OBJECTIVE: To determine transplacental passage of topiramate and its transport to colostrum, mature maternal milk and breastfed infants, we examined data from 27 women treated with topiramate from 2004 to 2020. METHODS: In this cohort study, maternal serum, umbilical cord serum, milk and infant serum levels were measured by gas chromatography in the delivery subgroup, the colostrum subgroup (3-4 days postpartum) and the mature milk subgroup (7-30 days postpartum). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk levels were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum and infant/maternal serum levels. RESULTS: Topiramate levels varied from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum, and the mean umbilical cord/maternal serum ratio was 0.93 ± 0.11. At 3-4 days after delivery, topiramate concentrations were 1.4-8.4 mg/L in maternal serum, 1.5-8.6 mg/L in milk and 0.3-4.4 mg/L in infant serum. The mean milk/maternal serum ratio was 0.99 ± 0.45, and the mean infant/maternal serum ratio was 0.25 ± 0.15. At 7-30 days after delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. The mean milk/maternal serum ratio was 1.07 ± 0.31, and the mean infant/maternal serum ratio was 0.51 ± 0.27. CONCLUSIONS: We extended information about free transplacental passage of topiramate and its extensive transport to maternal milk with lower serum concentrations in breastfed infants in the largest group of patients ever reported to our knowledge. DATA AVAILABILITY STATEMENT: Authors declare that take full responsibility for the data, the analyses and interpretation, and the conduct of the research; that they have full access to all of the data; and that they have the right to publish all data. Authors were not participations in industry-sponsored research and corporate activities for evaluation of a manuscript.
- MeSH
- antikonvulziva aplikace a dávkování analýza metabolismus MeSH
- dospělí MeSH
- kohortové studie MeSH
- kojení MeSH
- laktace účinky léků metabolismus MeSH
- lidé MeSH
- mateřské mléko účinky léků metabolismus MeSH
- mladý dospělý MeSH
- monitorování léčiv metody MeSH
- novorozenec MeSH
- topiramat aplikace a dávkování analýza metabolismus MeSH
- vedení porodu metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: To receive information about carbamazepine and its active metabolite 10,11-epoxide transport into mature milk and suckling infants. METHODS: In this cohort study, maternal serum, mature milk, and infant serum carbamazepine and epoxide levels were measured between the 6th and 29th postnatal day (carbamazepine in 1990-2017, epoxide in 1997-2017). Paired maternal serum, infant serum and milk levels were used for the assessment of ratios of this levels. The influence of combined treatment with enzyme-inducing antiepileptic drugs and valproic acid was assessed. Relationship between maternal serum, infant serum, and milk levels was also evaluated. RESULTS: Maternal carbamazepine levels were 1.4-10.4 mg/L, milk 0.5-6.7 mg/L and infant 0.5-2.6 mg/L. Maternal 10,11-epoxide levels were 0.3-5.4 mg/L, milk 0.3-3.7 mg/L and infant 0.3-0.6 mg/L. Highly significant correlations were observed exclusively between milk and maternal serum levels of both carbamazepine and 10,11-epoxide. Concomitant administration of enzyme-inducing antiepileptic drugs significantly increased the maternal apparent oral clearance of carbamazepine by approximately 130%. Carbamazepine combined with valproic acid significantly increased epoxide levels in milk and maternal serum but not in breastfed infants. CONCLUSIONS: In breastfed infants, carbamazepine levels did not reach the lower limit of the therapeutic range used for the general epileptic population, and the majority of epoxide levels were less than the lower limit of quantification. Routine monitoring of carbamazepine in these infants is not compulsory. However, observation of breastfed infants is desirable. If signs of potential adverse reactions are evident, infant serum concentrations should be monitor.
