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PubMedDate not supplied

Pharmacokinetics and metabolism of vigabatrin following a single oral dose of [14C]vigabatrin in healthy male volunteers.

14C-labeled vigabatrin (50 microCi), an antiepileptic drug, was administered to six healthy male volunteers as a single oral dose containing 1500 mg of vigabatrin to determine the disposition profile of 14C and parent drug, and to investigate the metabolism of vigabatrin in humans. Vigabatrin was well tolerated by all subjects. There were no clinically important changes in any clinical laboratory parameter. Plasma concentration profiles of both 14C and vigabatrin exhibited biexponential decay. AUC, Cmax, Tmax, and terminal phase t1/2, for 14C were consistently greater than vigabatrin (248.2 vs. 176.0 micrograms-hr/ml; 48.8 vs. 42.8 micrograms/ml; 0.7 vs. 0.6 hr; and 9.5 vs. 7.7 hr, respectively). Mean renal clearance, oral clearance, and volume of distribution for 14C was consistently lower than vigabatrin (1.20 vs. 1.45 ml/min/kg; 1.26 vs. 1.77 ml/min/kg; and 1.01 vs. 1.18 liters/kg, respectively). The mean percentage of recovery of 14C in urine was higher than vigabatrin (95.4 vs. 82.0%). The mean percentage of recovery of 14C in feces was 1.0%. Concentration ratios of 14C showed that vigabatrin distributes into red blood cells at a concentration of 30-80% of that in plasma. The concentration of vigabatrin in saliva was approximately 10% of that in the plasma. The main radioactive component eliminated in the urine was vigabatrin. Two minor urinary metabolites (< 5% of total dose) of vigabatrin were detected using liquid scintillation counting of HPLC eluant fractions. One urinary metabolite was identified by thermospray-LC/MS as the lactam metabolite of vigabatrin.

Administration, Oral↗
PubMed1993

Determination of GABA and vigabatrin in human plasma by a rapid and simple HPLC method: correlation between clinical response to vigabatrin and increase in plasma GABA.

The novel antiepileptic drug vigabatrin (Sabril) acts by inhibiting degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), increasing the GABA concentrations in the brain. Because the GABA degrading enzyme GABA aminotransferase (GABA-T) is also present in peripheral tissues, including blood platelets, measurement of plasma GABA levels might be a useful indication of the pharmacological response to vigabatrin during therapeutic monitoring. However, because of the very low concentrations of GABA in plasma, the few methods available for plasma GABA analysis are time-consuming, difficult to perform and/or not selective enough because of potential interference with other plasma constituents. In the present study, a rapid, selective and sensitive amino acid analysis HPLC method has been developed for plasma GABA determination with fluorescence detection, using o-phthaldialdehyde as a precolumn derivatizing agent. By employing a 3 microns particle size reversed-phase column and a multi-step gradient system of two solvents, the very low endogenous concentration of GABA in human plasma could be reproducibly quantitated without interference of other endogenous compounds. Incubation of human plasma samples with GABA degrading enzyme(s) resulted in an almost total loss of the GABA peak, thus demonstrating the specificity of the method for GABA analysis. In addition to GABA and other endogenous amino acids, the HPLC method could be used to quantitate plasma levels of vigabatrin. Thus, this improved HPLC amino acid assay might be used to examine whether concomitant monitoring of plasma GABA and vigabatrin is useful for clinical purposes. This was examined in 20 epileptic patients undergoing chronic treatment with vigabatrin. The average plasma GABA level of these 20 patients did not differ significantly from non-epileptic controls. However, when epileptic patients were subdivided according to their clinical response to vigabatrin, vigabatrin responders had significantly higher GABA levels than nonresponders or controls. In contrast to the difference in plasma GABA, vigabatrin responders and nonresponders did not differ in dose or plasma level of vigabatrin. These data may indicate that determination of plasma GABA is a valuable non-invasive method for therapeutic monitoring in patients on medication with vigabatrin.

