Anticonvulsant Levels Research Articles

Drug transporters are altered in brain, liver and kidney of rats with chronic epilepsy induced by lithium–pilocarpine

Objective: Pharmacoresistance is a common problem hindering treatment of epilepsy. A possible cause for this resistance is the overexpression of efflux drug transporters, e.g. P-glycoprotein (P-gp), which may decrease extracellular antiepileptic drugs levels in brains of intractable epilepsy patients. Another transmembrane drug transporter is the organic anion transporting polypeptide 2 (Oatp2), which is colocalized with P-gp in many polarized tissues. However, a role for Oatp2 in the development of multidrug resistance has not been established. In the present work, we investigated the expression of drug transporters Oatp2 and P-gp in brain, liver and kidney of rats with chronic epilepsy induced by lithium–pilocarpine.Methods: Chronic epilepsy was elicited after status epilepticus (SE) induced by lithium–pilocarpine in adult Wistar rats. Following SE, expression of Oatp2 and P-gp protein was detected by immunohistochemistry and Western blot analysis and messenger RNA (mRNA) using reverse transcription polymerase chain reaction (RT-PCR). Levels of the drug transporters were compared in brain, liver and kidney of chronic epileptic and control rats.Results: Both Oatp2 and P-gp were expressed in the brain, liver and kidney but predominantly in the brain. In the brain, Oatp2 and P-gp immunopositive cells were observed in brain capillary endothelium and choroid plexus epithelium. Compared with control rats, Oatp2 protein expression in brain was significantly decreased, while P-gp was obviously increased in chronic epileptic rats. P-gp mRNA was also significantly higher in brains of chronic epileptic rats, whereas the expression of Oatp2 did not change. Organic anion transporting polypeptide 2 and P-gp did not change at the mRNA or protein level with epilepsy in the liver or kidney.Conclusions: Organic anion transporting polypeptide 2 and P-gp colocalized in tissues that are important in drug absorption, metabolism and excretion. Seizures seem to induce the cerebral changes of P-gp and Oatp2. However, the changes of expression of two transporters exhibit the opposite trend. Organic anion transporting polypeptide 2 might play a different role than P-gp in intractable epilepsy. Our data provide a basis for the assessment of the role of uptake transporters and efflux pumps in the development of intractable epilepsy.

Balance impairment in chronic antiepileptic drug users: A twin and sibling study

Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED-discordant, twin and sibling matched-pair approach, and assessed clinically relevant subgroups: AED polytherapy; longer-duration AED; and falls history. Twenty-nine same-sex (mean age 44.9 years, 59% female), ambulatory, community-dwelling twin and sibling pairs, discordant for AED exposure (and AED-indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum samples for 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and immunoreactive parathyroid hormone (iPTH) levels were taken. There were significant mean within-pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within-pair differences were seen in fasting serum levels of 1,25(OH)(2)D, 25OHD and iPTH after Bonferroni correction. Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.

Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs

Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. Patients 18-50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B(12), and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 microm; physiologic range 5-13 microm] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm; normal > 6.8 nm) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) microm, respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) microm]. Oxcarbazepine and topiramate might cause hyper-tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper-tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy.

Epilepsy in the elderly.

The elderly, often defined as those 65 years or older, are the most rapidly growing segment of the population, and onset of epilepsy is higher in this age group than in any other. This paper reviews recent developments, including a new proposed definition of epilepsy, a transgenic mouse model of Alzheimer's disease that exhibits complex partial seizures, evidence that the highest incidence of epilepsy may occur after admission to a nursing home, a challenge to the vitamin D hypothesis of osteoporosis associated with antiepileptic drugs (AEDs), evidence that the genetic complement of hepatic isoenzymes is more predictive of metabolic rate than age, and data showing that there is considerable variability in serum levels of AEDs in many nursing home residents during constant dosing conditions.

