Inhibition of Atropine Metabolism by Organophosphate Pesticides

Meer, M. J. Van Der; Hundt, H. K. L.; Müller, F. O.

doi:10.1177/096032718300200409

Cited by 12 publications

(5 citation statements)

References 2 publications

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“…The pharmacokinetics of the drug may change when administered intramuscularly or after exposure to an organophosphate. For example, one study found that atropine metabolism was inhibited in people who had ingested organophosphate pesticides (Van der Meer et al, 1983). Furthermore, we only administered midazolam, ATS and 2-PAM once while SAR was administered several times so it is unlikely that these MCMs influenced the metabolism of SAR at later doses.…”

Section: Discussionmentioning

confidence: 99%

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Gage

Putra

Gomez-Estrada

et al. 2021

Front. Cell. Neurosci.

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Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of status epilepticus (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.

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Section: Discussionmentioning

confidence: 99%

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Gage

Putra

Gomez-Estrada

et al. 2021

Front. Cell. Neurosci.

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“…In humans, Van der Meer et al (147) reported complete inhibition of atropine metabolism in OP-poisoned patients and that this was owed to the inhibition of hepatic microsomal enzymes.…”

Section: Possible Effect Of Ops On Hepatic Biotransformationmentioning

confidence: 99%

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Karami‐Mohajeri

Ahmadipour

Rahimi

et al. 2017

Archives of Industrial Hygiene and Toxicology

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Organophosphorus pesticides (OPs) are widely used volatile pesticides that have harmful effects on the liver in acute and chronic exposures. This review article summarises and discusses a wide collection of studies published over the last 40 years reporting on the effects of OPs on the liver, in an attempt to propose general mechanisms of OP hepatotoxicity and possible treatment. Several key biological processes have been reported as involved in OP-induced hepatotoxicity such as disturbances in the antioxidant defence system, oxidative stress, apoptosis, and mitochondrial and microsomal metabolism. Most studies show that antioxidants can attenuate oxidative stress and the consequent changes in liver function. However, few studies have examined the relationship between OP structures and the severity and mechanism of their action. We hope that future in vitro, in vivo, and clinical trials will answer the remaining questions about the mechanisms of OP hepatotoxicity and its management.

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“…In contrast, in the urine of a healthy volunteer five metabolic products were detected: atropine, noratropine, equatorial N-oxide, tropic acid and tropine. Thus, the organophosphate pesticides appear to inhibit the microsomal mono-oxygenase enzymes associated with the metabolism of atropine (56).…”

Section: Metabolism and Excretionmentioning

confidence: 99%

Pharmacokinetic implications for the clinical use of atropine, scopolamine and glycopyrrolate

Kanto

Klotz

1988

Acta Anaesthesiol Scand

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Several specific and sensitive new methods for determining atropine and its metabolites in biological fluids have increased the possibility to characterise the pharmacokinetic properties of this antimuscarinic agent. Following i.v. injection, atropine disappears very quickly from the circulation, resembling its fast onset of action. Age, but not sex, appears to have a clear effect on its kinetics, explaining at least partly the higher sensitivity of very young and very old patients to this anticholinergic agent. Following i.m. or oral atropine administration, typical anticholinergic effects coincide quite well with the absorption rate of the drug, indicating that the premedication should be given about 1 and 2 h before induction of anaesthesia. A sufficient absorption after rectal administration offers an alternative treatment, especially in children. Differing from its placental transfer, atropine has a delayed and incomplete lumbar cerebrospinal fluid penetration, indicating a fundamental difference between these two biological membranes. Oropharyngeally administered atropine has a very variable absorption, but inhaled or intratracheally given drug has produced interesting new results, e.g. pulmonary atropine administration appears to have clinical significance in special situations, such as cardiac arrest and organophosphate poisoning (military personnel). Depending on the method used, different data on the metabolism and excretion for atropine have been reported and therefore further studies are needed in this respect. The pharmacokinetics of scopolamine and glycopyrrolate and their relation to clinical response are poorly understood.

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Inhibition of Atropine Metabolism by Organophosphate Pesticides

Cited by 12 publications

References 2 publications

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Pharmacokinetic implications for the clinical use of atropine, scopolamine and glycopyrrolate

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