Adult↗
PubMed1996

A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Vigabatrin Protocol 024 Investigative Cohort.

This study compared the efficacy and tolerability of vigabatrin 3/day as add-on therapy with that of placebo in patients with focal epilepsy whose complex partial seizures were difficult to control with established antiepilepsy drug therapy. We enrolled 203 patients; 182 (90 placebo; 92 vigabatrin) received drug therapy under double-blind conditions. We increased the daily dosage to 2.5 g/day during a 4-week titration segment and maintained it at 3 g/day during the 12-week maintenance segment. By analyses we found a statistically significant lower frequency of seizures (complex seizures plus partial seizures secondarily generalized) at the end of the study for patients receiving vigabatrin than for those receiving placebo. The median monthly frequency was reduced by three seizures per 28 days in the placebo group (baseline, 8.3; end of study, 7.5) (p = 0.0002). Therapeutic success (a 50% reduction from baseline in mean monthly seizure frequency) was attained in 40 of the vigabatrin patients (43%) compared with 17 of those treated with placebo (19%) (p < 0.001). Vigabatrin significantly increased the mean number of seizure-free days per 28 days (2.2 days) compared with placebo (0.5 days) (p = 0.0024). Mean trough serum vigabatrin concentration during therapy was 8.6 +/- 7.7 micrograms/ml. The oral clearance of vigabatrin was determined to be 7.8 L/hr, and the elimination half-life was 8.4 hours. No clinically important changes in MRI, evoked potential, or other laboratory tests were noted during vigabatrin treatment. The results of this study indicate that 3 g/day vigabatrin is more effective than placebo as add-on therapy. Vigabatrin was well tolerated, compliance was high with twice-daily administration, and therapy did not result in clinically relevant drug interactions.

Adolescent↗
PubMed1999

Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group.

BACKGROUND: Vigabatrin is a newly licensed drug for use in patients with epilepsy. We investigated whether this drug was comparable to standard first-line monotherapy in efficacy and incidence of adverse events. METHODS: We enrolled 459 patients with newly diagnosed, previously untreated partial epileptic seizures from 44 European centres and randomly assigned them carbamazepine 600 mg daily (n=230) or vigabatrin 2 g daily (n=229). After initial maintenance doses were reached, doses were adjusted downwards (in the case of adverse events) or upwards (in the case of seizures) by the clinician. The primary outcome was time to withdrawal because of lack of efficacy or adverse events. Secondary outcomes included efficacy (time to 6-month remission of seizures, time to first seizure after initial dose stabilisation), and adverse events (incidence and severity). Analysis was by intention to treat. FINDINGS: Time to withdrawal for lack of efficacy or adverse events did not differ between groups (p=0.318). Vigabatrin was better tolerated than carbamazepine with fewer withdrawals, but was more frequently associated with psychiatric symptoms (58 [25%] vs 34 [15%]) and weight gain (25 [11%] vs 12 [5%]). Carbamazepine was associated with rash (22 [10%] vs seven [3%]). All efficacy outcomes favoured carbamazepine and failed to show equivalence between the two drugs. No significant difference was found for time to achieve 6 months of remission from seizures (p=0.058), but the most powerful outcome, time to first seizure after the first 6 weeks from randomisation, showed carbamazepine to be significantly more effective than vigabatrin (p=0.0001). INTERPRETATION: Vigabatrin seems less effective but better tolerated than carbamazepine, which is the first-choice drug for the treatment of partial epilepsies. Vigabatrin cannot therefore be recommended as a first-line drug for monotherapy in this group of patients.

Adolescent↗
PubMed2002

The effects of GABA and vigabatrin on horizontal cell responses to light and the effect of vigabatrin on the electroretinogram.