- MeSH
- antikonvulziva metabolismus farmakokinetika MeSH
- biotransformace MeSH
- dospělí MeSH
- enzymová indukce účinky léků MeSH
- epoxidové sloučeniny metabolismus MeSH
- karbamazepin metabolismus farmakokinetika MeSH
- kohortové studie MeSH
- kojení MeSH
- kyselina valproová farmakokinetika MeSH
- lékové interakce MeSH
- lidé MeSH
- mateřské mléko chemie metabolismus MeSH
- mladý dospělý MeSH
- monitorování léčiv MeSH
- novorozenec MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Lamotrigine has become the most frequently prescribed drug in the treatment of pregnant women with epilepsy. Although some relevant studies have found a wide milk/maternal serum as well as infant/maternal serum concentration ratio, different infant ages at the time of sampling and small number of patients preclude comparison. The aim of this study was to provide a consistent evaluation. METHODS: Data of 43 nursing women treated by lamotrigine were evaluated retrospectively. The authors followed the transport of lamotrigine during the first postnatal month from mothers to breastfed infants through maternal milk between the years 2002 and 2017. RESULTS: Lamotrigine concentrations varied from 1.1 to 14.9 mg/L in the maternal serum, from <0.66 to 9.1 mg/L in the milk and between <0.66 and 6.9 mg/L in the infant serum. The milk/maternal serum concentration ratio ranged from <0.18 to 0.74 and the infant/maternal serum concentration ratio measured between <0.15 and 0.74. Highly significant correlations were found between milk and maternal serum levels and between infant serum levels and milk, maternal serum levels, lamotrigine daily dose, and also maternal dose related to the body weight. CONCLUSIONS: The authors confirmed the wide range of the milk/maternal serum concentration ratio and the infant/maternal serum concentration ratio. Although the degree of lamotrigine exposure to the breastfed infants was smaller than during gestation, 16% of the infant serum levels measured were within the therapeutic range used for the general epileptic population. Lamotrigine concentration monitoring in breastfed infant, in our opinion, is the most relevant aspect for the analysis of actual lamotrigine exposure in infants, especially in those with clinical symptoms.
- MeSH
- antikonvulziva krev metabolismus terapeutické užití MeSH
- epilepsie krev farmakoterapie metabolismus MeSH
- kojení metody MeSH
- lamotrigin krev metabolismus terapeutické užití MeSH
- lidé MeSH
- mateřské mléko metabolismus MeSH
- matky MeSH
- novorozenec MeSH
- retrospektivní studie MeSH
- sérum chemie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Valproic acid (VPA) is currently one of the four most often prescribed antiepileptic drugs (AEDs) in pregnancy. However, only a small number of studies have measured suckling infant serum levels of the drug. We studied the transport of VPA from breastfeeding mothers to the mature milk and breastfed infants and the influence of comedication with enzyme-inducing AEDs. The data of 30 nursing women treated by VPA were analyzed retrospectively. Mature milk, maternal, and infant serum levels were collected between the 6th and 32nd postnatal day and measured by gas chromatography during the years 1996-2017. Valproic acid levels varied from 5.4 to 69.0 mg/L (mean: 39.0 ± 16.1 mg/L) in the maternal serum, from <1.0 to 16.7 mg/L (mean: 1.6 ± 3.9 mg/L) in the milk, and from <1.0 to 17.5 mg/L (mean: 4.2 ± 4.3 mg/L) in the infant serum. The milk/maternal serum level ratio ranged from <0.03 to 0.25 (mean: 0.03 ± 0.06) and the infant/maternal serum level ratio from <0.03 to 0.61 (mean: 0.11 ± 0.13). Sixty-seven percent of milk and 33% of infant VPA concentrations were below the limit of quantification. No correlations were observed between maternal serum and milk levels or between maternal and infant serum levels. In conclusion, none of the milk or infant serum VPA levels reached the lower limit of the reference range used for the general population with epilepsy, so the degree of VPA exposure in breastfed infants is less than during gestation. Nevertheless, if signs of potential adverse reactions manifest, infant serum concentrations should be measured.
