Teratogenicity of Antiepileptic Drugs: Analysis of Possible Risk Factors

Kaneko, Sunao; Otani, Koichi; Fukushima, Yutaka; Ogawa, Yoshihiro; Nomura, Y; Ono, Takamasa; Nakane, Yoshibumi; Teranishi, Takashi; Goto, Masashi

doi:10.1111/j.1528-1157.1988.tb03746.x

Cited by 170 publications

(67 citation statements)

References 19 publications

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“…The developing central nervous system (CNS) in the neonatal period has been found to be more vulnerable to the neurotoxic effects of phenytoin because of the higher brain concentration of phenytoin (Kaneko et al, 1988). Prenatal exposure to phenytoin may result in a spectrum of structural, developmental and behavioural changes known as fetal hydantoin syndrome (Nanda et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters

Imosemi

Osinubi

2011

Int. J. Morphol.

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. Phenytoin-induced toxicity in the postnatal developing cerebellum of Wistar rats, effect of Calotropis procera on histomorphometric parameters. Int. J. Morphol., 29(2):331-338, 2011. SUMMARY:The role of methanolic leaf extracts of Calotropis procera in phenytoin-induced toxicity on histomorphometric variables in the postnatal developing cerebellum of Wistar rat was studied. Pregnant rats were treated orally with 50 mg/kg phenytoin in pre and post natal life and 300 mg/kg methanolic leaf extract of Calotropis procera 1 hour prior to phenytoin administration. 200 mg/kg vitamin C (standard antioxidant) was also administered orally 1 hour prior to phenytoin treatment. The control animals received water. Standard diet of rat pellets and water were provided ad libitum. At the end of the experiment, the offspring of days 1, 7, 14, 21, 28 and 50 post partum, five per group were sacrificed by cervical dislocation. The cerebellum of all groups were dissected out and processed for histomorphometric studies. The results showed in the developing cerebellum of phenytoin treated animals, a delayed cell maturation in the external granular layer, reduction of the molecular layer, astrocytic gliosis and loss of Purkinje cells on day 50 postpartum. Administration of extracts of Calotropis procera and vitamin C though reversed these changes when compared with the phenytoin treated group, but not significantly when compared with the control. In conclusion, supplementation with methanolic extracts of Calotropis procera reduced the rate at which phenytoin induced toxicity in the postnatal developing cerebellum of Wistar rat.

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Section: Introductionmentioning

confidence: 99%

Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters

Imosemi

Osinubi

2011

Int. J. Morphol.

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“…Teratogenic effects resulting from AED treatment occur in 5-6% of infants born to women with epilepsy, which is almost double the rate of the general population (46). Certain AED combinations are associated with enhanced risk (e.g., VPA), and an enzyme-inducing AED (e.g., PB, PHT, and CBZ) enhances the risk of malformations and hepatotoxicity and therefore alternative AEDs should perhaps be considered (47)(48)(49). Furthermore, there is evidence to suggest, from a study of a relatively small number of patients receiving polytherapy, that the incidence of malformations increases with increasing number of AEDs; exposure to two, three, or four AEDs is associated with an incidence rate of malformations of 5.5, 11, and 23%, respectively (50).…”

Section: Pregnancymentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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“…[1][2][3] The risks have been reported as 3.1% to 9.0% for major congenital malformations (MCMs), 37% for one minor abnormality (MA), and 11% for 2 MAs in offspring with in utero exposure to AEDs. 2,4 Several studies found that AED polytherapy poses a higher risk of malformation (8.6%) than that of AED monotherapy (4.5%). [4][5][6] The risk of MCMs increases to 4% to 9% after in utero exposure to the first-generation AEDs.…”

mentioning

confidence: 99%

“…2,4 Several studies found that AED polytherapy poses a higher risk of malformation (8.6%) than that of AED monotherapy (4.5%). [4][5][6] The risk of MCMs increases to 4% to 9% after in utero exposure to the first-generation AEDs. 5,7 The percentage of MCMs was reported as 6.5% for phenobarbital, 8 3.7% for phenytoin, 9 and 2.2% for carbamazepine.…”

mentioning

confidence: 99%

Antiepileptic drug use by pregnant women enrolled in Florida Medicaid

2015

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Objective: The study aims were to investigate secular trends in antiepileptic drug (AED) use in women during pregnancy, and to compare the use of first-and second-generation AEDs.Methods: Study participants consisted of female Florida Medicaid beneficiaries, older than 15 years, and pregnant within the time period 1999 to 2009. Fifteen AEDs were categorized into first and second generation of AEDs. Continuous use of AEDs was defined as at least 2 consecutive AED prescriptions totaling more than a 30-day supply. Polytherapy was defined as 2 or more AEDs continuously used for at least 30 overlapping days. Annual prevalence was estimated and compared.

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Teratogenicity of Antiepileptic Drugs: Analysis of Possible Risk Factors

Cited by 170 publications

References 19 publications

Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters

Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters

The Importance of Drug Interactions in Epilepsy Therapy

Antiepileptic drug use by pregnant women enrolled in Florida Medicaid

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