Conclusions: CETA may be a more sensitive system than the bi-directional transport assay to detect transport of drugs with high passive diffusion across the BBB. We conclude that PHT, PB, OXC, ESL, CBZ-E, S-LC, and LCM, but not ESM, CBZ, RPM, ZNS, and PGB, are transported by human Pgp. These data suggest that resistance to PHT, PB, ESL, OXC and LCM might be attributed to increased efflux function of Pgp because they or their active metabolites are Pgp substrates. The CTC haplotype exhibited increased directional transport activity by Pgp. The effects of MDR1 polymorphisms on AED transport may provide a molecular explanation of the association between the polymorphisms and pharmacoresistance. This knowledge may help guide the design of genetic-based individualized therapy of epilepsy. / Methods: Stable transfected clones of human MDR1 haplotypes combining 1236C>T, 2677G>T/A, and 3435C>T in LLC-PK1 cells were established and validated. The expression level and localization of Pgp were measured. Bi-directional transport assays or concentration equilibrium transport assays (CETA) were performed by using MDR1-transfected and non-transfected cells to determine the substrate status of the following AEDs: phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), carbamazepine (CBZ), eslicarbazepine acetate (ESL), oxcarbazepine (OXC), (S)-licarbazepine (S-LC), carbamazepine-10,11-epoxide (CBZ-E), rufinamide (RFM), lacosamide (LCM), zonisamide (ZNS), and pregabalin (PGB). LLC-PK1 cells transfected with MDR1 variants were used to evaluate the effects of MDR1 polymorphisms on transport activity of AEDs in CETA. / Purpose: Epilepsy is a major neurological disorder, affecting more than 50 million people worldwide. Antiepileptic drugs (AEDs) do not effectively treat 30--40% of patients. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. Single nucleotide polymorphisms (SNPs) 1236C>T, 2677G>T and 3435C>T have been associated with drug-resistant epilepsy and were sometimes found to have effects on Pgp activities. But whether (or which) AEDs are transported by Pgp remains unclear, and there is no direct evidence showing that polymorphisms affect the transport of AEDs by Pgp. Therefore, we propose to use monolayers of cells transfected with the MDR1 variants to investigate 1) which AEDs are substrates for Pgp; and 2) the effect of MDR1 polymorphisms (1236C>T, 2677G>T, and 3435C>T) on AED transport. / Results: In CETA, PHT, PB, and LCM were transported by MDR1-transfected cells from basolateral to apical sides, while RFM, ZNS, PGB and ESM were not transported. Pgp did not transport CBZ, but did transport its active metabolite CBZ-E. Pgp also pumped ESL, OXC, and their active metabolite S-LC. The transport of these drugs can be completely blocked by Pgp inhibitor verapamil or tariquidar. In bi-directional transport assays, the Papp for the basolateral to apical direction in MDR1-transfected cells was significantly higher than in non-transfected cells for PHT, OXC, ESL, and S-LC, and not for PB, CBZ-E, CBZ, or ESM. / To compare the extent of basolateral-to-apical transport efficiency of different variants, we calculated the amount of the transported drugs divided by expression level of MDR1 in the apical chamber for each variant. In the G418 selection condition, compared with reference haplotype CGC, the CTC haplotype increased Pgp activity to transport OXC and ESL, while the CGT and CTT haplotypes did not significantly affect Pgp function. In the vincristine sulfate selection condition, compared with CGC, the haplotype CTT decreased Pgp activity, while other haplotypes, including CGC, CGT, CAC, CTC, TGC, TGT, TTT, and TTC, did not affect function. Selection by vincristine sulfate may raise expression of Pgp and eliminate differences among the variants. / Zhang, Chunbo. / Advisers: Vincent Hon Leung Lee; Lawrence William Baum; Zhong Zuo; Patrick Kwok Leung Kwan. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 192-221). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Recent years have seen a rapid increase in the search for new compounds to be employed in the treatment of convulsions associated with epilepsy and related ailments. The properties desired are a higher degree of effectiveness and lower toxicity than those already in use. This thesis describes the effect of methylation of the 5-alkylmercapto-5-phenylhydantoins.