When used as an antiepileptic drug in humans vigabatrin, which is a GABA analogue and an inhibitor of GABA-aminotransferase, often causes peripheral visual field loss. This could result from increases in endogenous GABA levels. Accordingly we have investigated the effects of GABA on horizontal cells (HCs) of the rabbit retina, and of vigabatrin, when applied for only a few minutes, on HCs and on the electroretinogram (ERG). The intracellular HC and ERG records were first obtained from isolated rabbit retinas during perfusion with a physiological solution. The perfusate was then changed to one containing GABA (2 mM) or vigabatrin (25, 40 or 150 microM) for at least 5 min, and then returned to the control solution. 2 mM GABA significantly but reversibly reduced the light responses of HCs elicited by diffuse light (at -4 log intensity) to 52 +/- 17% (SD, n = 7). Vigabatrin had no significant effect on the light responses of HCs (n = 7), and no effect on the b-wave (n = 4), but the PIII-component of the ERG was slightly but significantly reduced to 84 +/- 5% (SD, n = 5). The high dosage of GABA needed to affect the light responses of HCs could be due to strong GABA uptake systems in the intact rabbit retina. It is, however, possible that in humans receiving long-term treatment with vigabatrin, high levels of GABA occur because of the inhibition of GABA- aminotransferase. It seems, from these observations, that neurons like on-bipolar cells, which are contributors to the b-wave, and HCs are uninfluenced by vigabatrin in short-term experiments. The slightly reduced slow PIII-component, however, indicates an influence on the glial Müller cells which are the main contributors to the slow PIII-component.

Animals↗
PubMed2000

Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in patients with partial seizures. In this study, the efficacy and tolerability of VGB as adjunctive therapy were evaluated in patients with refractory epilepsy. Adult patients with a definite diagnosis of complex partial seizures and/or partial seizures secondarily generalized were recruited from 10 Canadian centres. Patients were randomized to receive either active medication or placebo in a double- blind fashion and entered a 36-week titration and maintenance phase with regularly scheduled visits. Both efficacy parameters and safety assessments were monitored. Clinical laboratory, evoked potential studies, MRI, and neuropsychological tests were also performed. Forty-eight percent of VGB-treated patients vs. 26 percent of placebo-treated patients had a 50 percent or greater reduction in the frequency of complex partial seizures and partial seizures secondarily generalized. Vigabatrin was well tolerated by the majority of patients. Minor neurological side effects were observed in a number of patients in both treatment groups. No serious systemic toxicity was observed. No changes in evoked potential studies or MRI findings were noted. Vigabatrin was found to be an effective and well-tolerated antiepileptic drug when used as adjunctive therapy in patients with difficult to control complex partial seizures and for partial seizures secondarily generalized. Vigabatrin is a selective irreversible inhibitor of the GABA- degradating enzyme GABA transaminase and has shown efficacy in a number of clinical trials in patients with difficult to control partial seizures. Vigabatrin has been found most effective against complex partial and secondarily generalized tonic-clonic seizures in both adults and children. Vigabatrin has also been shown to reduce infantile spasms secondary to various aetiologies and is most effective in spasms associated with tuberous sclerosis. The aim of this study was to further extend the clinical experience with VGB as adjunctive therapy in the treatment of adult patients with difficult to control complex partial seizures and/or partial seizures secondarily generalized. In addition to the assessments of efficacy and tolerability to VGB, neuropsychological evaluations were also carried out.

Adolescent↗
PubMed1994

Vigabatrin in uncontrolled seizures: Belgian clinical experience. The Belgian Vigabatrin Evaluation Group.

