Double-Blind Dose Reduction Study of Vigabatrin in Complex Partial Epilepsy

Seventy-five epilepsy patients with at least two complex partial seizures/month were treated with gamma-vinyl GABA (GVG) 3 g/day for 3 months. Forty-one patients (54%) showed a reduction of greater than or equal to 50% in seizures. The median monthly seizure frequency decreased from 11.5 to 4 seizures/month. Twenty percent of patients had an improvement in general performance without a significant reduction in seizures. The responders entered the second phase of the study, in which 28 patients were randomly allocated to 3 g/day and 25 patients to 1.5 g/day GVG under double-blind conditions. The dosage of 3 g/day appeared to be clearly more effective than 1.5 g/day. However, even with 1.5 g/day GVG the seizure frequency was significantly reduced as compared to baseline. Drowsiness was the most commonly observed side effect, and it diminished with continued treatment. In three cases side effects led to the withdrawal of GVG therapy.     

Treatment with Vigabatrin May Mimic α-Aminoadipic Aciduria

Summary: Purpose : We describe a secondary effect of treatment with vigabatrin (VGB). A significant increase in α-aminoadipic acid (AAA) occurred in plasma and urine of VGB-treated children, thus mimicking a known rare metabolic disease, α-aminoadipic aciduria (AAAuria).
Methods : We studied eight children, aged from 3 months to 5 years, who were receiving VGB for drug-resistant partial epilepsies. Plasma and urine amino acids were assayed with ninhydrin detection on an automated Beckman 6300 analyzer.
Results : In eight out of eight children, there was a significant increase of AAA in plasma and in urine. Plasma values ranged from 7 to 18 μ M (control values, < 5) and urinary values from 67 to 274 mmol/mol creatinine (control values, < 25).
Conclusions : The concentrations of AAA in these VGB-treated children were as high as the concentrations found in the inherited metabolic disease, AAAuria. This could lead to incorrect diagnosis and to inappropriate genetic counseling. Thus whenever a genetic metabolic disease is suspected, amino acid chromatography testing should be performed before initiation of treatment with VGB.     

Effect of γ-Vinyl GABA on Interictal Spikes and Sharp Waves in Patients with Intractable Complex Partial Seizures

The effect of gamma-vinyl GABA (GVG) on the interictal electroencephalogram (EEG) was studied in 13 patients with intractable complex partial seizures who participated in a single-blind, add-on, multicenter clinical trial of GVG. Precise operational definitions of epileptiform paroxysms were used to evaluate records before and after 3 months and 1 year of treatment with GVG. After 3 months of treatment, six patients exhibited reduction of both epileptiform paroxysms and seizure frequency, four had no change in seizure frequency nor in the EEG, and three had a reduction in seizure frequency but no concomitant reduction of epileptiform paroxysms in the EEG. Ten patients remained in the study after 1 year of treatment. In 4 patients both seizure frequency and EEG epileptiform paroxysms continued to decrease, in 1 patient both seizure frequency and number of EEG paroxysms increased, and in the remaining 3 there was no correlation between seizure frequency and EEG changes.     

Vigabatrin

Summary: γ-Aminobutyric acid (GABA) was first proposed as a putative inhibitory neurotransmitter by Elliot and van Gelder in 1958. Since then, numerous efforts have been made to find ways to increase GABA at its receptor sites, based on the findings that decreased GABA results in convulsions in animals and that agents enhancing GABA-mediated functions can have antiepi-leptic effects. However, the relationship between GABA levels and seizures is not simple. Seizures can occur even in the presence of elevated GABA levels. Indeed, it is possible that regional biochemical differences in the brain can be important. The antiepileptic effects of GABA depend on the mechanism whereby GABA-mediated inhibition is enhanced. Since the 1970s, several compounds have been developed that are designed to act in some manner on the GABA system. These compounds affect GABA-mediated inhibition at different levels and appear to have varied effects, depending on their mechanism of action. To date, specific antiepileptic drugs (AEDs) with potential GABA-inhibitory effects have been designed either to have GABA agonist properties, to inhibit GABA catabolism, to inhibit GABA uptake, or to facilitate GABA release or facilitate GABA_A receptor activity. Vigabatrin (VGB) was designed specifically to inhibit GABA transaminase and thereby increase the availability of GABA in the brain. Study data and clinical experience over the past 14 years have demonstrated VGB to be an effective AED.     

