Protein binding of four antiepileptic drugs in maternal and umbilical cord serum.

The total and protein free levels of 4 antiepileptic drugs (AEDs) in serum from 35 maternity patients who had been treated with AED monotherapy throughout pregnancy were studied. Results were compared with those in the umbilical cord serum at the time of delivery, and the placental transfer of AEDs was evaluated from the viewpoint of the protein binding capacity of the drug. The materials consisted of 35 samples of maternal and umbilical cord serum in total and included 13 patients on phenobarbital (PB), 7 on phenytoin (PHT), 7 on carbamazepine (CBZ) and 8 on valproic acid (VPA). The mean fetal/maternal total concentration ratios were 0.86, 0.91, 0.73 and 1.59 for PB, PHT, CBZ and VPA, respectively, only the VPA ratio being above 1. On the other hand, the mean fetal/maternal free fraction ratios were 1.13, 1.10, 1.42 and 0.50 for PB, PHT, CBZ and VPA, respectively, only the VPA ratio being less than 1. Correlation of the 2 ratios showed a reciprocal proportion with a correlation coefficient of -0.90 (P < 0.005). It was considered that the fetal/maternal total concentration ratio of 4 AEDs was regulated by the fetal/maternal free fraction ratio of the corresponding AEDs and that the difference in fetal/maternal free fraction ratio depended on the type of drug being administered.     

Effects of Discontinuation of Phenytoin, Carbamazepine, and Valproate on Concomitant Antiepileptic Medication

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.     

抗癫痫药物对癫痫患者甲状腺激素水平影响的研究

目的 研究癫痫患者甲状腺激素水平和抗癫痫药物对其影响以及与疗效之间的关系。方法 测定已确诊的45例未服用过抗癫痫药物的癫痫患者血清甲状腺激素水平并与30例健康对照组进行比较。再经卡马西平、苯妥英钠、丙戊酸钠三种抗癫痫药物分组单药治疗3个月、6个月、年后观察甲状腺激素水平的变化及与疗效之间的关系。结果 未服用抗癫痫药物的新诊断癫痫患者游离甲状腺素（FT4）水平显著低于健康对照组,经苯妥英钠、卡马西平分别治疗3个月、6个月、1年后T4、FT4、FT3显著低于治疗前水平,TSH无显著性变化。经丙戊酸钠治疗后的不同时间段各甲状腺激素水平与治疗前比较无显著性差异（P＞0．05）。甲状腺激素水平的变化与化疗效之间似无相关性。结论 癫痫的反复发作虽未经抗癫痫药物治疗已存在FT4水平的降低。苯妥英钠、卡马西平可明显造成癫痫患者的亚临床甲状腺功能降低（T4、FT4、FT3下降）,丙戊酸钠对患者甲状腺激素水平无显著影响。甲状腺激素水平的变化与疗效之间无相关性。     

Cross-reactivity pattern of rash from current aromatic antiepileptic drugs

We have investigated cross-reactivity of rash among the current aromatic antiepileptic drugs, particularly between the new and the traditional compounds. A retrospective survey of medical records concerning all aromatic antiepileptic drug (AED) treatment in consecutive adult patients with epilepsy was performed. Altogether 663 patients were included comprising 2567 exposures to AEDs. Skin reactions occurred in 93 patients and sequential rashes related to aromatic drugs in 17. Phenytoin (PHT), carbamazepine (CBZ) and oxcarbazepine (OXC) caused rashes in the range of 27-35% in patients with a history of another AED-related rash, whereas lamotrigine (LTG) caused another rash in 17%. A history of an AED-related rash was significantly associated with reactions to PHT, CBZ, and OXC (p<0.001). The association was only borderline significant for LTG (p=0.05). Nevertheless, the occurrence was consistently increased in all subgroups with reactions to other AEDs. A CBZ rash was not significantly associated with an LTG reaction, and vice versa, but the number of patients was limited. Less than one third of patients with a CBZ rash also reacted to OXC. No evidence for increased severity of sequential rashes was found. Clinicians should be aware of the cross-reactivity of the aromatic AEDs regarding cutaneous adverse events, as well as their differences in this respect. LTG appears to be involved in cross-reactions less often than CBZ, OXC and PHT.     

