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Research ArticlePerspectives in Pharmacology

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

Edna F. R. Pereira, Yasco Aracava, Louis J. DeTolla Jr., E. Jeffrey Beecham, G. William Basinger Jr., Edgar J. Wakayama and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 313-321; DOI: https://doi.org/10.1124/jpet.114.214932
Edna F. R. Pereira
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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Yasco Aracava
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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Louis J. DeTolla Jr.
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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E. Jeffrey Beecham
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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G. William Basinger Jr.
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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Edgar J. Wakayama
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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Edson X. Albuquerque
Division of Translational Toxicology, Department of Epidemiology and Public Health (E.F.R.P., Y.A., E.X.A.), and Program of Comparative Medicine and Departments of Pathology, Medicine, and Epidemiology and Public Health (L.J.D.), University of Maryland School of Medicine, Baltimore, Maryland; Countervail Corporation, Charlotte, North Carolina (E.J.B., G.W.B.); and Biomedical Advanced Research and Development Authority and Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Washington, DC (E.J.W.)
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Abstract

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.

Footnotes

    • Received March 25, 2014.
    • Accepted June 5, 2014.
  • This work was supported in part by funds from the National Institutes of Health National Institute of Neurological Disorders and Stroke CounterACT Program [Grant U01-NS059344]; and by federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under contract with Countervail Corp. [Contract HHSO100201100030C].

  • The opinions and assertions contained herein are the private views of the coauthors and do not represent the official position or policies of the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, the CounterACT program, the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, or the US Government.

  • dx.doi.org/10.1124/jpet.114.214932.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticlePerspectives in Pharmacology

Acute and Delayed Clinical Manifestations of OP Toxicity

Edna F. R. Pereira, Yasco Aracava, Louis J. DeTolla, E. Jeffrey Beecham, G. William Basinger, Edgar J. Wakayama and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 313-321; DOI: https://doi.org/10.1124/jpet.114.214932

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Research ArticlePerspectives in Pharmacology

Acute and Delayed Clinical Manifestations of OP Toxicity

Edna F. R. Pereira, Yasco Aracava, Louis J. DeTolla, E. Jeffrey Beecham, G. William Basinger, Edgar J. Wakayama and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 313-321; DOI: https://doi.org/10.1124/jpet.114.214932
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    • Clinical Manifestations of Human Exposure to OP Compounds: Acute and Long-Term Clinical Signs and Symptoms
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