Vigabatrin

Vigabatrin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that irreversibly inhibits the catabolism of GABA by GABA transaminase. It produces a dose-dependent increase in extracellular GABA, and has been shown to result in increasing seizure suppression.

Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent.[Pubmed:28230253]

Epilepsia. 2017 Apr;58(4):674-682.

OBJECTIVE: Although the link between Vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena. METHODS: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. RESULTS: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). SIGNIFICANCE: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.

The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study.[Pubmed:27941319]

Cell Physiol Biochem. 2016;40(5):831-846.

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.

Determination of enantiomeric vigabatrin by derivatization with diacetyl-l-tartaric anhydride followed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.[Pubmed:27866846]

J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jan 1;1040:199-207.

Vigabatrin, one of the most widely used antiepileptic drugs, is marketed and administered as a racemic mixture, while only S-enantiomer is therapeutically effective. In the present study, diacetyl-l-tartaric acid anhydride was used as an inexpensive and effective chiral derivatization reagent to produce tartaric acid monoester derivatives of Vigabatrin enantiomers that could be readily resolved by reversed phase chromatography. Derivatization conditions were statistically optimized by response surface methodology, resulting in an optimal reaction temperature of 44 degrees C and an optimal reaction time of 30min. The derivatized diastereomers of Vigabatrin and internal standard (gabapentin) were analyzed using ultra-high performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry. For this analysis, an Agilent ZORBAX Rapid Resolution High Definition Eclipse Plus C18 column (100mmx2.1mm, 1.8mum) was employed for chromatographic separation using 10mM ammonium formate (pH 3.0) and methanol as mobile phase at a flow rate of 0.2mLmin(-1). The established method was validated in terms of specificity, linearity, precision, accuracy, dilution integrity, recovery, matrix effect, stability, and incurred sample reanalysis. It was linear over a range of 0.25-100.0mgL(-1) for both S- and R-enantiomers (R(2)>/=0.9987 for both). Intra- and inter-day precisions and accuracies were within acceptable ranges. The method was successfully applied to determine the levels of Vigabatrin enantiomers in mouse serum after administration of Vigabatrin racemate.

Vigabatrin(γ-Vinyl-GABA; Sabril) is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that irreversibly inhibits the catabolism of GABA by GABA transaminase.

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