P03-363 - Minding the levels: about a clinical case with neuropsychiatric manifestations

Introduction and aimsPsychiatry makes use of a wide range of medications, such as anti-epileptic drugs in the treatment of affective disorders, impulsive behavior or epilepsy. The authors aim to present a particular clinical presentation in order to reinforce the awareness of the side effects of our prescriptions.Case report54 year-old man, epileptic, medicated with Sodium Valproate (VPA) and Phenobarbital, admitted to our hospital due to insomnia, irritability and aggressiveness with two weeks of duration. Early evaluations showed disorientation, slow and poor speech, and prejudice ideas towards his family. Disequilibrium, asterixis and slurred speech imposed evaluation by Neurology. Analytic evaluations demonstrated high phenobarbital and ammonia levels. Both anti-epileptics were slowly withdrawn, with clinical resolution.DiscussionVPA may be associated with elevation of ammonia levels, and eventually with encephalopathy without evidence of liver failure. There is a wide range of clinical presentations of hyperammonemic encephalopathy ranging from decreased level of consciousness, irritability, agitation, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. On the other hand, high doses of phenobarbital may have similar presentations which could be potentiated by VPA.ConclusionThere was a good correlation between the fall in serum ammonia levels, clinical improvement, and anti-epileptics withdrawal, suggesting the implication of medication in this clinical picture. The case illustrates the need to check ammonia and anti-epileptic levels, and to consider this diagnosis in patients taking VPA and Phenobarbital who present with new neuropsychiatric manifestations.

Correlation between Serum Level of Antiepileptic Drugs and their Side Effects

The aim of the study is to investigate the relation between serum levels of anticonvulsants and their side effects. This is a prospective cross sectional hospital based study conducted at Al Shaab Teaching Hospital. 120 patients were included in the study. The AEDs used were phenytoin, phenobarbitone, carbamazibine, and sodium valproate. The results showed that the side effects among the studied group were not uncommon. There was no relationship between serum levels of AEDs and their side effects.

Focal lesions in the splenium of the corpus callosum in patients with epilepsy

A focal lesion in the splenium of the corpus callosum is a rare finding in patients with epilepsy. Intoxication with antiepileptic drugs, edema after generalized seizures, or a rapid change of antiepileptic drug levels have been proposed as possible mechanisms. The aim of the present study was to analyze the relationship between this lesion and possible etiologic factors. We analyzed the magnetic resonance imaging (MRI) scans of 1,050 patients undergoing prolonged video-EEG (electroencephalography) monitoring and identified 24 patients with a focal lesion in the splenium of the corpus callosum. Twenty-four age- and gender-matched temporal lobe epilepsy patients without such a lesion served as a control group. We evaluated the following parameters for their possible etiologic significance: epilepsy syndrome, seizure types in medical history, seizure frequency during the past year prior to admission for prolonged video-EEG monitoring, localization of interictal spikes and ictal EEG patterns in patients with focal epilepsies as documented during prolonged video-EEG-monitoring, seizure types and seizure frequency during prolonged video-EEG monitoring, past as well as current antiepileptic medication, withdrawal of antiepileptic drugs during monitoring including duration of medication withdrawal, and finally drug levels above the therapeutic range. The parameters analyzed showed no significant difference between the group of patients with focal lesions in the splenium of the corpus callosum and the control group. We could not identify a single etiologic factor responsible for the lesion in the splenium of the corpus callosum.

MDR1/ABCB1 Polymorphisms and Multidrug Resistance In Epilepsy: in and out of Fashion