Clobazam Has Equivalent Efficacy to Carbamazepine and Phenytoin as Monotherapy for Childhood Epilepsy

Summary: Purpose: To compare the effectiveness of mono-therapy clobazam (CLB) to carbamazepine (CBZ) and phenytoin (PHT) in children with epilepsy.
Methods: Children aged 2–16 years with newly diagnosed epilepsy or previous failure of one drug (for poor efficacy or side effects) were assigned to one of two study arms and then randomized–CLB versus CBZ or CLB versus PHT. Eligible children had partial epilepsies or only generalized tonic-clonic seizures. After a drug initiation protocol, monotherapy treatment mimicked the usual routines used by Canadian child neurologists. Blinding used a "double dummy" technique with blinded medication serum levels (6–point scale). Intention to treat analysis using survival curves assessed the primary end-point–length of retention on the initial medication during the year after randomization.
Results: Fifteen centers entered 235 patients: 159 randomized to CLB versus CBZ and 76 to CLB versus PHT. Altogether, in all study arms, 119 received CLB, 78 CBZ, and 38 PHT. Overall, 56% continued to receive the original medication for l year with no difference between CLB and standard therapy (CBZ and PHT). Seizure control was equivalent for all three medications, as were side effects. PHT and CBZ induced more biologic side effects, such as rash, while CLB induced slightly more behavioral effects. Tolerance developed in 7.5% of patients receiving CLB, 4.2% with CBZ and 6.7% with PHT.
Conclusions: CLB should be considered as "first line" monotherapy along with CBZ and PHT for all partial and selected generalized childhood epilepsies.     

Antiepileptic Drug Therapy and Sexual Function in Men with Epilepsy

Summary: Purpose: To study the effects of antiepileptic drugs (AEDs) on sex hormone levels and sexual activity in a group of men attending a hospital-based epilepsy clinic. Methods: One hundred eighteen men being treated with AED therapy, 32 with epilepsy but not receiving AEDs, and 34 controls were recruited. All subjects were aged 18–65 years. Blood (20 ml) was removed for hormone assays, after which each subject completed a validated questionnaire [Sexuality Experience Scores (Frenken and Vennix, 1981)] aimed at exploring the individuals' sexual activity and attitudes to sexual morality. Results: Men taking carbamazepine (CBZ) only had significantly higher mean sex hormone-binding globulin (SHBG) levels than the control group. The CBZ group also had a significantly lower mean DHEAS concentration than the control, untreated, and sodium valproate (VPA) monotherapy groups. The phenytoin monotherapy group (PHT) had a significantly higher mean SHBG than both the control and untreated groups, and had a significantly higher mean total testosterone (TT) value than the control untreated, CBZ, and VPA groups, and a significantly lower mean DHEAS than the controls, untreated, and VPA groups. Men receiving more than one AED had significantly higher mean SHBG concentrations compared with control, untreated, and VPA groups. In addition, the poly-therapy group's mean TT was significantly higher than the control and VPA groups, although its mean DHEAS concentration was lower than the control, untreated, and VPA groups. There were no significant differences between the study groups in mean FT, Budrostenedione (AND), or estradiol levels. But the CBZ, PHT, and polytherapy groups had significantly lower mean free and rogen index (FAI) than the controls. The CBZ group had a lower mean FAI than the VPA group. The poly-therapy group had a lower FAI than the untreated group. Sexuality Experience Scores (SES) showed that those men receiving AEDs embraced a stricter sexual morality than the controls and untreated, and expressed greater satisfaction with their marriages than the control and untreated groups. Conclusions: Seizure type did not affect SES scores. Multiple regression showed men who had received further education were less accepting of strict sexual morality.     

Assessment of colour vision in epileptic patients exposed to single-drug therapy.

