Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the new topics in epileptology is the ABC proteins, which seem to control whether or not anti-epileptic drugs (AEDs) can come in contact with and affect the epileptogenic areas that cause seizures. The goal of this report is to simplify the concepts involved in these proteins and then to review the progress made in the field, especially of one protein called P-glycoprotein (P-gp). First, the ABC proteins are reviewed, mainly P-gp, which appears to alter drug permeability (like an extra blood-brain barrier). The possibility is discussed that changes in P-gp are the result of many seizures; are caused by the AEDs, or truly reflect pharmacoresistance. The different locations where these changes can be seen include the endothelial cells, glia and also neurons. The polymorphism of P-gp, called C3435T, probably has little functional significance and finally the importance of inhibitors of P-g to reverse pharmacoresistance is emphasized. Tariquidar (XR9576) is likely to be a good candidate that appears to inhibit these proteins and therefore to allow the AEDs to control the intractable seizures that may account for nearly 40% of our patients.
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PMID:One of the hottest topics in epileptology: ABC proteins. Their inhibition may be the future for patients with intractable seizures. 1859 22

Status epilepticus (SE) is a neurological emergency, characterized by continuous or intermittent seizures without full recovery of consciousness between seizures, which can result in death or neurological sequelae. In about one third of patients, SE is unresponsive to sequential treatment with first- and second-line antiepileptic drugs (AEDs). At least in part, this drug resistance may be due to AED target alterations induced by SE, such as reduced membrane expression of GABA(A) receptors. Apart from target alterations by receptor trafficking, SE is known to increase the brain expression of drug efflux transporters such as P-glycoprotein (Pgp), which might reduce concentrations of AEDs at their brain targets. However, it is not known whether overexpression of Pgp develops rapidly enough after onset of SE to be of any functional consequence for drug treatment. Therefore, we studied whether overexpression of Pgp at the blood-brain barrier is involved in refractory SE. Two rat SE models were used, the lithium/pilocarpine model and induction of SE by sustained electrical stimulation of the basolateral amygdala (BLA). Four AEDs, diazepam (DZP), phenobarbital (PB) and phenytoin (PHT) or fosphenytoin (FPHT) were administered at different times after onset of SE. In the pilocarpine model, once self-sustained SE was established, none of the AEDs alone was effective in terminating SE, but sequential injection of PB and DZP stopped SE. Administration of the Pgp inhibitor tariquidar did not prevent or counteract resistance to AEDs. In the BLA model, DZP and PB terminated SE in the majority of rats, whereas PHT or FPHT were ineffective. Immunohistochemical staining of Pgp did not indicate any increase of Pgp expression in brain capillary endothelial cells during SE, whereas significant overexpression was determined in both models 48 h after SE. The data suggest that, at least under the conditions of the present study, alterations in Pgp are not critically involved in refractory SE.
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PMID:Resistance to antiepileptic drugs and expression of P-glycoprotein in two rat models of status epilepticus. 1876 Sep 5

Multiple drug resistance is a common problem in the treatment of epilepsy, and approximately 30% of patients continue to have seizures despite all therapeutic interventions. Among various classes of drug transporters, genetic variants of P-glycoprotein (P-gp) encoded by the ABCB1 (ATP-binding cassette subfamily B member 1) gene have been associated with drug-refractory epilepsy. Our aim was to investigate the effect of the 1236C>T(rs1128503), 2677G>T/A(rs2032582), and 3435C>T(rs1045642) single-nucleotide polymorphisms of ABCB1 (or MDR1) on drug resistance in north Indian patients with epilepsy. Genotyping was performed in 101 control subjects and 325 patients with epilepsy, of whom 94 were drug resistant and 231 drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital, and valproate was also performed to confirm compliance in 20% of the patients. Genotype and haplotype frequencies of these polymorphisms did not differ between drug-resistant and drug-responsive patients. Our results demonstrate ABCB1 polymorphisms are not associated with drug resistance in north Indian epileptic patients.
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PMID:No association of ABCB1 polymorphisms with drug-refractory epilepsy in a north Indian population. 1881 36

Approximately one-third of patients with epilepsy display an inherent resistance to pharmacological therapy, manifest as continuing seizures despite maximal tolerated doses of anti-epileptic drugs. One hypothesis for the underlying mechanism of anti-epileptic drug pharmacoresistance is lower drug entry to the epileptic neurones due to the activity of multidrug efflux pumps from the ATP Binding Cassette (ABC) superfamily at the blood-brain barrier. There has been a steady accumulation of animal and human data supporting this theory, particularly for ABC(B1) (P-glycoprotein). However, much of this evidence is indirect. In the present study, several anti-epileptic drugs (carbamazepine, valproic acid, phenytoin, lamotrigine and primidone) were examined for their ability to interact with three ABC transporters that have been implicated pharmacoresistance of anti-epileptic drugs - ABC(B1), ABC(C1) and ABC(G2). Interaction of anti-epileptic drugs with the transporters was assessed by determining whether they could reverse the ability of multidrug ABC transporters to confer a drug resistance phenotype on cancer cell lines. None of these compounds was able to affect the phenotype, suggesting an absence of any interaction with the multidrug transporters. This finding was further investigated by examination of transporter activity; namely the ability to reduce steady-state intracellular [(3)H]-radiolabelled drug accumulation. None of the anti-epileptic drugs affected labelled drug accumulation by any of the triumvirate of multidrug transporters examined, indicating that they are unlikely to be substrates. The lack of direct modulation by anti-epileptic drugs of ABC transporter function suggests that these proteins do not contribute significantly to resistance in epilepsy.
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PMID:Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations. 1883 65