The antiepileptic activity of vigabatrin has been established in several double-blind, placebo-controlled, clinical trials. The purpose of this study was to evaluate the efficacy and tolerability of this new antiepileptic drug in normal clinical practice rather than in controlled studies. A total of 102 patients (46 females and 56 males, ranging in age from 1 to 62 years) with previously uncontrolled seizures were treated with vigabatrin (0.5-4 g/day) as add-on medication, on an individual patient basis by 39 neurologists, for a mean duration of 235 days (range 30-520 days). Efficacy of vigabatrin was assessed after 3 months of therapy. Sixty-five patients (63.7%) showed a > 50% decrease in seizure frequency, and 12 patients (11.7%) became seizure-free. Thirty-one patients (29.4%) experienced a < 50% decrease or no change in seizure frequency, and 6 patients (5.9%) had an increase in seizure frequency. Adverse events, nearly all of mild severity, were reported in 27 patients (26.5%). These data are remarkably similar to previous placebo-controlled studies and support that vigabatrin is beneficial to a significant number of patients with previously uncontrolled seizures.

Adolescent↗
PubMed1992

Single-blind, placebo-controlled multicenter trial of vigabatrin in the treatment of epilepsy. The Italian Study Group on Vigabatrin.

A single-blind, placebo-controlled multicenter trial of vigabatrin was carried out in 101 epileptic patients (mostly with partial seizures) refractory to conventional therapy. The study design included four consecutive periods: (i) an observation phase (run-in), (ii) a placebo period, (iii) fixed-dosage add-on vigabatrin (2 g/day) and (iv) dose titration (up to a maximum of 4 g/day) to optimize clinical response. Each period lasted 8 weeks, except for the titration phase, which could be extended to 16 weeks. 90 patients completed the trial. Eleven dropped out, one patient developing absence status and 4 cases showing an increased seizure frequency. In the patients completing the trial, the median number of seizures/month decreased from 16 (inter-quartile range 8-34) during placebo to 5 (2-10) during the last 8 weeks on vigabatrin (p < 0.0001). Both partial and generalized tonic clonic (mostly secondary) seizures were significantly reduced. A greater than 50% reduction in seizure frequency (compared to placebo) was observed in 60 patients. Sedation and weight gain were the most frequently reported adverse events.

Adolescent↗
PubMed2000

Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) has been shown in a number of clinical trials with varying designs to be effective and well-tolerated as both add-on therapy and monotherapy in epilepsy with partial seizures with or without secondary generalization as well as in infantile spasms. The present study is an open, long-term (1 year) extension of a randomized double-blind placebo-controlled multicentre Canadian trial of VGB in resistant partial adult epilepsy. The present study was designed to examine the safety and long-term efficacy of VGB. Completers of the preceding double-blind study had their dose of VGB titrated to 4 g/day over 3 weeks. Patients were evaluated every 2-4 weeks and at week 14 were allowed to continue only if they achieved a 50% seizure reduction compared with pre-VGB baseline. In addition to neurological and physical examinations, safety was assessed by a cognitive psychosocial test battery, visual and somatosensory evoked potentials and MRI scans. Ninety-seven of 100 eligible patients entered the study, 53 of whom completed the 52 weeks. Fifty-eight percent of the patients had a greater than 50% seizure reduction in seizures vs. pre-VGB baseline. Seizure reductions of 56% and 45%, respectively, were seen in the VGB and placebo groups from the preceding study. Fifty-four percent of patients were judged by the investigators to have experienced at least a moderate therapeutic effect. Discontinuations were 29% for lack of efficacy and 12% for adverse effects. There was a mean weight gain of 3.7 +/- 0.2 kg by end of study. Neurologica/psychiatric side effects were the most common reason for withdrawal including three behavioral reactions attributed to the drug which required temporary hospitalization. There were no abnormalities on laboratory or special tests and there was a tendency for improvement on most tests of cognitive function and mood. Vigabatrin, as an add-on agent, is well-tolerated and can be of long-term benefit in a substantial proportion of patients with intractable partial epilepsy.

Adolescent↗
PubMed1992

Effects of single and multiple increasing doses of vigabatrin on brain GABA metabolism and correlation with vigabatrin plasma concentration.

