Elaine Butler

Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (MDR1) Gene and Response to Antiepileptic Drug Treatment

Summary:  Purpose: P‐glycoprotein (P‐gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P‐gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C‐variant, which is associated with higher expression and increased activity of P‐gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic.

Circulating Hormones and Pituitary Responsiveness in Young Epileptic Men Receiving Long‐Term Antiepileptic Medication

Summary: Impairment of libido and sexual potency are commonly reported by male epileptic patients. This may be partly a consequence of medication. Circulating hormones were measured in 53 postpubertal male epileptic patients <45 years of age and in an age‐matched control group (n = 40), consisting of 14 untreated epileptic patients and 26 unmedicated healthy subjects. A subgroup also underwent a combined gonadotrophin‐ and thyrotro‐phin‐releasing hormone (LH‐RH/TRH) pituitary stimulation test. Untreated patients did not differ from healthy subjects for any parameter, and their data were combined for comparison with the treated epileptic patients. Total testosterone (T), androstenedione, and basal follicle‐stimulating hormone concentrations were similar in all patient groups. Patients receiving more than one drug had higher sex hormone binding globulin (SHBG) (p < 0.01) and lower free T and dehydroepiandrosterone sulphate (DHAS) levels (both p < 0.001) than controls. Carbam‐azepine (CBZ) monotherapy also reduced free T (p < 0.05) and DHAS (p < 0.001) and increased basal prolactin (p < 0.01). In these two groups of patients, basal luteinising hormone (LH) was elevated (p < 0.01), presumably as a pituitary response to increased T catabolism. There was a negative correlation between free T and circulating CBZ (r = ‐ 0.54, p < 0.05) in the monotherapy patients. Phenytoin (PHT) was associated with a rise in SHBG (p < 0.01) and a fall in DHAS (p < 0.001). Basal LH was also elevated, but this just failed to reach statistical significance (p < 0.1). Valproate (VPA) did not appear to affect the level of any measured hormone. Pituitary responsiveness to LH‐RH/TRH was similar for all groups, except for stimulated prolactin (PRL) levels, which were highest in the CBZ monotherapy patients (p < 0.05). These data suggest a differential, and possibly deleterious, influence of enzyme‐inducing antiepileptic drugs (AEDs) on sex hormone levels. Patients receiving more than one AED showed the greatest perturbation in hormone profile. Valproate may provide a useful alternative for male epileptic patients reporting sexual dysfunction.

P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.

Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls. AEDs were administered by subcutaneous injection and serum and brain drug concentrations determined at 30, 60, and 240min post-dosing. The brain-serum concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild-type controls at all time points investigated. No consistent effects were observed with any other AED investigated. These findings suggest that topiramate may be a substrate for P-gp-mediated transport. Further studies employing a range of model systems are required to substantiate this observation and to address the potential role of drug transporters in refractory epilepsy.

Visual field constriction: Accumulation of vigabatrin but not tiagabine in the retina

Background: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with γ-aminobutyric acid (GABA)–related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye. Methods: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. Results: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain. Conclusions: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.

Vigabatrin, but not gabapentin or topiramate, produces concentration-related effects on enzymes and intermediates of the GABA shunt in rat brain and retina

Summary:  Purpose: The antiepileptic drug (AED) vigabatrin (VGB), which exerts its pharmacologic effects on the γ‐aminobutyric acid (GABA) system, causes concentric visual field constriction in >40% of exposed adults. This may be a class effect of all agents with GABA‐related mechanisms of action. We compared the concentration‐related effects of VGB in rat brain and eye with those of gabapentin (GBP) and topiramate (TPM), both of which have been reported to elevate brain GABA concentrations in humans.

Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study

There have been anecdotal reports of raised glutamic acid decarboxylase (GAD) autoantibodies in patients with refractory epilepsy. We measured serum GAD autoantibodies in 105 patients with idiopathic or symptomatic epilepsy. There was no significant difference in the absolute titre of GAD autoantibody between patients with controlled and uncontrolled epilepsy. However, four female patients with uncontrolled epilepsy had levels that were over three times above the highest detected in the seizure-free group, three of whom also tested positive for pancreatic islet cell antibodies. Larger scale studies, perhaps comparing different epilepsy syndromes, are required to determine the exact clinical role of GAD autoantibodies in epilepsy.

Cognitive function in adult epileptic patients established on anticonvulsant monotherapy

A battery of psychometric tests was administered to 110 patients with epilepsy and to 24 non-epileptic controls. Eighty-four patients had been established on treatment with a single anticonvulsant drug (35 carbamazepine (CBZ), 30 sodium valproate (VPA), 19 phenytoin (PHT)) at unaltered dosage for the previous 3 months. The remaining 26 patients were untreated at the time of study. No individual test discriminated between the groups. Tests were converted to standard scores and summated to give overall psychomotor, memory and side-effect assessments. There were no important differences between the performances of untreated epileptic patients and non-epileptic controls. The CBZ-treated patients had poorer psychomotor scores than both control groups and the VPA-treated patients (all P less than 0.05). The PHT patients scored less well on the composite memory scale than did VPA patients and non-epileptic controls (both P less than 0.05). There were no significant differences in subjective side-effects among the groups. This study demonstrated that anticonvulsant monotherapy has little effect on overall cognitive function in patients tolerating treatment. Psychomotor performance appeared to be selectively influenced by CBZ and memory impaired by PHT. VPA may be the drug to chose when cognitive function is an important consideration. Different cognitive modalities can be affected by different first-line anticonvulsants and this should be taken into account when choosing the most appropriate drug for an individual patient.

Neurochemical actions of gabapentin in mouse brain

Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.

Regional Expression of Multidrug Resistance Genes in Genetically Epilepsy-prone Rat Brain after a Single Audiogenic Seizure

Summary:  Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P‐glycoprotein (P‐gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P‐gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy‐prone rat (GEPR) brain after a single audiogenic seizure.

Intradose and Circadian Variation in Circulating Carbamazepine and Its Epoxide in Epileptic Patients: A Consequence of Autoinduction of Metabolism

Summary: : Total and free carbamazepine (CBZ), and CBZ 10,11 epoxide (CBZ‐E) concentrations were measured over 24 h in 19 patients receiving CBZ 400 mg b.i.d. either as monotherapy (n = 13) or combined with another anticonvulsant (n = 6). Differences in CBZ and CBZ‐E disposition between day and night dosing were minor. Mean plasma CBZ concentrations were higher and CBZ‐E/CBZ ratios were lower in the monotherapy patients. Variations in total and free plasma CBZ levels were comparable in the monotherapy and polypharmacy groups. Peak free and total CBZ concentrations coincided at 4 h postdose. Free CBZ levels correlated significantly with total in each patient. The extent of variation in total plasma CBZ concentration during 24 h correlated significantly with antipyrine clearance in the monotherapy group. Circadian rhythms are unlikely to influence CBZ disposition to a clinically relevant extent. Measurement of peak and trough CBZ concentrations should improve the value of therapeutic drug monitoring. The diurnal variation in CBZ concentration appears related to the degree of autoinduction of metabolism and is substantial enough to warrant the development of a slow‐release preparation of the drug.