The purpose of the present study was to evaluate the effect of kainic acid (KA)-induced acute seizures on the pharmacokinetic profiles of antiepileptic drug, carbamazepine (CBZ) in mice. Experimental acute seizure in mice was induced by intraperitoneal injection of KA (30 mg/kg), and mice were provided for experiments after 48 h of KA treatment. The portal plasma concentrations of CBZ and its metabolite carbamazepine-10,11-epoxide (CBZ-epo) had trends to decrease as compared to the control mice, whereas the brain CBZ and CBZ-epo concentrations was actually lower in KA treated mice. On the other hand, the exsorption of CBZ from blood to the intestinal lumen via P-glycoprotein (P-gp) in KA treated-mice was significantly increased in parallel with that of Rhodamine-123 (Rho123), a P-gp substrate. Western blotting analysis for intestinal and cerebral P-gp showed that the P-gp expression was induced in the KA-treated mice. The apparent brain-to-plasma concentration ratio (Kp) of CBZ in the KA-treated mice showed significant decrease but that of CBZ-epo did not. Moreover, in the KA-treated mice, the percentage of protein binding was significantly increased, and found to be an inverse proportion in the relationship between the Kp and protein binding of CBZ. In conclusion, the mechanism responsible for a decreased brain CBZ concentration in the KA-induced seizure mice is based on the up-regulation of P-gp function in tissues and plasma protein binding of CBZ.
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PMID:Evaluation of carbamazepine pharmacokinetic profiles in mice with kainic acid-induced acute seizures. 1904 17

We report on the use of the voltage-gated calcium channel blocker (Vg-CCB), verapamil, as an add-on anticonvulsant medication in two girls, 4 and 14 years of age, who were affected by severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, a channelopathy caused by abnormalities in the voltage-gated sodium channel neuronal type alpha1 subunit (SCN1A) gene at 2q24. Both girls had pharmacoresistant epilepsy and developmental delay. Mutation analysis for the SCN1A gene revealed a missense mutation in exon 2 in the 4-year-old girl. Verapamil was co-administered in both children with a prompt response in controlling status epilepticus, myoclonic jerks, and partial and generalized seizures. The therapeutic effect lasted 13 months in the 14-year-old girl, while it is still present after a 20-month follow-up period in the 4-year-old girl who, in addition, has experienced improvement in motor and language development. The verapamil vVg-CCB, which crosses the blood-brain barrier (BBB): (a) inhibits the P-glycoprotein, an active efflux transporter protein expressed in normal tissue, including the brain, which is believed to contribute to the in situ phenomenon of multidrug resistance; and (b) may regulate membrane depolarization induced by abnormal sodium channels functions by modulating the abnormal Ca++ influxes into neurons with subsequent cell resting. This is the first report on long-lasting verapamil therapy in SMEI. The functional consequences of such in vivo modulating effects on Ca++ channels could contribute to rational targeting for future molecular therapeutic approaches in pharmacoresistant epileptic channelopathies.
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PMID:Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. 1948 7

A 9-year-old girl was managed according to the COPRALL 04 protocol for treatment of a relapse of acute lymphoblastic leukemia. Owing to a previous case of disseminated fusariosis, posaconazole was started 5 days before initiation of chemotherapy. Six days after the last dose of vincristine, the child reported symptoms of severe peripheral neuropathy, abdominal cramps, and constipation. After this, she developed fluctuations in her level of consciousness and seizures. After cessation of therapy with posaconazole, a complete resolution of the above occurred within 7 days. This case illustrates the possibility of vincristine toxicity exacerbated by coadministration of posaconazole. As posaconazole is an inhibitor of the isoenzyme CYP3A4, interactions with drugs that are metabolized via this pathway, such as vincristine, can be anticipated. Another possibility is that, like itraconazole, posaconazole may also inhibit P-glycoprotein-mediated vincristine efflux. Although case reports of neurotoxicity owing to possible interaction between itraconazole and vincristine exist in the literature, only 1 case report relating to the possible interaction between posaconazole and vincristine exists. Clinicians should be made aware of this possible drug-drug interaction.
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PMID:Posaconazole-increased vincristine neurotoxicity in a child: a case report. 1934 85