UNLABELLED: The effects of increasing (50-1600 mg/kg/day) doses of vigabatrin (GVG) both as single doses and after 8 or 28 days of treatment have been studied in 19 groups of 10 adult Wistar rats. The parameters studied were brain gamma-aminobutyric acid-transaminase (GABA-T) activity, GABA concentration and L-glutamate decarboxylase (GAD) activity. Single increasing doses of GVG progressively inhibited GABA-T activity, but a residual activity of about 40% was observed with the highest doses. GABA concentration increased in a dose-dependent manner but a ceiling was not reached. GAD activity was slightly inhibited at low doses and stimulated at high ones. When treatment was continued for 8 days, more marked effects of GVG on GABA-T and GABA, a more severe toxicity and higher GVG plasma concentrations were observed. GAD was inhibited instead of stimulated by high GVG doses. After 28 days of treatment the effects of GVG on GABA-T and GABA were similar to those after 8 days. However, toxic effects decreased and lower GVG plasma concentrations were found. IN CONCLUSION: (a) the more marked brain GABAergic effects observed after 8 days of treatment with GVG may explain the greater anticonvulsant effects observed by others in animals, and (b) GVG plasma concentrations correlate well with changes in brain GABA-T and GABA, and may partly explain changes in the effects of GVG related to the length of treatment.

4-Aminobutyrate Transaminase↗
PubMed1995

Vigabatrin in unsatisfactory controlled epilepsies. Swiss Vigabatrin Study Group.

One hundred and twenty-seven patients with uncontrolled epilepsy have been treated in an open add-on study with vigabatrin with a mean follow up of ten months. Mean duration of epilepsy prior to treatment was seven-teen years. Patients with partial seizures, with and without secondary generalisation responded best with 44% achieving a greater than 50% reduction in seizure frequency. Adverse events were primarily CNS related and reversible, two patients were withdrawn because of somnolence and eight because of behavioral disturbances. Reduction of concomittant AEDs was difficult in this population with chronic epilepsy.

Adolescent↗
PubMed2000

A controlled study of vigabatrin and visual abnormalities.

AIMS: To assess the visual function in epileptic patients who have received vigabatrin; to compare this with the visual function in similar epileptic patients who have never received vigabatrin; to investigate whether the severity of visual field defect (VFD) is related to the dose of vigabatrin; to consider other factors that may correlate with the severity of VFD. METHODS: 21 consecutive patients who had taken vigabatrin at some time in their lives were enrolled from the epilepsy clinic of the Royal Shrewsbury Hospital and were compared with a group of 11 otherwise similar patients with epilepsy who had never received vigabatrin. One patient taking vigabatrin was excluded from the study because her visual field results were unreliable because of multi-infarct dementia. 15 patients were taking vigabatrin at the time of the study (VC), the other five had taken vigabatrin some time in the past (VP). Each patient underwent static perimetry using either the two point or the three point full field 120 screening program on the Humphrey visual field analyser, followed by an ophthalmic examination to rule out ocular causes for VFDs. The visual fields from each patient were then analysed using a method devised to convert the VFD into percentage defect in both eyes. In patients with known cerebral pathology that may affect the visual pathway, only the unaffected homonymous hemifield was used. RESULTS: Nine of 20 (45%) patients in the vigabatrin group (VC and VP) complained of blurring of vision compared with two of 11 (18%) controls. Four patients (20%) in the vigabatrin group described flickering lights compared with one control (9%). None had a posterior vitreous detachment. Three of 30 (7.5%) eyes in the VC group had distant visual acuity of 6/12 or worse compared with three of 22 (9%) controls and five of 30 (16.7%) had near visual acuity worse than N6 compared with one of 22 (4.5%) in the control group. A mean of 1.73 Ishihara plates were misread in VC patients compared with 0.2 in the VP group and 0.18 in the controls. 11 of 15 (73.3%) patients in the VC group had greater than 10% VFDs as opposed to one of 11 (9.1%) controls (chi(2) test, p=0. 002). In 12 of 15 (80%) VC patients the percentage VFD was greater in the nasal hemifields than the temporal hemifields compared with six of 11 (54.5%) controls. Significant correlation was found between the severity of VFD and the total dose of vigabatrin ingested for the 20 patients exposed to vigabatrin (VC and VP: Spearman correlation coefficient=0.525; p=0.002), for the 15 patients taking vigabatrin at the time of examination (VC: Spearman correlation coefficient=0.568; p=0.002). CONCLUSION: This pilot study suggested that epileptic patients taking vigabatrin are at much higher risk of developing VFDs compared with epileptic patients on other antiepileptic drugs. The total ingested dose of vigabatrin correlated significantly with the severity of VFDs especially in those patients who had not stopped taking vigabatrin. In our group we found that those who had taken a total dose of 1500 g or more of vigabatrin were at risk of developing significant visual field defects.