been satisfied for the transporter hypothesis, however, only in rodent models of epilepsy as yet [7]. Accordingly, P-gp expression is: increased in epileptogenic brain tissue of rodents; associated with lower brain levels of AEDs; higher in AED-resistant rats than in responsive animals; and most importantly, co-administration of the highly selective P-gp inhibitor, tariquidar, reverses AED resistance. Thus, it is reasonable to conclude that P-gp plays a significant role in mediating resistance to AEDs in rodent models of temporal lobe epilepsy and that inhibition of P-gp can circumvent this mechanism – however, whether this phenomenon extends to at least some human refractory epilepsy remains unclear [7]. Increased brain expression of efflux transporters, such as P-gp, could be a result either of prolonged or frequent seizures, as demonstrated in rodent models of epilepsy, or of genetic factors, such as polymorphisms in the ABCB1 gene or, theoretically, of both [2]. Siddiqui et al. were the first to report that a SNP in the ABCB1 gene is associated with resistance to multiple AEDs, leading to the suggestion that drug resistance in epilepsy might be genetically determined [8]. In this study, patients with AED-resistant epilepsy were more likely to have the CC genotype at the ABCB1 C3435T polymorphism, which is associated with increased expression of the protein, than the TT genotype [8]. Since then, different studies of various designs have tried to confirm the association between the 3435C>T polymorphism and AED resistance in epilepsy, but most of these subsequent studies were negative [9]. A recent meta-ana lysis of 11 case–control studies involving 3371 patients (1646 patients with drug-resistant epilepsy and 1725 controls) did not identify a significant association between AED resistance and ABCB1 polymorphisms, including the 3435 SNP [10]. However, in most of these pharmacogenetic studies, patients were treated with various AEDs, ignoring the fact that not all AEDs are substrates Resistance to multiple anti-epileptic drugs (AEDs) is a significant problem in epilepsy affecting at least 30% of patients with this common and often devastating disease [1]. One prominent hypothesis to explain this multidrug resistance suggests an inadequate penetration or excess efflux of AEDs across the blood–brain barrier (BBB) as a result of overexpressed efflux transporters, such as P-glycoprotein (P-gp), the encoded product of the multidrug resistance-1 (MDR1, ABCB1) gene [2]. Drug efflux transporters such as P-gp have a major impact on the pharmacological behavior of most clinically used drugs, critically affecting drug absorption, disposition and elimination in the body [3]. The idea that enhanced BBB expression of P-gp could be involved in AED resistance was first proposed by Tishler et al. in 1995, who reported that P-gp and ABCB1 are markedly increased in brain tissue of pa tients with medically intractable partial epilepsy [4]. This finding was subsequently confirmed by several other groups and formed the basis of the transporter hypothesis of intractable epilepsy [5].

Manajemen Epilepsi pada Kehamilan

Epilepsy is recognized as the commonest serious neurological disorder in the world. Women with epilepsy experience several gender-related physical and social problems. They constitute high obstetric risk because of reduced fertility, risk of seizures during pregnancy, and complications of pregnancy. Hormonal and other factors can alter the pharmacokinetics of antiepileptic drugs during pregnancy and puerperium. Antenatal exposure to antiepileptic drugs, particularly at higher dosage and in polytherapy, increases the risk of fetal malformation. Recent reports raise the possibility of selective developmental language deficits and neurocognitive deficits with antenatal exposure to antiepileptic drugs. There are concerns regarding the effect of traces of antiepileptic drugs that pass to the infant during breast-feeding. The pre conception management is the cornerstone for epilepsy care in Women with epilepsy. A careful reappraisal of each case should ascertain the diagnosis, the need for continued antiepileptic drugs therapy, selection of appropriate antiepileptic drugs, optimization of the dosage, and prescription of folic acid. During pregnancy, the fetal status needs to be monitored with estimation of serum a-feto-protein and ultrasound screening for malformations. The dosage of antiepileptic drugs can be adjusted according to clinical requirement and blood levels of antiepileptic drugs. Several institutions recommend oral vitamin K toward the end of pregnancy when enzymeinducing. Key Words : epilepsy, pregnancy, management, complication

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

Complex time‐dependent alterations in the brain expression of different drug efflux transporter genes after status epilepticus

Frequent epileptic seizures or prolonged seizure activity (status epilepticus, SE) is known to increase the brain expression of drug efflux transporter genes and proteins, such as P-glycoprotein (Pgp) and members of the multidrug resistance protein (MRP) family, which might reduce brain levels of antiepileptic drugs and, therefore, be involved in drug resistance. However, the time course of alterations in Pgp or MRPs after seizures or SE is only incompletely known. This prompted us to study the time course of alterations in the expression of different efflux transporter genes (Mdr1a, Mdr1b, MRP1, MRP2, MRP5) at various times after a pilocarpine-induced SE in limbic brain regions, using quantitative real-time polymerase chain reaction (RT-PCR) (qPCR). Unexpectedly, between 6 and 24 h after onset of SE, genes encoding Pgp (Mdr1a, Mdr1b), Mrp1, and Mrp5 were downregulated in hippocampus, amygdala, or piriform cortex. This initial decrease in expression was followed by normalization and then increased expression, which became maximal 2 days after SE. One explanation for the initial decrease in transporter expression could be SE-induced acute inflammatory processes, because proinflammatory cytokines are known to suppress the expression of Pgp and other efflux transporters. To directly address this possibility, we quantified the hippocampal mRNA expression of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, showing a marked SE-induced increase in these cytokines, which paralleled the decreased expression of efflux transporters. Taken together, these findings indicate that alterations in expression of drug efflux transporters after prolonged seizure activity are more complex than previously thought.