In the epileptic brain, seizure activity induces expression of the blood-brain barrier efflux transporter, P-glycoprotein, thereby limiting brain penetration and therapeutic efficacy of antiepileptic drugs. We recently provided the first evidence that seizures drive P-glycoprotein induction through a pathway that involves glutamate-signaling through the NMDA receptor and cyclooxygenase-2 (COX-2). Based on these data, we hypothesized that selective inhibition of COX-2 could prevent seizure-induced P-glycoprotein up-regulation. In the present study, we found that the highly selective COX-2 inhibitors, NS-398 and indomethacin heptyl ester, blocked the glutamate-induced increase in P-glycoprotein expression and transport function in isolated rat brain capillaries. Importantly, consistent with this, the COX-2 inhibitor, celecoxib, blocked seizure-induced up-regulation of P-glycoprotein expression in brain capillaries of rats in vivo. To explore further the role of COX-2 in signaling P-glycoprotein induction, we analyzed COX-2 protein expression in capillary endothelial cells in brain sections from rats that had undergone pilocarpine-induced seizures and in isolated capillaries exposed to glutamate and found no change from control levels. However, in isolated rat brain capillaries, the COX-2 substrate, arachidonic acid, significantly increased P-glycoprotein transport activity and expression indicating that enhanced substrate flux to COX-2 rather than increased COX-2 expression drives P-glycoprotein up-regulation. Together, these results provide the first in vivo proof-of-principle that specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier for improving pharmacotherapy of drug-resistant epilepsy.
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PMID:Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. 1937 77

Previous evidence has shown that chronic 3-mercaptopropionic acid (MP) administration induced brain P-glycoprotein (P-gp) overexpression altering target site accumulation of phenytoin. The aim of the present work was to assess the involvement of P-glycoprotein in carbamazepine and phenobarbital hippocampal pharmacokinetics in an experimental model of epilepsy, induced by repetitive MP administration. Seizures were induced in Wistar rats by injection of MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular brain antiepileptic levels, a concentric probe was inserted into the hippocampus. Animals were administered with carbamazepine (10 mg kg(-1), i.v.) or phenobarbital (20 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle or nimodipine (2 mg kg(-1)), a well known P-glycoprotein inhibitor. No differences were found in hippocampal concentrations of carbamazepine comparing all groups. In vehicle pre-treated rats, hippocampal phenobarbital concentrations were lower in MP (maximal concentration, C(max): 6.0+/-0.6 microg ml(-1), p<0.05) than in C animals (C(max): 9.4+/-0.9 microg ml(-1)). Control rats pre-treated with nimodipine showed similar results (C(max): 10.7+/-0.6 microg ml(-1)) than those pre-treated with vehicle. Nimodipine pre-treatment in MP rats enhanced hippocampal phenobarbital concentrations (C(max): 10.2+/-1.0 microg ml(-1), p<0.05) as compared with vehicle pre-treatment. Results of our work suggest that P-glycoprotein (P-gp) overexpression by repetitive seizures induced by MP administration does not modify brain bioavailability of carbamazepine. Conversely, hippocampal levels of phenobarbital are reduced in MP rats with regard to non-epileptic rats, suggesting a potential role of P-gp overexpression in pharmacoresistance to phenobarbital.
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PMID:Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid. 1942 15

Up-regulation of the blood-brain barrier efflux transporter P-glycoprotein in central nervous system disorders results in restricted brain access and limited efficacy of therapeutic drugs. In epilepsies, seizure activity strongly triggers expression of P-glycoprotein. Here, we identified the prostaglandin E2 receptor, EP1, as a key factor in the signaling pathway that mediates seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier. In the rat pilocarpine model, status epilepticus significantly increased P-glycoprotein expression by 92 to 197% in the hippocampal hilus and granule cell layer as well as the piriform cortex. The EP1 receptor antagonist 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide hydrochloride (SC-51089) abolished seizure-induced P-glycoprotein up-regulation and retained its expression at the control level. The control of P-glycoprotein expression despite prolonged seizure activity suggests that EP1 receptor antagonism will also improve antiepileptic drug efficacy. Preliminary evidence for this concept has been obtained using a massive kindling paradigm during which animals received a subchronic SC-51089 treatment. After withdrawal of the EP1 receptor antagonist, a low dose of the P-glycoprotein substrate phenobarbital resulted in an anticonvulsant effect in this pretreated group, whereas the same dosage of phenobarbital did not exert a significant effect in the respective control group. In conclusion, our data demonstrate that EP1 is a key signaling factor in the regulatory pathway that drives P-glycoprotein up-regulation during seizures. These findings suggest new intriguing possibilities to prevent and interrupt P-glycoprotein overexpression in epilepsy. Future studies are necessary to further evaluate the appropriateness of the strategy to enhance the efficacy of antiepileptic drugs.
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PMID:Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation. 1949 86


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