Modulation of vigabatrin induced cerebellar injury: the role of caspase-3 and RIPK1/RIPK3-regulated cell death pathways.

Vigabatrin is the drug of choice in resistant epilepsy and infantile spasms. Ataxia, tremors, and abnormal gait have been frequently reported following its use indicating cerebellar involvement. This study aimed, for the first time, to investigate the involvement of necroptosis and apoptosis in the VG-induced cerebellar cell loss and the possible protective role of combined omega-3 and vitamin B12 supplementation. Fifty Sprague-Dawley adult male rats (160-200 g) were divided into equal five groups: the control group received normal saline, VG200 and VG400 groups received VG (200 mg or 400 mg/kg, respectively), VG200 + OB and VG400 + OB groups received combined VG (200 mg or 400 mg/kg, respectively), vitamin B12 (1 mg/kg), and omega-3 (1 g/kg). All medications were given daily by gavage for four weeks. Histopathological changes were examined in H&E and luxol fast blue (LFB) stained sections. Immunohistochemical staining for caspase-3 and receptor-interacting serine/threonine-protein kinase-1 (RIPK1) as well as quantitative real-time polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP), caspase-3, and receptor-interacting serine/threonine-protein kinase-3 (RIPK3) genes were performed. VG caused a decrease in the granular layer thickness and Purkinje cell number, vacuolations, demyelination, suppression of MBP gene expression, and induction of caspases-3, RIPK1, and RIPK3 in a dose-related manner. Combined supplementation with B12 and omega-3 improved the cerebellar histology, increased MBP, and decreased apoptotic and necroptotic markers. In conclusion, VG-induced neuronal cell loss is dose-dependent and related to both apoptosis and necroptosis. This could either be ameliorated (in low-dose VG) or reduced (in high-dose VG) by combined supplementation with B12 and omega-3.

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects.

Vigabatrin (VGB; (S)-(+)/(R)-(-) 4-aminohex-5-enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA-T), manifests use-limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6-8 animals/dose) for 12 days. VGB enantiomers, total GABA and ß-alanine (BALA), 4-guanidinobutyrate (4-GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC. Plasma VGB concentrations increased linearly by dose (3 ± 0.76 (35 mg/kg/d); 15.1 ± 1.4 (70 mg/kg/d); 34.6 ± 3.2 µmol/L (140 mg/kg/d); mean ± SEM) with an S/R ratio of 0.74 ± 0.02 (n = 14). Steady state S/R ratios (35, 70 mg/kg/d doses) were highest in eye (5.5 ± 0.2; P < 0.0001), followed by VC (3.9 ± 0.4), PFC (3.6 ± 0.3), liver (2.9 ± 0.1), and brain (1.5 ± 0.1; n = 13-14 each). Total VGB content of eye exceeded that of brain, PFC and VC at all doses. High-dose VGB diminished endogenous metabolite production, especially in PFC and VC. GABA significantly increased in all tissues (all doses) except brain; BALA increases were confined to liver and VC; and 4-GBA was prominently increased in brain, PFC and VC (and eye at high dose). Linear correlations between enantiomers and GABA were observed in all tissues, but only in PFC/VC for BALA, 4-GBA, and creatine. Preferential accumulation of the VGB S isomer in eye and VC may provide new insight into VGB ocular toxicity.

Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity?

Vigabatrin (VGB; γ-vinylGABA) is a unique antiepileptic directly elevating CNS GABA via inactivation of the GABA metabolic enzyme GABA-transaminase. VGB is effective in treating infantile spasms, a rare seizure disorder associated with significant morbidity. The potential for unexplained bilateral constriction of the visual field associated with VGB intervention can severely limit its temporal utility. Removal of this potential adverse effect with adjuvant intervention(s) would represent a significant advance in epilepsy therapeutics.

The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study.

BACKGROUND/AIMS: Retinal toxicity is one of the most commonly discussed and concerning adverse effects of vigabatrin (VGB). The present study explored the relationship between the VGB elicited retinal toxicity, photopic exposure, and taurine deficiency, aiming at screening for risk factors to minimize the adverse effects of VGB. METHODS: The effects of VGB on function and morphology of mouse retinas were examined via a series of in vivo tests, including electroretinography (ERG), Spectral domain optical coherence tomography (SD-OCT), and optokinetic testing. Moreover, VGB-treated mice were in addition treated with taurine to verify possible protective effects against retinal toxicity. RESULTS: A close relationship between VGB induced retinal toxicity and light exposure was observed. The VGB-treated mice which were reared in darkness preserved better visual function and retinal architectures as verified by the optokinetic tests, OCT and ERG examinations. The retinal taurine level of the VBG-treated mice which were exposed to light were significantly lower than that of the VBG mice reared in darkness. Furthermore, several in vivo evidence provided by our research confirmed that the VGB induced morphological and functional impairments could be partially alleviated by taurine treatment. The present study showed the retinal toxicity of VGB by in vivo measurements. CONCLUSION: The VGB induced retinal toxicity is closely associated with photopic exposure and taurine deficiency. Patients who are taking VGB might benefit from minimization of light exposure and dietetic taurine supplements.

Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.

We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.

Vigabatrin prevents seizure in swine subjected to hyperbaric hyperoxia.

Oxygen is the most widely used therapeutic strategy to prevent and treat decompression sickness (DCS). Oxygen prebreathe (OPB) eliminated DCS in 20-kg swine after rapid decompression from saturation at 60 feet of seawater (fsw). However, hyperbaric oxygen (HBO) has risks. As oxygen partial pressure increases, so do its toxic effects. Central nervous system (CNS) oxygen toxicity is the most severe side effect, manifesting as seizure. An adjunctive therapeutic is needed to extend OPB strategies to deeper depths and prevent/delay seizure onset. The Food and Drug Administration-approved anti-epileptic vigabatrin has prevented HBO-induced seizures in rats up to 132 fsw. This study aimed to confirm the rat findings in a higher animal model and determine whether acute high-dose vigabatrin evokes retinotoxicity symptoms seen with chronic use clinically in humans. Vigabatrin dose escalation studies were conducted 20-kg swine exposed to HBO at 132 or 165 fsw. The saline group had seizure latencies of 7 and 11 min at 165 and 132 fsw, respectively. Vigabatrin at 180 mg/kg significantly increased latency (13 and 27 min at 165 and 132 fsw, respectively); 250 mg/kg abolished seizure activity at all depths. Functional electroretinogram and histology of the retinas showed no signs of retinal toxicity in any of the vigabatrin=treated animals. In the 250 mg/kg group there was no evidence of CNS oxygen toxicity; however, pulmonary oxygen toxicity limited HBO exposure. Together, the findings from this study show that vigabatrin therapy is efficacious at preventing CNS oxygen toxicity in swine, and a single dose is not acutely associated with retinotoxicity.

Vigabatrin (VGB) administered during late gestation lowers maternal folate concentration and causes pregnancy loss, fetal growth restriction and skeletal hypoplasia in the mouse.

Vigabatrin (VGB) has several therapeutic advantages over older antiepileptic drugs (AED), but there is a lack of information about its potential reproductive toxicologic effects. Our aim was to evaluate the consequences of VGB administered during late gestation on fetal growth and development in the mouse. Based on the results of our previous study, we administered groups of mice a single dose of 450 mg/kg VGB on one of gestation days (GD) 15, 16 or 17. Fetuses were collected on GD 18. VGB groups had a significant incidence of fetal death, abortion, intrauterine growth restriction (IUGR), and hypoplasia of the axial skeleton, metacarpals, metatarsal and phalanges. Abortion was characterized by visible hemorrhagic expulsion of the embryos with their membranes. Maternal plasma folate (FA) and vitamin B12 concentrations were found to be markedly reduced within 12h of VGB treatment. Mice were supplemented with FA from GD 12 through GD 17 with or without a single dose of VGB on GD 15. This group had no abortions. Their fetuses had better body weight and lower frequency of IUGR than those of the non-supplemented VGB group. These data suggest that reductions in maternal FA and vitamin B12 concentrations play an important role in fetal loss, IUGR and skeletal hypoplasia induced by VGB during late gestation in the mouse. In view of the finding that a significant maternal toxicity is associated with this dose regimen, additional groups of mice were treated with 350 mg/kg VGB during embryogenesis and late gestation. This treatment was found to be maternally nontoxic. However, this low dose also resulted in significant fetal loss and IUGR when treatment occurred during late gestation. These data support the hypothesis that late gestation is particularly susceptible to VGB-induced fetal loss and IUGR in the mouse.

Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity.

OBJECTIVE: Although vigabatrin irreversibly constricts the visual field, it remains a potent therapy for infantile spasms and a third-line drug for refractory epilepsies. In albino animals, this drug induces a reduction in retinal cell function, retinal disorganization, and cone photoreceptor damage. The objective of this study was to investigate the light dependence of the vigabatrin-elicited retinal toxicity and to screen for molecules preventing this secondary effect of vigabatrin. METHODS: Rats and mice were treated daily with 40 and 3mg vigabatrin, respectively. Retinal cell lesions were demonstrated by assessing cell function with electroretinogram measurements, and quantifying retinal disorganization, gliosis, and cone cell densities. RESULTS: Vigabatrin-elicited retinal lesions were prevented by maintaining animals in darkness during treatment. Different mechanisms including taurine deficiency were reported to produce such phototoxicity; we therefore measured amino acid plasma levels in vigabatrin-treated animals. Taurine levels were 67% lower in vigabatrin-treated animals than in control animals. Taurine supplementation reduced all components of retinal lesions in both rats and mice. Among six vigabatrin-treated infants, the taurine plasma level was found to be below normal in three patients and undetectable in two patients. INTERPRETATION: These results indicate that vigabatrin generates a taurine deficiency responsible for its retinal phototoxicity. Future studies will investigate whether cotreatment with taurine and vigabatrin can limit epileptic seizures without inducing the constriction of the visual field. Patients taking vigabatrin could gain immediate benefit from reduced light exposures and dietetic advice on taurine-rich foods.

Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction.

This study examined the safety and efficacy of gamma vinyl-GABA (GVG, vigabatrin) for the treatment of methamphetamine and/or cocaine addiction. A total of 30 subjects, who met DSM-IV criteria for methamphetamine and/or cocaine dependence, were enrolled in an open label 9-week safety study. The protocol was specifically designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy. Patients were screened twice weekly for the presence of urinary cocaine, methamphetamine, heroin, alcohol, and marijuana. In total, 18/30 subjects completed the study and 16/18 tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity. Furthermore, it did not produce changes in vital signs even with continued use of methamphetamine and cocaine. Thus, under conditions that appear to be appropriate for the successful treatment of methamphetamine and/or cocaine addiction, GVG is safe.

[New antiepileptic drugs in pregnancy: outcome of 12 exposed pregnancies]. / Exposition in utero aux nouveaux antiépileptiques: issue de grossesse de 12 patientes traitées.

There is currently little evidence available concerning the risks of foetal exposure to new anti-epileptic drugs such as lamotrigine, vigabatrin, gabapentine, topiramate. A small number of malformations without organ specificity have been described and are not easy to interpret because of the existence of concomitant treatments. We have reported a series of 12 pregnancies with exposure to recent anti-epilepticdrugs and that were reported to the Post-marketing Surveillance office in Tours, France. Five concerned Lamictal of which 2 related to monotherapy, one concerned Epitomax used in monotherapy and there were 6 cases of polytherapy including Sabril. Associated drug therapies were Depakine, Tegretol, Rivotril and Urbanyl. Six of the patients were on folic acid supplements. The average age of the women was 26.5 years. In each case, treatment had been initiated before conception and was continued for at least 3 months. Of the 12 babies born, only one presented with a malformation (aplasia of the muscle of the left lower lip and asymmetrical abduction of the hips) following exposure to Lamictal and Depakine. Four infants, two of whom were premature, showed signs of neonatal stress: transient respiratory distress and difficulty in taking feeding-bottles following exposure throughout the pregnancy to Epitomax; suction disorders, hypotonia and vomiting were observed after exposure to Sabril, Tegretol and Rivotril throughout the pregnancy; respiratory distress and apnoea--bradycardia were observed after exposure throughout the pregnancy to Lamictal and Urbanyl; respiratory distress and thrombocytopaenia were observed after exposure throughout the pregnancy to Lamictal". This small series confirms that the current data concerning the teratogenicity of new anti-epileptic drugs are as yet insufficient to exclude any teratogenic risk. Consequently, strict adherence to current recommendations relating to drug use during pregnancy is essential. The treatment of all patients wishing to become pregnant should be discussed.

Visual function is stable in patients who continue long-term vigabatrin therapy: implications for clinical decision making.

PURPOSE: Vigabatrin (VGB) has been shown to cause visual field constriction and other forms of mild visual dysfunction. We determined the safety of continuing VGB therapy in patients who had received prolonged treatment (>2 years) with the drug by serially monitoring changes in visual function over a 1-year period of continued therapy. We also followed up patients who discontinued VGB to see whether alternative therapies are effective. METHODS: Fifteen of 17 patients who continued VGB therapy had visual-function testing (visual acuity, color vision, kinetic and static perimetry) every 3 months for 1 year. Eighteen patients who discontinued VGB were given alternative antiepileptic drugs (AEDs); their seizure responses were measured after > or =3 months of treatment. RESULTS: Patients continuing VGB showed no worsening of visual acuity, color vision, or visual-field constriction beyond that measured in the initial test. Many patients who discontinued VGB had good seizure control with either newer or previously unsuccessful AEDs. CONCLUSIONS: For patients who have an excellent response to VGB and only mild visual changes, continued therapy may be safe with close visual monitoring. Patients who do not have a significant reduction in seizures or who experience considerable visual dysfunction with VGB may respond well to alternative therapies.

Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.

PURPOSE: This postmarketing surveillance study of lamotrigine (LTG) was performed to provide complementary data to large-scale Prescription-Event Monitoring study with a retrospective case records survey in five tertiary referral epilepsy centres in the United Kingdom. METHODS: Adverse events were recorded and compared with those of two other new antiepileptic drugs (AEDs), gabapentin (GBP) and vigabatrin (VGB). All deaths were followed up and standardised mortality ratios (SMRs) were calculated. Serious adverse events were assessed individually. RESULTS: A total of 2,701 patients was identified as being exposed to LTG and/or the comparators. It was necessary to exclude 1,326 patients because LTG and/or comparators had been commenced outside the study centres. The adverse events with LTG reported by this study were similar to those reported in the literature. Skin rash was the major adverse event. Life-threatening hepatic failure, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation, and renal failure were reported. No death could be directly attributed to the use of LTG. The SMR was slightly higher than that reported in the literature; this probably reflects severity of epilepsy in the study population. CONCLUSIONS: The safety profile of LTG was similar to that in the large-scale Prescription-Event Monitoring study and generally acceptable. Life-threatening adverse reactions were rare.