Comparisons of the mortality and clinical presentations of status epilepticus in private practice community and university hospital settings in Richmond, Virginia

We prospectively compared the clinical course of 119 patients treated for status epilepticus (SE) in private practice community hospitals and 344 SE patients treated in the VCU university hospitals in Richmond, Virginia USA over a 2-year period to test the hypothesis that SE presents with the same mortality and clinical patterns in both clinical settings. Of the patients reviewed, the major etiologies for SE were cerebrovascular disease, decreased anti-epileptic drug levels in epileptic patients, anoxia–hypoxia, and remote symptomatic. The other etiologies included were alcohol related, trauma, central nervous system infections, tumors, systemic infection, metabolic disorders, idiopathic, and hemorrhage. These observations provide the first direct prospective comparison of SE present in university and private practice community hospital settings in the same geographic area. Mortality was the highest in the elderly population while the pediatric population had low mortality in both clinical settings. Etiology risk factors for outcome were similar for both the populations. The data also suggest that the higher degree of illness severity in university hospitals may be associated with a higher incidence of SE, but not with mortality or a different clinical presentation of the condition. The results of this study demonstrate that SE has the same mortality and is present in an essentially identical manner in university and private practice community hospitals and underscores the fact that mortality in SE is not just associated with tertiary care hospitals and the importance of recognizing the severity of SE in the private practice setting.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.

Epileptic disorders in pregnancy: an overview

Much new information has now become available regarding outcomes of women with epilepsy (WWE) and pregnancy. Valproate is associated with a risk of major congenital malformations within a range of 6.2-10.7%, though antiepileptic drugs (AEDs) other than valproate when used as monotherapy are associated with major congenital malformation rates ranging from 2.9 to 3.6%; the rate of major congenital malformations in WWE not treated with AEDs was similar to this at 3.1%. Seizure freedom in 9-12 months before pregnancy is associated with seizure freedom during pregnancy. A decline in AED levels can be expected during pregnancy, most dramatically for lamotrigine (but with marked variability between patients) and least with carbamazepine. Neonates born to WWE taking AEDs who receive vitamin K 1 mg intramuscularly at birth are not at additional risk of hemorrhagic disease of the newborn. The use of valproate and polytherapy with any AED combinations should be avoided, if clinically appropriate, during pregnancy. Seizure freedom in 9-12 months before pregnancy should be a goal. AED levels should be maintained at or near the therapeutic level known for that individual patient, with frequent monitoring during pregnancy as appropriate for the patient and the AED.

Rapid Anti-Epileptic Drug Assay

The usefulness of rapid anti-epileptic drug assay in a paediatric neurology clinic was assessed. Compared with a method in which results were not available for seven to 10 days, there was an increased likelihood that levels would be within the target range, particularly for carbamazepine. Increased parental discussion, and therefore involvement with dosage, was possible. Management of children receiving phenytoin was more efficient and non-compliance could be dealt with immediately. When anti-epileptic drug levels are measured, rapid assay, with results available while the patient is still in the clinic, should be a standard facility.

Generic substitution in the treatment of epilepsy

There are concerns that generic and brand antiepileptic drugs (AEDs) may not be therapeutically equivalent. This study investigated how generic AED substitution may have negative consequences. Sixty-nine of 150 physicians who participated in a large survey on generic AED substitution completed a case review form regarding a patient who experienced a loss of seizure control due to a generic AED. Nineteen were excluded from analysis. Fifty patients, well-controlled on a brand AED, subsequently experienced a breakthrough seizure or increased seizure frequency after switching to a generic without other provoking factors. AEDs included phenytoin (15 cases), valproic acid (14), carbamazepine (7), gabapentin (8), and zonisamide (8). Two patients were on a combination of two AEDs, both of which were switched to generics. In 26 cases serum AED levels were known both before and after generic substitution. Twenty-one had lower levels at the time of the breakthrough seizure on the generic medication. Loss of seizure control had a negative impact on quality of life, including loss of driving privileges (n = 30) and missed school/work days (n = 9). Changing from a brand antiepileptic drug (AED) to a generic may result in seizures. This raises the concern that current Food and Drug therapeutic equivalence testing regulations may not be adequate for AEDs and suggests that more clinical evidence is needed. Physicians, pharmacists, patients, and policy makers should be aware that for some patients there may be risks associated with switching from brand to generic AEDs.