Relationship Between Platelet and Brain GABA Transaminase Inhibition by Single and Multiple Doses of Vigabatrin in Rats

Vigabatrin (gamma-vinyl-GABA, GVG) is an inhibitor of brain GABA transaminase (GABA-T) that also inhibits platelet GABA-T in rats and humans. We have compared the effects of single and multiple doses of GVG on both enzymes in 19 groups of 10 adult male Wistar rats, treated with increasing GVG doses (0-1,600 mg/kg/day) for 1, 8, and 28 days. The platelet GABA-T was more sensitive to the inhibitory effects of GVG than the brain enzyme was especially with low dosages of GVG. After 8 days of treatment, higher GVG plasma levels and a higher inhibition of both enzymes were shown. However, after 28 days, lower GVG plasma levels and similar inhibition of both enzymes compared to the eighth day were found. Correlations between platelet and brain GABA-T for individual rats were statistically significant after 1 day (r = 0.40, p less than 0.01) but not after 8 and 28 days of treatment because of the total inhibition of platelet GABA-T and only partial inhibition of brain GABA-T. We concluded the following: (a) platelet GABA-T is more inhibited than brain GABA-T when low doses of GVG are used and (b) multiple doses reach a higher inhibition of both enzymes than single doses, which could be explained by an increase in GVG concentrations.     

Acute Effects of Vigabatrin on Brain GABA and Homocarnosine in Patients with Complex Partial Seizures

PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and maintenance of VGB as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week.     

Vigabatrin extracellular pharmacokinetics and concurrent γ-aminobutyric acid neurotransmitter effects in rat frontal cortex and hippocampus using microdialysis

Purpose:   To investigate the pharmacokinetic interrelationship of vigabatrin in blood and the brain (frontal cortex vs. hippocampus) and to ascertain the relationship between brain extracellular vigabatrin concentrations and concurrent γ-aminobutyric acid (GABA) concentrations.
Methods:   Sprague-Dawley rats were implanted with a jugular vein catheter for blood sampling, and microdialysis probes in the frontal cortex and hippocampus for extracellular fluid (ECF) sampling. Vigabatrin was administered intraperitoneally at two different doses (500 and 1,000 mg/kg), and blood and ECF were collected at timed intervals up to 8 h. Rats were freely moving and behaving. Vigabatrin (sera and ECF) and GABA (ECF) concentrations were measured with use of high performance liquid chromatography (HPLC).
Results:   Vigabatrin concentrations in blood rose linearly and dose-dependently, and vigabatrin rapidly appeared in the brain as evidenced by the detection of vigabatrin in the ECF of both the frontal cortex and hippocampus at time of first sampling (15 min). However, frontal cortex concentrations were twofold greater than those of the hippocampus. Furthermore, GABA concentrations increased five-fold in the frontal cortex but were unaffected in the hippocampus. In addition, GABA concentrations began to increase approximately 3 h after vigabatrin administration at a time when vigabatrin concentrations were in exponential decline.
Conclusions:   Vigabatrin distribution in the brain is region specific, with frontal cortex concentrations substantially greater than those seen in the hippocampus. Elevation of GABA concentrations did not reflect the concentration profile of vigabatrin but reflected its regional distribution.     

Experimental Febrile Convulsions in Epileptic Chickens: The Anticonvulsant Effect of Elevated γ-Aminobutyric Acid Concentrations

The high seizure susceptibility in epileptic chickens is due to an autosomal recessive mutation. In 3-day-old chicks homozygous for the epilepsy gene (epileptics), elevation of body temperature using microwave diathermy evoked an initial febrile seizure resembling the clonic seizures evoked in epileptic chicks by photic stimulation. After complete recovery, this was followed by a clonic-tonic seizure. In nonepileptic heterozygote hatchmates (carriers) of the same age, only the latter seizure pattern was observed. In 16- to 17-day-old chicks of either phenotype, both seizure patterns were observed during hyperthermia. In all cases, the temperature at which seizures occurred was significantly lower in epileptic than in nonepileptic chicks, indicating a lower threshold for febrile seizures when there is an inherited predisposition to convulse. The occurrence of seizures was dependent on the body temperature and not on the rate of rise of temperature. Elevation of the brain gamma-aminobutyric acid (GABA) concentrations by administration of the GABA transaminase inhibitor gamma-vinyl GABA reduced the incidence of the initial febrile seizures and increased the latency in those birds that were not fully protected.     