- MeSH
- antikonvulziva krev metabolismus MeSH
- dospělí MeSH
- epilepsie farmakoterapie MeSH
- kojenec MeSH
- kojení * MeSH
- kombinovaná farmakoterapie MeSH
- komplikace těhotenství farmakoterapie MeSH
- kyselina valproová krev metabolismus MeSH
- lidé MeSH
- mateřské mléko účinky léků MeSH
- matky MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- retrospektivní studie MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels. MATERIALS AND METHODS: Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 - 2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios. RESULTS: The levels varied from 5.3 - 59.5 mg/L in maternal and 5.4 - 72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 - 2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy. CONCLUSIONS: There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects.
- MeSH
- antikonvulziva metabolismus terapeutické užití MeSH
- biologické markery metabolismus MeSH
- epilepsie krev farmakoterapie MeSH
- fetální krev metabolismus MeSH
- komplikace těhotenství krev farmakoterapie MeSH
- kyselina valproová metabolismus terapeutické užití MeSH
- lidé MeSH
- novorozenec MeSH
- retrospektivní studie MeSH
- těhotenství MeSH
- tělesná hmotnost fyziologie MeSH
- tělesná výška fyziologie MeSH
- vedení porodu MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The anticonvulsant drug carbamazepine is considered as an indicator of sewage water pollution: however, its uptake by plants and effect on metabolism have not been sufficiently documented, let alone its metabolite (10,11-epoxycarbamazepine). In a model system of sterile, hydroponically cultivated Zea mays (as C4 plant) and Helianthus annuus (as C3 plant), the uptake and effect of carbamazepine and 10,11-epoxycarbamazepine were studied in comparison with those of acetaminophen and ibuprofen. Ibuprofen and acetaminophen were effectively extracted from drug-supplemented media by both plants, while the uptake of more hydrophobic carbamazepine was much lower. On the other hand, the carbamazepine metabolite, 10,11-epoxycarbamazepine, was, unlike sunflower, willingly taken up by maize plants (after 96 h 88 % of the initial concentration) and effectively stored in maize tissues. In addition, the effect of the studied pharmaceuticals on the plant metabolism (enzymes of Hatch-Slack cycle, peroxidases) was followed. The activity of bound peroxidases, which could cause xylem vessel lignification and reduction of xenobiotic uptake, was at the level of control plants in maize leaves contrary to sunflower. Therefore, our results indicate that maize has the potential to remove 10,11-epoxycarbamazepine from contaminated soils.
- MeSH
- antikonvulziva analýza metabolismus MeSH
- biodegradace MeSH
- Helianthus účinky léků růst a vývoj metabolismus MeSH
- hydroponie MeSH
- karbamazepin analogy a deriváty analýza metabolismus MeSH
- kukuřice setá účinky léků růst a vývoj metabolismus MeSH
- látky znečišťující půdu analýza metabolismus MeSH
- listy rostlin účinky léků růst a vývoj metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Oxcarbazepine, a second generation antiepileptic drug belonging to the family of dibenz[b,f]azepines, is subjected to a rapid and extensive biotransformation. Oxcarbazepine demonstrates a low potential for drug interactions because its biotransformation is mainly mediated by the reduction pathway instead of oxidative pathways, which are very susceptible to drug interactions. The reductive metabolism of oxcarbazepine yields a 10-monohydroxy derivative (10,11-dihydro-10-hydroxy-carbazepine), which is responsible for the pharmacological activity. The identity and localization of enzymes participating in the reduction of oxcarbazepine in response to this active metabolite have remained unknown until now. Thus, we investigated the reductive metabolism of oxcarbazepine in human liver subcellular fractions and using recombinant carbonyl reducing enzymes. The reduction of oxcarbazepine was shown to occur largely in the liver cytosol rather than liver microsomes. Furthermore, the activity and stereospecificity of cytosolic carbonyl reducing enzymes toward oxcarbazepine were assessed. Of the eight tested enzymes, six reductases were identified to contribute to the reduction of oxcarbazepine. The highest activities were demonstrated by AKR1C1, AKR1C2, AKR1C3, and AKR1C4. The contribution of CBR1 and CBR3 to the reduction of oxcarbazepine was also significant, although their role in oxcarbazepine metabolism in vivo is unclear.