[20] 172 [45] leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1974) from the Dept. of Medicine, University of Adelaide

No description available.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Thesis (M. P. H.)--University of Hong Kong, 2008 . / Also available in print.

The suspected teratogenicity of Diphenylhydantoin (DPH) in man is important, especially to the 0.3 to 0.5% of pregnant women who are epileptic and, therefore, candidates for anticonvulsant drug therapy. To separate the teratogenic effect of epilepsy from DPH treatment, an animal model closely approximating the human condition was developed to meet the following criteria: (i) the test animal must have spontaneous seizures (ii) the seizures must be controlled or eliminated by DPH treatment (iii) the drug must be administered orally (iv) serum DPH levels must fall within the optimal human therapeutic range between 5 and 20 micrograms per ml serum (v) treatment must begin prior to mating and continue throughout gestation (vi) the offspring of treated animals must exhibit the spectrum of malformations observed in the offspring of epileptic women The first criterion was met by mutant quaking (qk) mice. The seizure activity of these animals was reduced (from 2.1 to .34 seizures per mouse day) by DPH treatment. To separate the effect of this gene from that of the DPH in the etiology of the malformations, heterozygous (+/qk) and homozygous non- quaking (+/+) mice were also studied. Monitoring of DPH levels with the SYVA Emit spectrophotometry assay technique indicated serum concentrations within the human therapeutic range at 40 and 60 mg/kg body weight dosages. The incidence of fetuses born with skeletal or soft-tissue abnormalities increased with increasing DPH dosages. This was observed in all three genotypes. The ability of the untreated quaking (qk/qk) dams to -produce normal offspring implicates the drug rather than the mutant gene as the cause of malformations. A preliminary application of this animal model produced what can be considered the mouse equivalent of the fetal hydantion syndrome. The similarities between the human and mouse syndromes include prenatal growth deficiency, neural, cardiac, orofacial, ocular and genitourinary anomalies. Further large-scale application of the model should provide insight into the role of DPH in the etiology of the malformations observed amongst the offspring of epileptic women on hydantoin anticonvulsant drug therapy. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

No derivatives of 5-phenylhydantoin with an oxygen atom attached directly in the five position of the hydantoin nucleus have been found in the literature. It was therefore considered of interest to synthesize a series of compounds of this type to determine the effect of the change of the position of the oxygen atom on anticonvulsant activity.

Background: In recent years, there has been an increase in the use of automated healthcare databases for drug safety in pregnancy evaluation; their suitability for this purpose needs to be evaluated. Aim: To evaluate the utility of the United Kingdom’s General Practice Research Database (GPRD) to act as an alternative to pregnancy registries, using anticonvulsants as a case study. Methods: Pregnancies in women with epilepsy were identified and first trimester anticonvulsant exposure was determined. Major congenital malformations in the offspring were identified and verified. The risk of major congenital malformations following exposure to a range of anticonvulsants was calculated and compared to those reported by the UK Epilepsy and Pregnancy Register. The ability to identify a known teratogenic association using GPRD data was also assessed. An algorithm was created to identify and classify different types of pregnancy loss in an automated manner. Results: The risks of a pregnancy outcome with a major congenital malformation following first trimester anticonvulsant exposures, were found to be similar in the GPRD to those of the UK Register. The number of exposures to individual products in the GPRD was often small and therefore lacked statistical power. It was, however, possible to identify a known teratogenic association using data from the GPRD. Verification of the algorithm developed to classify pregnancy losses demonstrated that, although not perfect, it would be a beneficial tool when using the GPRD for drug safety in pregnancy research. Conclusion: It is unlikely a single data source or study design will be sufficient for monitoring all aspects of the safety of medicine use during pregnancy. The GPRD has the potential to make a valuable contribution to this field of research and could play an important role in complementing the work of other surveillance systems.