Pre- rather than co-application of vigabatrin increases the efficacy of tiagabine in hippocampal slices

PURPOSE: The antiepileptic drug vigabatrin (VGB) increases intracellular availability of the inhibitory transmitter gamma-aminobutyric acid (GABA) by inhibition of GABA-transaminase. A blockade of the GABA uptake is the main mechanism of action of tiagabine (TGB). Based on this, the two antiepileptic drugs (AEDs) can be speculated to act synergistically so that their combined antiepileptic efficacy is supraadditive. METHODS: To test this, experiments were performed on hippocampal slices of guinea-pigs. As an epilepsy model, epileptiform field potentials (EFPs) were induced by omission of Mg2+ from the bath solution and recorded in stratum pyramidale of the CA3 region. VGB (7.5 microM) and TGB (0.75 microM) were added to the superfusate. RESULTS: VGB, given alone, failed to decrease the repetition rate of EFPs. Similarly, TGB applied alone only transiently led to a nonsignificant reduction of the EFP frequency. Combining VGB and TGB, their suppressive efficacy increased, yielding a significant reduction of EFP frequency, which, however, again did not persist. Pretreatment of the preparations with VGB for 2 h, followed by additional application of TGB, or TGB alone, drastically and persistently potentiated the effects. CONCLUSIONS: These results demonstrate that VGB and TGB show favorable pharmacodynamic interactions, provided VGB is allowed to block intracellular GABA degradation before GABA uptake block by TGB.     

γ-Vinyl GABA (Vigabatrin) in Epilepsy: Clinical, Neurochemical, and Neurophysiologic Monitoring in Epileptic Patients

We report long-term clinical, neurochemical, and electrophysiologic data of gamma-vinyl GABA (GVG, vigabatrin) in three groups of patients. GVG was started as add-on therapy for 75 patients with refractory complex partial seizures (group A) and for 36 mentally handicapped patients with severe epilepsy (group B). The third group (C) consisted of 20 patients with carbamazepine (CBZ) monotherapy, in half of whom GVG monotherapy was substituted. After 3 months, 55% of patients in group A and 42% in group B were responders (reduction in seizure frequency greater than 50%). After 6 (group A) and 3 years (group B) of follow-up, 27 and 33% of the patients, respectively, still had good response to GVG. Neurochemical measurements showed a twofold increase in CSF GABA concentrations and minimal or no changes in other neurotransmitter-related parameters. In group C, substitution of GVG as medication tended to normalize the lengthened latencies in somatosensory evoked potentials (SEPs) observed during CBZ treatment.     

Valproate Effect on γ-Aminobutyric Acid Release in Pars Reticulata of Substantia Nigra: Combination of Push-pull Perfusion and Fluorescence Histochemistry

Summary: To study further the previously demonstrated suppressive in vivo effect of sodium valproate (VPA) on y-aminobutyric acid (GABA) release in the preoptic area, we examined GABA neurotransmission in substantia nigra (SN), using the push-pull cannula technique in freely moving ovariectomized rats. To clarify whether the area in the substantia nigra that is actually perfused is pars reticulata, known to receive rich GABAergic input from striatum, we used the retrograde fluorescence tracer fast blue (FB) after each perfusion experiment, applying the tracer through the push-pull cannula. Nigral perfusion with VPA caused significant suppression of local GABA release. This effect was more marked in a subgroup of animals showing retrograde labeled cell bodies in striatum, i.e., animals with a tracer application site and therefore also a perfusion site precisely in pars reticulata. Our data suggest that VPA inhibits GABA release in rat SN as it does in the preoptic area, which may be in agreement with our hypothesis of enhanced GABAergic neurotransmission by VPA, causing suppression of presynaptic GABA release through negative feedback actions on the GABA autoreceptor complex. Furthermore, the combination of push-pull cannula technique and retrograde fluorescence tracer application appears to be an important tool to prove afferent connections of the area actually perfused in neuronal networks.     

Comparative Study of the Anticonvulsant Effect of γ-Aminobutyric Acid Agonists in the Feline Kindling Model of Epilepsy

We made a comparative study of the anticon-vulsant effect of GABA agonists on feline amygdala or hippocampal kindled seizures. Progabide (PGB) [γ-ami-nobutyric acid (GABA) receptor agonist 25–100 mg/kg intraperitoneally, i.p.] significantly reduced both the kindled seizure stage and after discharge (AD) duration in a dose-dependent manner. SKF89976A (GABA uptake inhibitor 0.5–2.0 mg/kg i.p.) also significantly reduced the kindled seizure stage. Toxic doses of SKF89976A caused generalized paroxysmal EEG discharges and myoclonus, but AD generation in the kindled focus was suppressed completely. Furthermore, γ-vinyl GABA (GABA cata-bolic enzyme inhibitor, GVG 50–200 mg/kg i.p.) significantly reduced the seizure stage, while causing prolongation of the AD duration. In contrast, baclofen (selective GABA_B receptor agonist, 1 or 5 mg/kg) did not show anticonvulsant effects on any parameters of kindled seizures. Therefore, these GABA agonists, which potentiate the inhibitory function of the GABA_A systems, have potent anticonvulsant effects on partial onset and secondarily generalized limbic seizures.     