Adult↗
PubMed1992

Vigabatrin. Clinical pharmacokinetics.

Vigabatrin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is supplied as a racemic mixture, with the S(+) enantiomer possessing pharmacological activity. [R,S]-Vigabatrin plasma concentrations can be estimated using high-performance liquid chromatographic methods. Only gas chromatography-mass spectrometry methods allow quantification of the S(+) and R(-) enantiomers. Vigabatrin was rapidly absorbed reaching peak concentrations within 1 to 2h. Area under plasma concentration-time curves indicated dose-linear pharmacokinetics. There was no effect of food on the absorption of vigabatrin. The absorption characteristics of the enantiomers were similar to those of the [R,S]-vigabatrin. No chiral inversion was detected after administration of the pure S(+) enantiomer. Vigabatrin is not protein bound. The apparent volume of distribution of [R,S]-vigabatrin was approximately 0.8 L/kg. Despite the lack of protein binding, cerebrospinal concentrations of the [R,S]-vigabatrin were only 10% of the plasma concentration 6h after a single oral dose. The half-life of [R,S]-vigabatrin was between 5.3 and 7.4h, the half-life of the enantiomers were 7.5 and 8.1h for the S(+) and the R(-) forms, respectively. The major route of elimination was renal excretion; urinary recovery of the [R,S]-vigabatrin was close to 70%. Pharmacokinetic studies in epileptic children did not show any significant effect of maturation on the disposition of the S(+) enantiomer: the half-life and the renal clearance were similar to adult values. Data suggest a lower bioavailability in children. In adults with epilepsy, the half-life of the [R,S]-vigabatrin ranged from 4.2 and 5.6h, similar to that measured in healthy adults. In elderly nonepileptic volunteers the pharmacokinetics of the enantiomers of vigabatrin showed delayed absorption, a major increase in peak concentration and a prolonged half-life. These changes were attributed to decreased renal clearance of vigabatrin. A nonlinear relationship between renal clearance and creatinine clearance was suggested. Vigabatrin caused a 20% fall in plasma phenytoin concentrations, the mechanism of which has not been elucidated. There were no other interactions with most concurrently administered anticonvulsants. The usual dosage of vigabatrin as add-on treatment in adults is 2 to 4g daily. Higher dosages up to 80 mg/kg daily were required in children. A dosage adjustment was recommended in any patient with decreased renal clearance. Although anticonvulsant effects were clearly related to dosage, monitoring of plasma concentrations of vigabatrin as a guide to dosage is unlikely to be of as much value as with other antiepileptic drugs. The action of the drug long outlasts its presence in plasma.

Administration, Oral↗
PubMed2001

Visual field defects with vigabatrin: epidemiology and therapeutic implications.

