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Abstract
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,within clinical range. Injectate included 3H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivitymeasured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period.Drug levelsmeasured by liquid chromatography coupled to mass spectrometry (LC-MS). Resultsgiven 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 and was dose-dependent except at E19; 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.
Highlights
Epilepsy is a neurological disorder characterised by seizures of varying types and severity ranging from absence, in which the patient becomes unresponsive to stimuli, to tonic–clonic or atonic seizures, where the individual suffers a loss of motor control (Thijs et al, 2019)
Estimation of residual vascular space The ratio of 3H-dextran in cortex and brainstem compared with plasma, Dose dependent drug entry “For a dose of 30 mg/kg and 100 mg/kg there was no difference in entry into cerebrospinal fluid (CSF) at any of the three ages studied; in cortex and brainstem the entry of valproate was higher at P4 with the larger clinical dose, but not at the other ages (Figure 3).”
Much is known about adverse effects of antiepileptic drugs, in terms of the occurrence of congenital malformations when these drugs are taken early in pregnancy; less is known about the longer-term effects on brain development and behaviour in the offspring
Summary
Epilepsy is a neurological disorder characterised by seizures of varying types and severity ranging from absence, in which the patient becomes unresponsive to stimuli, to tonic–clonic or atonic seizures, where the individual suffers a loss of motor control (Thijs et al, 2019). There is a general requirement (e.g. 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) and 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 when used in the first trimester (see Abou-Khalil, 2019; Vajda, 2012). The starting point for such studies, as described here, is to determine the extent of age-related entry into the brain and CSF of valproate and lamotrigine used as mono- or combination therapies at doses which are within the clinical range. Conclusion: Results suggest that entry of valproate may be higher in version 2 (revision)
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