The effect on vision of associated treatments in patients taking vigabatrin: carbamazepine versus valproate

PURPOSE: To evaluate the effect on visual function of a concomitant antiepileptic drug (AED) in patients treated with vigabatrin (VGB). METHODS: Sixty-four consecutive patients with a history of partial seizures currently treated with VGB with either carbamazepine (CBZ) or valproate (VPA) were examined with automated kinetic perimetry, static perimetry, electrooculogram (EOG), and electroretinogram (ERG). An original device based on kinetic perimetry was developed to quantify the area of perception for each isopter. RESULTS: Fifty-two patients were finally included. The results showed a significant difference in patients treated with VGB-VPA compared with patients treated with VGB-CBZ concerning the mean defect of static perimetry and the peripheral and midperipheral isopter (III 4e and III 1a Goldmann equivalent, respectively) in kinetic perimetry. EOG and ERG results did not differ significantly between the two groups. CONCLUSIONS: The visual impairment due to visual field constriction was more important in patients treated with VGB and VPA compared with patients treated with VGB and CBZ. The origin of this difference between the two associations could not be related to any particular retinal electrophysiologic abnormality.     

Initial Observations on Effect of Vigabatrin on In Vivo 1H Spectroscopic Measurements of γ-Aminobutyric Acid, Glutamate, and Glutamine in Human Brain

Summary: Recent developments involving ¹H nuclear magnetic resonance (NMR) spectroscopic editing techniques have allowed noninvasive measurements of γ-aminobutyric acid (GABA) in human cerebrum. The additional information gained from GABA and macromolecule measurements permitted more precise glutamate (Glu) and glutamine (Gln) measurements. Occipital lobe GABA in 10 nonepileptic, healthy subjects was 1.0 μmol/g brain [95% confidence interval (CI) 0.9–1.1]. Vigabatrin (VGB) is a safe and effective antiepileptic drug (AED)that irreversibly inhibits neuronal and glial GABA transaminase. GABA levels were increased in all patients treated with VGB. With a standard dose of 3–6 g/day, GABA levels were 2.6 μmol/g (95% CI 2.3–2.8).Mean occipital GABA level measured in epileptic patients not receiving VGB was 0.9 μmol/g (95% CI 0.7–1.1). Gln was increased by 1.9 μmol/g and Glu was decreased by 0.8 μmol/g in patients receiving VGB as compared with patients receiving standard medications alone.     

Vigabatrin in the Treatment of Epilepsy: A Double-Blind, Placebo-Controlled Study

The efficacy and tolerability of vigabatrin (gamma-vinyl GABA, GVG), given as add-on therapy to 23 adult outpatients with severe drug-resistant epilepsy (17 with partial seizures), were studied using a double-blind, placebo-controlled, crossover design. The study consisted of two 7-week periods during which vigabatrin and placebo were administered in random sequence. Dosage was 1.0 g twice daily for patients weighing less than or equal to 65 kg and 1.5 g twice daily for patients weighing greater than 65 kg. Three patients were dropped from the study, two for reasons unrelated to treatment and one because of the appearance of vertigo, headache, dysarthria, and ataxia, which subsided rapidly when vigabatrin was stopped (3 g daily). Sixteen of the 20 patients available for analysis showed a decrease in the total number of seizures as compared with the placebo period. Of these, 12 showed a greater than 50% reduction in seizure frequency and 4 of the 12 showed a greater than 75% reduction. Both the total number of seizures and the number of partial seizures were significantly reduced by vigabatrin (p less than 0.01). Only in the patient who dropped out were severe adverse effects seen. The most frequently reported unwanted effect was mild drowsiness, which developed in seven patients on vigabatrin and in one on placebo. Positive effects, however, were also seen with six patients who reported an improved sense of well-being while receiving vigabatrin as compared with only 1 during the placebo period. No consistent changes in electrocardiogram (ECG), electroencephalogram (EEG), and visual-, auditory-, and somatosensory-evoked potentials were seen during the study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adverse Effects of Vigabatrin in Angelman Syndrome

Summary: New antiepileptic drugs designed for enhancing GABAergic inhibition, such as vigabatrin (VGB) may be effective in Angelman syndrome (AS), because associated convulsions could be related to a reduced GABA-receptor density or receptor abnormality. From our preliminary experiences in four children with AS treated with VGB, we conclude that it may induce and increase seizures in patients with AS.     