Diplopia, blurred vision and colour disturbances are well-known side effects associated with anti-epileptic drugs (AEDs). Farnsworth-Munsell 100-hue colour test (F-100) is an accepted and sensitive tool to detect changes in colour perception. To determine the impact of AEDs upon colour vision, we evaluated 37 consecutive patients with complex partial seizures exposed to monotherapy with phenytoin (PHT, carbamazepine (CBZ) or valproic acid (VPA). All had normal IQ and no congenital disturbances in colour vision or ocular diseases. Twenty normal controls were used for statistical analysis. Thirteen patients were exposed to PHT, 12 to CBZ and 12 to VPA. Visual colour perception was impaired in 30/37 (82%) of the study group. The most significant abnormality was detected in the blue-yellow axis in 10/13 patients exposed to PHT (p < 0.02) and in 8/12 treated with CBZ (p < 0.009). In 8/12 patients taking VPA, no significant abnormality was observed (p < 0.06). None of the studied patients complained of colour vision disturbances. Our findings strongly support the negative effect of AEDs upon colour vision discrimination, most likely due to changes at the retinal processing level. F-100 proved to be very useful to assess early toxicity due to AEDs.     

Differential effects of antiepileptic drugs on neuroactive steroids in men with epilepsy

PURPOSE: To compare serum levels of neuroactive steroids among men with epilepsy who take various antiepileptic drugs, untreated men with epilepsy and normal controls (NC). METHODS: Subjects were 85 men with localization-related epilepsy [unmedicated >6 months (No Rx)-10, carbamazepine (CBZ)-25, phenytoin (PHT)-25, lamotrigine (LTG)-25] and 25 NC. Sexual function scores (S-Score), hormone levels [dehydroepiandrosterone sulfate (DHEAS), bioactive (BA) testosterone (T), estradiol (BAE), and androstanediol (BAL)] and the ratios of inhibitory to excitatory neuroactive metabolites of T, i.e., BAL/BAE, were compared among groups. RESULTS: S-scores, DHEAS, and bioactive testosterone (BAT) were significantly (p < 0.05) lower and BAL and BAL/BAE were significantly higher among CBZ and PHT groups than among NC and LTG groups. LTG did not differ from NC in any of these measures. BAT correlated significantly with BAL/BAE for PHT (r = 0.44, p = 0.02) and CBZ (r = 0.42, p = 0.03) but not for NC (r = 0.03, p = NS) and LTG (r = 0.06, p = NS) groups. CONCLUSIONS: In comparison to LTG, enzyme inducing AEDs (CBZ, PHT) are associated with a more favorable neuroactive steroid balance (lower DHEAS and higher BAL/BAE) for seizure management, but at the expense of reduced serum bioavailable testosterone levels and sexual function.     

Thyroid Function with Antiepileptic Drugs

Serum thyroid hormone balance was assessed in 108 patients receiving chronic antiepileptic drug (AED) therapy. Forty-five patients were receiving carbamazepine (CBZ), 26 phenytoin (PHT), 16 CBZ-PHT, 11 valproate (VPA), and 10 CBZ-VPA. Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in patient groups receiving CBZ and/or PHT. Serum T4 concentrations were below the normal range in 24 (53.3%) CBZ patients, 11 (42.3%) PHT patients, 12 (75%) CBZ-PHT patients, and in all 10 patients (100%) receiving CBZ-VPA. Furthermore, serum levels of FT4 were below the normal range in 13 (28.9%) CBZ patients, 6 PHT (23.1%) patients, 5 (31.3%) CBZ-PHT patients, and 5 (50%) CBZ-VPA patients. Despite the decreased serum T4 and FT4 levels in these patients, serum basal and stimulated thyrotropin (TSH) concentrations were normal, except for the slightly increased basal TSH in the CBZ-VPA group. In the VPA group, the findings were different from those in other patients: T4 serum levels were unchanged and FT4, T3, and basal TSH levels increased, but stimulated TSH levels did not differ from those of the control group. The decrease in serum thyroid hormone levels during CBZ and/or PHT medication probably is caused by an accelerated hepatic plasma clearance of these hormones due to induction of hepatic microsomal enzyme systems by these AEDs. VPA, an AED with no liver enzyme-inducing properties, does not cause similar changes. The feedback mechanism is not activated, possibly because of a hypothalamic interference by CBZ and PHT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alteration of renal carnitine metabolism by anticonvulsant treatment

We administered therapeutic doses of valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PHB) to mice for 7 days, and 8 hours after the final dose we measured the concentrations of carnitine in serum, liver, kidney, skeletal muscle, and heart, and in the 7 days' accumulated urine. The results for serum and urine show that VPA induced a significant increase in renal clearance of acylcarnitine without affecting that of free carnitine, whereas CBZ, PHT, and PHB significant increased clearance of free carnitine but not that of acylcarnitine. Thus, VPA appears to reduce tubular resorption of acylcarnitine, and CBZ, PHT, and PHB appear to reduce tubular resorption of free carnitine.     

