Dose issues in antiepileptic therapy

Vajda, Frank J. E.

doi:10.1016/j.jocn.2012.05.003

Cited by 14 publications

(10 citation statements)

References 16 publications

(13 reference statements)

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“…Noncontrolled epileptic attacks during pregnancy produce high risk of injury to both mother and foetus [15]. However, VPA has been shown to cross the placenta and accumulate in the foetal circulation with higher concentration than that in the maternal blood, causing toxicity and teratogenicity [25].…”

Section: Introductionmentioning

confidence: 99%

Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

et al. 2018

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“…There are a few proposed mechanisms to explain the teratogenicity of VPA. Valproate can cross the placenta and accumulatesin high concentrationsin the embryonic circulation, increasing the risk of toxicity and teratogenity [10]. The transfer of VPA across the placenta is influenced by the transporter proteins of monocarboxylic acid [11].…”

Section: Theories Of Valproate Teratogenicitymentioning

confidence: 99%

Challenges of Valproate Treatment During Pregnancy: Pros and Cons

Arbune¹,

Craiu²,

Cuciureanu³

et al. 2020

Rev. Chim.

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Valproic acid and its salt, sodium valproate, are an effective treatment for epilepsy, the most common chronic neurologic disorder worldwide. Teratogenic associations reported after embryofetal exposure has limited the recommendations of valproate use in women of childbearing age, after careful evaluation of the benefits and risks of this medication. The mechanisms of valproate damage during pregnancy are complex and incompletely clarified up to date. Maternal and fetal impact of valproate is a critical issue, standing at the base of the new consensus on practical guidelines for clinical use of antiepileptic treatment in fertile women.

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“…by the US Federal Drug Administration) that all new drugs before being used in any patients should be tested in animals (usually rodents) for possible teratogenic effects. Such tests have shown that a well-established antiepileptic drug, valproate causes a significant number of congenital abnormalities in animals ( Jazayeri et al ., 2020 ) but also in humans; Tomson et al (2018) found that the risk for congenital malformation in children of mothers exposed to valproate was increased by 4–5-times especially at higher valproate doses, and particularly when used in the first trimester (see also Abou-Khalil, 2019 ; Vajda, 2012 ). The most common problems associated with gestational valproate use are cardiac malformations, hypospadias, renal defects, and neural tube defects, with higher doses increasing the risk of spina bifida ( Jentink et al ., 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain

et al. 2021

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Background: Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby’s development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods: Anaesthetised pregnant, non-pregnant adult females, postnatal and fetal rats were injected intraperitoneally with different doses, single or in combinations, of valproate and lamotrigine, all within clinical range. Injectate included 3H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivity was measured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period. Drug levels were measured by liquid chromatography coupled to mass spectrometry (LC-MS). Results are given as CSF or tissue/plasma% as index of drug entry. Results: Entry of valproate into brain and CSF was higher at E19 and P4 compared to adult but was not dose-dependent; placental transfer increased significantly at highest dose of 100mg/Kg. Lamotrigine entry into the brain was dose dependent only at E19. Chronic valproate treatment, or combination of valproate and lamotrigine had little effect on either drug entry, except for reduced valproate brain entry in adult brain with chronic treatment. Placental transfer decreased significantly after chronic valproate treatment. LC-MS measurement of valproate in adults confirmed that rat plasma values were within the clinical range and CSF/plasma and brain/plasma ratios for LC-MS and 3H-valproate were similar. Conclusion: Results suggest that entry of valproate may be higher in developing brain, the capacity of barrier mechanism is mostly unaffected by doses within the clinical range, with or without addition of lamotrigine. Chronic valproate exposure may result in upregulation in cellular mechanisms restricting its entry into the brain. Entry of lamotrigine was little different at different ages and was not dose dependent.

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Dose issues in antiepileptic therapy

Cited by 14 publications

References 16 publications

Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

Challenges of Valproate Treatment During Pregnancy: Pros and Cons

Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain

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