API

Aop: 94

AOP Title

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Sodium channel inhibition leading to congenital malformations

Short name:

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sodium channel inhibition 3

Authors

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Kellie Fay

Point of Contact

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Kellie Fay

Contributors

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  • Kellie Fay

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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Revision dates for related pages

Page Revision Date/Time
Inhibition, sodium channel September 16, 2017 10:15
Increased, Atrioventricular block and bradycardia September 16, 2017 10:14
Increased, Respiratory distress/arrest September 16, 2017 10:14
N/A, hypoxia December 03, 2016 16:37
Increased, amputations December 03, 2016 16:37
Decreased, Sodium conductance 1 September 16, 2017 10:15
Increased, Atrioventricular block and bradycardia leads to Increased, Respiratory distress/arrest December 03, 2016 16:37
Increased, Respiratory distress/arrest leads to N/A, hypoxia December 03, 2016 16:37
N/A, hypoxia leads to Increased, amputations December 03, 2016 16:37
Inhibition, sodium channel leads to Decreased, Sodium conductance 1 December 03, 2016 16:37
Decreased, Sodium conductance 1 leads to Increased, Atrioventricular block and bradycardia December 03, 2016 16:37

Abstract

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Anti-epileptic and anti-arrhythmic drugs which block voltage-gated ion channels (e.g., voltage-gated sodium channels) are associated with major congenital malformations including amputations.



Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Inhibition, sodium channel Inhibition, sodium channel

Key Events

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Title Short name
Increased, Atrioventricular block and bradycardia Increased, Atrioventricular block and bradycardia
Increased, Respiratory distress/arrest Increased, Respiratory distress/arrest
N/A, hypoxia N/A, hypoxia
Decreased, Sodium conductance 1 Decreased, Sodium conductance 1

Adverse Outcome

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Title Short name
Increased, amputations Increased, amputations

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Foetal Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
Human, rat, mouse Human, rat, mouse NCBI

Sex Applicability

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Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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Domain of Applicability

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Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Mammals exposed in utero to sodium channel blockers (or similar) have significantly higher rates of cardiovascular anomalies and amputations (shortened limbs, missing digits, etc). Hypoxic conditions generated from poor heart function during development result in hemorrhages in distal parts of the embryo/fetus (Danielsson et al., 2003; Webster et al., 1996; Webster 2007). Similar amputations may not be relevant for species which develop in an egg and receive their oxygen supply via diffusion from the surrounding environment (air or water).


Essentiality of the Key Events

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Molecular Initiating Event Summary, Key Event Summary
Rat whole embryo cultures exposed to sodium channel blockers (experimental drugs AZA and AZB)for 1 hr had severly reduced heart rates (bradycardia) but returned to normal within 1 hr of drug washout (Nilsson et al., 2013).


Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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Danielsson, B.R., Skold, A., and Azarbayjani, F. 2001. Class III Antiarrhythmics and Phenytoin: Teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Current Pharmaceutical Design 7:787-802.

Webster, W., Brown-Woodman, P., Snow, M., and Danielsson, B. 1996. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 53:168-175.

Webster, W.S. and Abela, D. 2007. The effect of hypoxia in development. Birth Defects Research Part C: Embryo Today: Reviews 81:215-228.