Value of therapeutic drug level monitoring and unbound (free) levels

Therapeutic drug monitoring (TDM) has declined with newer anti-epileptic drugs (AEDs) having no therapeutic window. Use of unbound (free) fraction has almost completely disappeared. The case reported highlights its importance and offers sound reason for its retention. A 66-year-old Caucasian man with known epilepsy was admitted with vomiting, ataxia and nystagmus presumably due to AED toxicity. Medications included valproate (VPA) 1g bd; phenytoin (PHT) 200mg tds; carbamazepine (CBZ) 400mg mane, 200mg midi, 400mg nocte; levetiracetam (LEV) 250mg bd. Initial AED-TDM revealed total serum levels of CBZ: 27micromol/L; PHT: 37micromol/L; VPA 499micromol/L, therapeutic or subtherapeutic. Free levels were subsequently measured demonstrating CBZ: 8.2micromol/L; PHT: 5micromol/L; VPA 93micromol/L. Consequently, VPA was initially omitted and dosage reduced with cessation of toxicity. AED regimen was greatly simplified and remained efficacious. This case highlights the value of TDM with polypharmacy and suggested AED toxicity. Total AED levels failed to identify the cause, which the unbound, free fraction identified. While total PHT was borderline subtherapeutic (37micromol/L; range: 40-80) the free level was therapeutic (5micromol/L; range: 4-8) and while VPA was therapeutic (VPA 499micromol/L; range: 300-750) the free level was supratherapeutic (93micromol/L; range: 30-75). Acknowledgement of discordance between total and free levels for highly protein-bound AED is highlighted.

Pharmacokinetics of antiepileptic drugs in pregnancy

A substantial proportion of women with epilepsy experience seizure deterioration during pregnancy. This is most likely explained by a drop in plasma levels of antiepileptic drugs (AEDs) as a consequence of altered drug pharmacokinetics. It has been known for many years that gestation induces the elimination of standard AEDs (phenytoin, barbiturates, carbamazepine and valproate). In general, newer AEDs have more simple pharmacokinetic properties and it should, therefore, be expected that the pharmacokinetics of these drugs are influenced in a simpler manner by physiological changes, such as pregnancy. However, within the last few years it has been established that the elimination of several newer AEDs is significantly accelerated during pregnancy. This is particularly the case for glucuronidated AEDs (i.e., lamotrigine) and the pharmacological active metabolite of oxcarbazepine (metabolite 10-hydroxycarbazepine). Recent observations show it is probable that the elimination of levetiracetam is also increased during pregnancy. Pharmacokinetic alterations during pregnancy show wide interindividual variability and the effects on the plasma levels are mostly unpredictable. Regular routine drug monitoring during pregnancy is therefore recommended. The future perspective involves the development of pharmacogenetic charting, which may assist in providing an individualized treatment strategy and refine preconceptional therapeutic planning to ensure the best possible health for the mother and developing child.

ABC Transporters during Epilepsy and Mechanisms Underlying Multidrug Resistance in Refractory Epilepsy

It is estimated 20-25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P-glycoprotein (P-gp) and others ABC transporters as multidrug-resistance-associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P-gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P-gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P-pg detection in vessel-related cells and later additional P-gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, was in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P-gp expression in excretory organs suggests that P-gp have a central role in drug elimination. Persistent low levels of AEDs in plasma and P-gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99mTc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) (a P-gp substrate), and the surgically treated cases showed P-gp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp over-expression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P-gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure-affected P-gp-positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P-gp-expressed cells that exhibit lower membrane potential (Deltapsi(0)=-10 to -20) compared to normal physiological Deltapsi(0) of -60 mV. Under this situation and irrespective to the P-gp pharmacoresistant property or type of drug treatment selected, P-gp-expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE.

Lack of Pharmacokinetic Interaction of Levetiracetam on Carbamazepine, Valproic Acid, Topiramate, and Lamotrigine in Children with Epilepsy

To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.