Interictal Cardiovascular Autonomic Responses in Patients with Epilepsy

Summary: Purpose: To evaluate the interictal autonomic nervous system function in 84 patients with epilepsy: 37 with newly diagnosed, previously untreated epilepsy, and 47 patients receiving long-term carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA) monotherapy, or CBZ plus PHT, or CBZ plus VPA for their seizure disorder. Methods: We assessed autonomic control of the cardiovascular regulatory system, by standardized cardiovascular reflex tests measuring changes in heart rate (HR) and blood pressure (BP) at rest and after certain stimuli. Results: The HR and BP responses were similar to those of control subjects in patients with newly diagnosed epilepsy. However, HR variation during normal breathing and maximum systolic BP increase in isometric work were diminished in patients, who had been treated with antiepileptic drugs (AEDs) for epilepsy for a long time. Diminished HR responses to the Valsalva maneuver were noted in patients receiving CBZ as monotherapy and during deep breathing in patients receiving CBZ combined with PHT or VPA. Furthermore, patients receiving CBZ had diminished BP responses in isometric work. When analyzed in relation to epilepsy type, suppressed HR responses in normal breathing were associated with primary generalized epilepsy (PGE), whereas diminished BP responses in isometric work were associated with partial epilepsy. Two patients with recently diagnosed partial epilepsy and 1 patient receiving long-term CBZ monotherapy for partial epilepsy had two abnormal cardiovascular response test results. Conclusions: Our results show that cardiovascular responses mediated by both the parasympathetic and sympathetic nervous system are diminished in patients with epilepsy. However, the changes appear to be clinically significant in only a few of them and appear to be associated with CBZ medication. Further studies are needed to detect the underlying complex interactions and clinical significance of autonomic nervous system dysfunction in patients with epilepsy.     

Rapid Switchover to Carbamazepine Using Pharmacokinetic Parameters

Summary: Purpose: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the singledose kinetic study can yield the desired concentration at steady state (C_ss); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period. Methods: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) andor primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean C_ss of 10.2 (±2.2) mgA. On day 2, patients received a CBZ dose equivalent to 10 mgkg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1: PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mgA was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED. Results: All patients completed the switchover to CBZ within a mean time period of 6 days (±2), reaching a mean maintenance dose of 1, 639 mg/day (±370) which yielded a mean C_SS of 11.3 (±3.2) mg/l. The maintenance dose had to be lowered by 20.4% (±8.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients 2–55 years (p = 0.017, Fisher's exact test). Conclusions: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.     

Carbamazepine and phenytoin: combination versus single drug therapy

The records of 18 patients with intractable partial seizures who were observed on an in-patient epilepsy unit during single drug treatment with carbamezepine (CBZ) or phenytoin (PHT) and during combination therapy with both drugs were evaluated retrospectively. Seizure frequency was significantly lower during combination therapy (p < 0.01) and toxicity, as measured by an eight point objective scale, did not increase significantly (p > 0.10). In addition subjective signs of clinical toiicity (e.g. nausea, ataxia, etc.) increased only slightly during combination versus monotherapy. These findings were consistently seen whether the data were evaluated in total (i.e. treatment periods at least 7 weeks) or evaluated by using standardized 35 day treatment periods. In the absence of a blinded clinical trial evaluating PHT/CBZ combination, these findings support consideration of this combination in Intractable patients who have failed rigorously administered mono-therapy trials, recognizing however that only a small percentage of patients will improve on combination therapy.     

Influence of D-Cycloserine on the Anticonvulsant Activity of Phenytoin and Carbamazepine Against Electroconvulsions in Mice

Summary: Purpose: D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl+-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. Methods: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electro-shock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. Results: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electro-convulsive seizures. DCS in a wide range of doses (1.25–40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. Conclusion: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.     