- MeSH
- alkoholoxidoreduktasy metabolismus MeSH
- antikonvulziva metabolismus MeSH
- cytosol enzymologie MeSH
- jaterní mikrozomy metabolismus MeSH
- játra enzymologie MeSH
- karbamazepin analogy a deriváty metabolismus MeSH
- lidé MeSH
- oxidace-redukce MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Spotřeba alkoholu v České republice je vysoká a představuje závažný medicínský problém. Je prokázána souvislost mezi užíváním alkoholu a výskytem epileptických záchvatů. Výskyt epileptických záchvatů je u alkoholiků 3 × vyšší než u zbytku populace. Riziko vzniku epileptických záchvatů u alkoholiků vzrůstá s dávkou užívaného alkoholu. Chronické užívání alkoholu vede k poruše regulace NMDA receptorů (zvýšená regulace) a GABA-A receptorů (snížená regulace). K poruše rovnováhy dojde při náhlém vysazení alkoholu se vznikem epileptických záchvatů známých pod pojmem “withdrawal seizures”. Alkoholová epilepsie je epileptický syndrom se třemi vývojovými stadii (Bartolomei, 2006). Pro první stadium jsou charakteristické záchvaty při náhlém vysazení alkoholu tzv. “withdraval seizures”, v druhém stadiu se vyskytují záchvaty nejenom při abstinenci, ale i mimo abstinenci. Ve třetím stadiu se vyskytují záchvaty, i když pacient plně a dlouhodobě abstinuje. V prvním stadiu není chronická léčba antiepileptiky indikována, ve stadiu druhém a třetím indikována je. Pacienti ve druhém a třetím stadiu onemocnění mají snížený záchvatový práh a jsou ohroženi vznikem opakovaných epileptických záchvatů. Chroničtí alkoholici mohou mít i jinou etiologii epilepsie, která s konzumací alkoholu nesouvisí (CMP, trauma, IGE). Tito nemocní jsou k chronické léčbě antiepileptiky indikováni. Chronický abúzus alkoholu snižuje sérovou hladinu některých antiepileptik (zejm. induktorů jaterních enzymů). U pacientů, kteří chronicky užívají alkohol a jsou léčeni antiepileptickou medikací, je třeba sledovat sérové hladiny u některých antiepileptik.
Alcohol consumption is very high in the Czech Republic and this gives rise to a considerable public health problem. The link between epilepsy and alcohol consumption is definite. Epileptic seizures are three times more frequent in abusers and increase with the amount per day of alcohol consumed. Both intoxication and withdrawal are recorded as the risk factors, but the withdrawal seizures attracts the most of attention. Long-term alcohol abuse impairs regulation of the NMDA and GABA-A receptors. The sudden deficit of alcohol results in alcohol withdrawal seizures. A manifestation of alcoholic epilepsy varies with respect to length of abuse. There are seizures related to withdrawal period at the first stage, seizures appearance in both withdrawal phase and consumption phase at the second stage and finally irreversible third stage of alcoholic epilepsy (Bartolomei, 2006). Epilepsy suffered by alcohol abusers can also have the same kinds of etiology as it has in general population (e.g.post-traumatic, post-stroke etc.) The chronic alcohol abuse influences also the metabolism of an AED that reduces level of the AED within the blood plasma. The repeatedly abstaining abusers (may be for the treatment of abuse) should be observed carefully. Recent studies conclude the antiepileptic treatment of alcohol abusers is necessary. However, the epilepsy and alcohol abuse treatment should be linked together.
- Klíčová slova
- alkoholová epilepsie,
- MeSH
- alkoholismus * komplikace metabolismus MeSH
- antikonvulziva krev metabolismus terapeutické užití MeSH
- epilepsie * farmakoterapie chemicky indukované komplikace MeSH
- ethanol metabolismus škodlivé účinky MeSH
- interakce mezi potravou a léky MeSH
- lidé MeSH
- pití alkoholu škodlivé účinky MeSH
- záchvaty při náhlém vysazení alkoholu farmakoterapie komplikace MeSH
- záchvaty farmakoterapie chemicky indukované komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