Vigabatrin is an antiepileptic drug (AED) that acts as a selective irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase. In 1997, 3 cases of severe symptomatic and persistent visual field constriction associated with vigabatrin treatment were described. During 1997 to 1998, similar concentric visual field constrictions were described in patients with drug-resistant epilepsy who were receiving vigabatrin concurrently with other AEDs. However, a study of patients treated with vigabatrin monotherapy alone showed that there was a causal relationship between vigabatrin treatment and the specific bilateral concentric visual field constriction. The Marketing Authorisation Holders survey (involving 335 vigabatrin recipients aged >14 years) indicated that 31% of patients [95% confidence interval (CI) 26 to 36%] had a visual field defect attributable to vigabatrin, compared with a 0% incidence of visual field defects (upper 95% CI 3%) in an unexposed control group. Other studies in adults have given similar overall prevalences, with a total of 169 of 528 patients diagnosed with vigabatrin-associated field defects (32%, 95% CI 28 to 36%). Male gender seems to be associated with an increase in the relative risk of visual field loss of approximately 2-fold. The pattern of defect is typically a bilateral, absolute concentric constriction of the visual field, the severity of which varies from mild to severe. Data gathered so far suggest that the cumulative incidence increases rapidly during the first 2 years of treatment and within the first 2 kg of vigabatrin intake, stabilising at 3 years and after a total vigabatrin dose of 3 kg. The prevalence of vigabatrin-associated field defects seems to be lower in children, but there are also methodological problems and greater variability in the assessment of visual fields in children. There is particular concern that the increased risk of the visual field defects will outweigh the benefit of the drug in patients who could be controlled with other AEDs. Vigabatrin should currently be used only in combination with other AEDs for patients with resistant partial epilepsy when all other appropriate drug combinations have proved inadequate or have not been tolerated. Regular visual field testing should be performed before the start of treatment and at regular intervals during treatment. Patients with pre-existent visual field defects due to other causes should not be treated with vigabatrin. Currently, the benefits of treating infantile spasms with vigabatrin monotherapy seem to outweigh the risks, but further prospective studies and follow-up of children receiving treatment are needed to evaluate the place of vigabatrin in this indication.

Animals↗
PubMed2001

Increased vigabatrin entry into the brain by polysorbate 80 and sodium caprate.

The effects of a non-ionic surfactant, polysorbate 80, and the sodium salt of the saturated fatty acid, sodium caprate (C10), as potential brain absorption enhancers for vigabatrin were studied. Vigabatrin is an enzyme-activated irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase that increases brain and cerebrospinal GABA concentrations in animals and man. Before intravenous administration, a range of concentrations of the surfactants were tested using erythrocyte lysis or the red blood cell lysis test to establish the non-toxic concentration range. Vigabatrin was dissolved in 0.1% polysorbate 80 and 0.1% sodium caprate and administered intravenously in doses of 4 mL kg(-1) to male Wistar rats (230-250 g; n = 3). Rats were killed 2 h after drug and surfactant administration and the brains were immediately removed and homogenized in 0.4 M perchloric acid. Selected ion monitoring electrospray mass spectrometry was used to determine the concentration of vigabatrin and GABA directly from the perchloric acid extract of the rat brain. This method was developed to increase the speed and efficiency of the analysis by removing the need for complex extraction and derivatization procedures while retaining the specificity of the mass spectrometer as a detector. The stability of both vigabatrin and GABA in perchloric acid was established by monitoring their pseudo molecular ions in standard solutions at timed intervals over 24 h. Although the detection level for vigabatrin and GABA was at least 50 pg, only GABA was detected in rat brain. Vigabatrin caused a small increase in whole brain GABA. However, GABA levels were higher in the samples with vigabatrin + enhancer than in the samples where vigabatrin alone was administered. One-way analysis of variance indicated a significant effect of the surfactants on GABA levels (F (5,17) = 11.86, P < 0.01) and vigabatrin absorption was presumed. The rectal temperature of the rats is lowered by the presence of vigabatrin in the brain. Vigabatrin alone decreased rectal temperature by 6%. When given with either polysorbate 80 or sodium caprate, the extent of temperature lowering was significantly greater (P < 0.001). There was no significant difference after 2 h between polysorbate 80 + vigabatrin, and sodium caprate + vigabatrin.

Animals↗