆

Shih¹,

Hulet²,

McDonough³

2006

Toxicology and Applied Pharmacology

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Behavioral toxicity of anticholinesterases in primates: Effects of daily repeated soman exposure

Cited by 13 publications

References 21 publications

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote

The effects of repeated low-dose sarin exposure☆

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