Pathophysiology of Soman intoxication in primates

Anzueto, Antonio; Berdine, Gilbert; Moore, Gary T.; Gleiser, Chester A.; Johnson, Donald E.; White, Curtis D.; Johanson, W. G.

doi:10.1016/0041-008x(86)90399-6

Cited by 43 publications

(17 citation statements)

References 36 publications

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“…Excess acetylcholine initiates rapid progression of miosis, hypersecretions, muscular fasciculation, tremors, seizures, convulsions, and death in laboratory rodents, NHPs, and man (Sidell 1997;Tryphonas and Clement 1996;Baze 1993). The rate of soman intoxication and observed clinical signs in African green monkeys were consistent with descriptions in the literature for the rhesus monkey, cynomolgus monkey, and baboon (Adams et al 1976;Adams 1990;Anzueto et al 1986). As Lipp (1968) had indicated, electrographic tonic-clonic seizures and motor convulsions were prominent aspects of the toxic symptomatology of soman intoxication in all animals at the doses studied, although it must be emphasized that only one animal was exposed at the lowest dose.…”

Section: Discussionsupporting

confidence: 76%

The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops)

Despain

McDonough

McMonagle

et al. 2007

Toxicology Mechanisms and Methods

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This study determines soman toxicity in African green monkeys (Chlorocebus aethiops) and is the first step in exploring the suitability of this species as a model for nerve agent studies. Male African green monkeys were surgically implanted with telemetry devices to monitor electroencephalographic (EEG) and electrocardiographic (ECG) activity. Blood was taken at various times to measure whole blood acetylcholinesterase (AChE) activity and cardiac troponin I (cTnI). Blood AChE activity relative to baseline was 0.0% to 2.5% 6 h after soman exposure and recovered to 31.9% to 72.0% by 30 days after exposure. The 6 h postexposure cTnI levels varied from 0.64 to 6.55 ng/mL, suggesting cardiac damage. Soman was prepared in saline to a concentration of 100 mug/mL. Using an up-down design for small samples, subjects were exposed to 5.01, 6.31, or 7.94 mug/kg soman IM. The first subject was given 5.01 mug/kg soman IM and survived. Three subjects received 6.31 mug/kg soman IM and survived. Three subjects received 7.94 mug/kg soman IM and died within 25 min, 26 min, or 6 h. In all subjects, toxic signs of muscle fasciculation, tremors, chewing, and profuse salivation developed within 2 to 7 min. Tonic-clonic motor convulsions and EEG seizure began between 2 and 18 min after tremor onset. The 48 h IM LD50 of soman in saline in the African green monkey was calculated to be 7.15 mug/kg. The signs and speed of soman intoxication in African green monkeys were consistent with those described in rhesus, cynomolguscynomolgus, and baboons.

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Section: Discussionsupporting

confidence: 76%

The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops)

Despain

McDonough

McMonagle

et al. 2007

Toxicology Mechanisms and Methods

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“…The clinical literature emphasizes the peripheral effects contributing to acute pulmonary insufficiency [11,13]. However this does not exclude early mortality in the field due to central apnea [14,15].In this study we used a rodent model to analyze the dynamics of respiratory and cardiovascular collapse during acute OP poisoning. We found that poisoning caused a rapidly lethal central apnea.…”

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confidence: 99%

Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model

Gaspari

Paydarfar

2007

NeuroToxicology

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INTRODUCTIONOrganophosphate (OP) poisoning produces a cholinergic crisis by blockade of acetylcholinesterase in the central and peripheral nervous systems. Acute effects of poisoning include central apnea [1][2][3][4], seizures [5,6], bronchorrhea, bronchoconstriction, muscle weakness, myosis, urination, and salivation [7][8][9][10]. The morbidity and mortality from acute OP poisoning is attributed to respiratory failure [11] but the relative contributions of the central and peripheral effects in producing collapse of the respiratory system [12] is unclear. The clinical literature emphasizes the peripheral effects contributing to acute pulmonary insufficiency [11,13]. However this does not exclude early mortality in the field due to central apnea [14,15].In this study we used a rodent model to analyze the dynamics of respiratory and cardiovascular collapse during acute OP poisoning. We found that poisoning caused a rapidly lethal central apnea. Central apnea consistently occurred soon after the poisoning but pulmonary insufficiency was more variable in both timing and severity. Mortality was reduced in animals that were sustained solely by artificial ventilation; however most ventilated animals exhibited signs of impaired gas exchange due to pulmonary insufficiency. Our findings support the hypothesis that OP poisoning in this animal model causes a sequential "two hit" insult, with rapid central apnea followed by delayed impairment of pulmonary gas exchange with prominent airway secretions. MATERIALS AND METHODSWe studied 27 male Wistar rats, weighing 275-325 gm (Charles River Laboratories, Wilmington, MA). The University of Massachusetts Medical School Institutional Animal Care and Utilization Committee approved all experimental procedures and protocols. The animal model used in this study is a novel preparation for OP research and the procedures are described in detail below.Corresponding Author: Romolo J Gaspari, MD, MSc, Assistant Professor, Department of Emergency Medicine, University of Massachusetts School of Medicine, 55 Lake Ave North, Worcester, MA 01655, Phone -508-334-7943, Fax -508-421-1490, Gasparir@UMMHC.org, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Surgical ProceduresSurgical procedures were performed under general anesthesia with 1.5 -2.2% isoflurane (Abbott Labs, North Chicago, IL) titrated to achieve a respiratory rate of 50-60 breaths per minute. All surgical procedures were performed under 100% oxygen. The animals were restrained in a supine position with the head extended and limbs abducted. Adequacy of anesthesia was confir...

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“…Convulsions are usually associated with blood lactic acidosis during seizures in man (Osnes and Hermansen, 1972) and in animals exposed to OP (e.g. rats, (Husain et al, 1987) or baboons (Anzueto et al, 1986)). The strong increase in blood lactate we observed in our paradigm is congruent with these reports.…”

Section: Discussionmentioning

confidence: 99%