常用抗癫痫药对大鼠胚胎毒性的比较

对临床常用的三种抗癫痫药(AEDs)苯妥英钠(PHT)、丙戊酸内(VPA)和卡马西平(CBZ)进行胚胎毒性的比较,以期找到一种胚胎毒性较低的AEDs。用人类平均治疗量的10倍AEDs给予怀孕母鼠。孕末时,对其胎鼠进行胚胎毒性的鉴定。PHT组除了上枕骨骨化程度低于对照组外,未见其它胚胎毒性。VPA和CBZ组的胚胎毒性高于对照组。VPA组又高于CBZ组。VPA胚胎毒性最强,CBZ次之,PHT最弱。     

A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy

PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.     

Pregnancy and teratogenicity of antiepileptic drugs

Maternal use of antiepileptic drugs (AEDs) during pregnancy has been associated with an increased risk of congenital abnormalities in the fetus. This is partly attributable to AEDs. We aimed to analyse seizure frequency and the rate and type of any congenital malformation related to pregnancies in women with epilepsy in this prospective study. Eighty four pregnant women with epilepsy on AEDs were followed for congenital malformations. Z test was used for statistical analysis. Pregnancy did not influence the seizure frequency in 64 (76.2%) pregnancies. The seizure frequency increased in 16 (19.04%) pregnancies. In 4 (4.76%) pregnancies the number of seizures decreased during pregnancy. Overall percentage of congenital malformations in infants of mothers with epilepsy treated with AEDs was 10%, versus 3.65% in the general Turkish population. Percentages of malformations in children of pregnancies in women with epilepsy on antiepileptic drugs (AEDs) were; 6.52% (3/46) for carbamazepine (CBZ), 14.28% (2/14) for phenytoin (PHT), 13.33% (2/15)for valproic acid (VPA) and 20% (1/5) for phenobarbital (PB). This comfirms previous reports that all four AEDs (CBZ, PHT VPA, PB) are associated with an increased risk of congenital malformations, although CBZ seems to be the the safest agent in monotherapy.     

A comparative study of serum F protein and other liver function tests as an index of hepatocellular damage in epileptic patients

Gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) may not be sensitive indicators of hepatocellular damage in patients taking anticonvulsant drugs as raised levels may only reflect enzyme induction. Aspartate aminotransferase (AST) is a specific, but relatively insensitive marker of liver damage and has a poor correlation with liver histology. Serum F protein is found in high concentration in the liver and levels are not influenced by enzyme induction. We measured serum F protein levels in patients taking carbamazepine (CBZ) and phenytoin (PHT) as monotherapy and in patients receiving multiple drugs. We compared the results with patients taking sodium valproate (VPA). Serum F protein levels were elevated in 6%, 22% and 13% of patients receiving CBZ, PHT and VPA, respectively. Raised GGT levels were reported for both the CBZ (26%) and PHT (78%) groups. Raised ALP levels were observed in 16%, 25% and 4% of the CBZ, PHT and VPA groups, respectively. Raised levels of serum F protein in the VPA group and the absence of any associated increases in either GGT or AST may further support the suggestion that serum F protein is an indicator of hepatocellular dysfunction associated with anticonvulsant therapy. However, further correlation with liver histology is required.     

In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: insights into the mechanisms of pharmacoresistance

Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15-34 microM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg(2+)-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60-200 microM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.     

Adherence to antiepileptic drugs and beliefs about medication among predominantly ethnic minority patients with epilepsy

The current study examined beliefs about medication and their association with adherence to antiepileptic drugs (AEDs) among predominantly ethnic minority, low-income patients with epilepsy (PWE). Seventy-two PWE completed standardized questionnaires. The Beliefs about Medicines Questionnaire was used to assess perceptions about AEDs and medications in general. Adherence was measured with the Morisky 4-item scale and via participant self-rating. On the Morisky scale, 63% of patients endorsed at least one item for nonadherence; forgetfulness was most often endorsed (50%). There was a significant relationship between seizure frequency and adherence (Morisky: r = 0.33, P = 0.006; self-rating: r = − 0.35, P = 0.003). Patients with lower self-rated adherence expressed greater concerns about AEDs (r = − 0.25, P = 0.036) and beliefs that medications, in general, may be intrinsically harmful (r = − 0.26, P = 0.032) and minimally beneficial (r = 0.36; P < 0.002), as compared with more adherent patients. These findings inform future educational interventions in this population of PWE.