Comparison of Progabide with Other Antiepileptic and GABAergic Drugs

The effect of the experimental antiepileptic gamma-aminobutyric acid (GABA) agonist drug progabide, [alpha-(chloro-4-phenyl)fluor-5-hydroxy-2-benzilideneamino]-4-buty ramide, on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs and with the effect of various GABA agonists and antagonists. Intravenous administration of 10-40 mg/kg progabide depressed excitatory transmission and descending periventricular inhibition, similar to carbamazepine and phenytoin. However, progabide depressed, rather than facilitated, segmental inhibition. The serum levels of progabide were comparable with those in patients receiving long-term treatment with progabide. The GABA antagonist bicuculline had the opposite effect of progabide on our experimental model, but the other GABA agonists THIP (4,5,6,7-tetrahydroisoxazolo-5,4-C-pyridine-3-ol) and muscimol did not have the same effects as progabide. THIP had no effect on excitatory transmission, periventricular inhibition, or segmental inhibition, whereas muscimol facilitated periventricular inhibition and sometimes segmental inhibition and had no effect on excitatory transmission. Our experiments thus indicate that progabide, but not THIP or muscimol, should have antiepileptic properties, in agreement with the clinical experiences that have been reported. The reason for the differential effect of these three GABA agonists remains to be elucidated.     

Vigabatrin in low doses selectively suppresses the clonic component of audiogenically kindled seizures in rats

PURPOSE: The effect of systemic administration of the gamma-aminobutyric acid (GABA)-transaminase inhibitor vigabatrin (VGB) on different components of convulsions was tested in the model of audiogenically kindled seizures, which consist of brainstem (running, tonus) and forebrain (clonus) elements. METHODS: Audiogenically susceptible rats of Krushinsky-Molodkina (KM), Wistar, and WAG/Rij strains received repeated sound stimulation (60 dB, 10-80 kHz) until kindled audiogenic seizures were reliably elicited. Kindled audiogenic seizures consisted of running, tonic, and generalized clonic phases in KM rats (severe audiogenic seizures) and of running and Racine stage 5 facial/forelimb clonus in Wistar and WAG/Rij rats (moderate seizures). Vehicle, 100, or 200 mg/kg of VGB was intraperitoneally injected 2, 4 and 24 h before the induction of kindled audiogenic seizures. RESULTS: At both doses, VGB did not change the seizure latency and the duration of running and tonic convulsions, but suppressed clonic ones in all rat strains. In KM rats, the mean duration of posttonic clonus was significantly reduced at 24 h after 100 mg/kg and from 4 h after 200 mg/kg. In Wistar and WAG/Rij rats, the mean duration of facial/forelimb clonus was reduced from 4 and 2 h after 100- and 200-mg/kg administration, respectively; 24 h after the high-dose injection, clonus was completely blocked in all rats of both strains. No difference in efficacy of VGB between Wistar and WAG/Rij rats was observed. CONCLUSIONS: VGB more effectively suppresses clonic convulsions than running and tonic ones in audiogenically kindled rats. It is supposed that this selective anticonvulsive effect of VGB results from different sensitivities of forebrain and brainstem epileptic networks to the presumed GABA enhancement.     

Effects of Vigabatrin on Cognitive Function and Mood When Used as Add-on Therapy in Patients with Intractable Epilepsy

Cognitive function and mood of patients with epilepsy who received 2 g/day vigabatrin (GVG) in addition to their usual antiepileptic drugs (AEDs) was assessed on two occasions: before start of treatment (baseline) and 4 weeks after start of treatment. A battery of selected psychological tasks measuring attention, mental speed, motor speed, central cognitive processing, and perceptuomotor performance was used, along with standardized, objective mood assessments. A comparison group (n = 15) of patients receiving stable medication was also tested to evaluate practice effects of the psychometric tests. Administration of 2 g/day GVG significantly decreased response time on a test of central cognitive processing ability (arithmetic). No adverse effect was noted on any other test of cognitive function or mood.