Intravenous and Inhalation Toxicokinetics of Sarin Stereoisomers in Atropinized Guinea Pigs

Spruit, Helma; Langenberg, J.P.; Trap, Henk C.; Wiel, H.J. van der; Helmich, Rob B.; Helden, H.P.M. van; Benschop, H. P.

doi:10.1006/taap.2000.9060

Cited by 41 publications

(21 citation statements)

References 14 publications

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“…Specifically, the sensitivity of guinea pigs to OP compounds closely resembles that of humans. For example, the intravenous LD 50 of sarin in guinea pigs (24 mg/kg) is only 1.7-fold higher than that reported for humans (Spruit et al, 2000; http://www.iom.edu/~/media/Files/Report%20Files/ 2007/Long-Term-Health-Effects-of-Participation-in-Project-SHAD-Shipboard-Hazard-and-Defense/SARINNERVEAGENT. pdf).…”

Section: Animal Models Of Op Intoxicationmentioning

confidence: 89%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

100

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The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.

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Section: Animal Models Of Op Intoxicationmentioning

confidence: 89%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

100

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“…Relationship between AChE and the Symptomatology. Recently, analytical methods have been developed to determine sarin directly in plasma (D'Agostino et al, 1999(D'Agostino et al, , 2001Spruit et al, 2000Spruit et al, , 2001. However, these assays are neither sensitive nor robust enough to detect concentrations of free sarin in brain tissues.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A₁Receptor AgonistN⁶-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

Bueters¹,

Joosen²,

Helden³

et al. 2002

J Pharmacol Exp Ther

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The objective of the present study was to develop a kinetics of pharmacodynamics model to properly describe and investigate the in vivo interaction between the selective adenosine A 1 agonist N 6 -cyclopentyladenosine (CPA), acetylcholinesterase (AChE) in blood and brain, and the AChE-inhibitor sarin (isopropylmethylphosphonofluoridate). The direct interaction of CPA (2 M) on the inhibition of AChE by sarin was studied in vitro in heparinized rat blood and in 10% (w/v) brain homogenate. CPA did not directly influence the sarin-mediated inactivation of AChE in either system. In sarin-poisoned (144 g/kg s.c.) rats not treated with CPA, AChE was completely inactivated in blood and brain within 7 min. CPA (2 mg/kg i.m.) treatment, 1 min after sarin administration, caused a small delay in the inhibition of AChE in blood. Treatment with CPA, 2 min before sarin, protected the neuronal AChE partially from being inhibited, but not the enzyme localized in blood. With a dose-response-time model the proportion of the dose of sarin reaching the site of action was estimated to be 48 Ϯ 12 or 13 Ϯ 3% after CPA post-or pretreatment, respectively. A correlation between the residual AChE activity in the brain and the incidence of cholinergic symptoms could be established with logistic regression analysis: lower inhibition of AChE in the brain precluded the onset of critical symptoms. In conclusion, CPA affects the concentration of sarin reaching the site of action, which contributes to the protection previously observed in sarin-poisoned rats.

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“…In fact, only a dose corresponding with 0.8 LD50 (19.2 ug/kg) has been studied (Benschop and Van Helden, 1993;Spruit et at, 2000). When we proposed this study it was our intention to compare the toxicokinetics for 2 LD50 in HuBuChE-pretreated guinea pigs with those for 0.8 LD50 in non-pretreated animals, assuming a dramatic effect on the toxicokinetics of HuBuChE pretreatment.…”

Section: Analysis Of Blank Blood Samples Showed No Peaks With the Sammentioning

confidence: 99%

“…Studies in which guinea pigs were exposed nose-only for a long period of time (300 min) to a low level of C(±)P(±)-soman (20 ppb) were also included. Short term and long term nose-only exposure to C(±)P(±)-soman and (±)-sarin in guinea pigs are routinely performed in our laboratory (Benschop et al, 1995;Benschop et al, 1998;Langenberg et al, 1998;Spruit et al, 2000), whereas the same technique was applied to exposure to marmosets after small modification of the exposure chamber . Studies on the toxicokinetics of the stereoisomers of (±)-VX after a lethal i.v.…”

Section: Ad a Toxicokinetic Studiesmentioning

confidence: 99%

“…During the last decade, we have performed various studies on the toxicokinetics of the stereoisomers of nerve agents in rat, guinea pig and marmoset (Benschop and De Jong, 1991;Benschop et al, 1995Benschop et al, , 1998Due et al, 1993Due et al, , 1994Langenberg et al, 1998;Spruit et al, 2000;Van der Schans et al, 2000). For this purpose, we developed analytical procedures which allow the quantitation of nerve agent stereoisomers in blood and tissues at levels down to and below those of toxicologic relevance.…”

Section: Ad a Toxicokinetic Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Pretreatment With Human Butyrylcholinesterase Scavengers on the Toxicokinetics and Binding of Nerve Agents in Guinea Pigs and Marmosets

Schans¹,

Pleijsier²,

Wiel³

et al. 2002

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Intravenous and Inhalation Toxicokinetics of Sarin Stereoisomers in Atropinized Guinea Pigs

Cited by 41 publications

References 14 publications

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Adenosine A₁Receptor AgonistN⁶-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

Effect of Pretreatment With Human Butyrylcholinesterase Scavengers on the Toxicokinetics and Binding of Nerve Agents in Guinea Pigs and Marmosets

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Intravenous and Inhalation Toxicokinetics of Sarin Stereoisomers in Atropinized Guinea Pigs

Cited by 41 publications

References 14 publications

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Adenosine A1Receptor AgonistN6-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

Effect of Pretreatment With Human Butyrylcholinesterase Scavengers on the Toxicokinetics and Binding of Nerve Agents in Guinea Pigs and Marmosets

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Product

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Adenosine A₁Receptor AgonistN⁶-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin