Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval

Tolman, Justin A.; Faulkner, Michele A.

doi:10.1517/14656560903451690

Cited by 46 publications

(28 citation statements)

References 79 publications

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“…One such drug, vigabatrin, targets GABA metabolism by inhibiting GABA transaminase (GABA-T), an enzyme directly downstream of GAD1. Vigabatrin thus functions to block GABA flux into the TCA cycle(40). Due to the essential role of GAD1-mediated GABA signaling in metastatic outgrowth, we hypothesize that vigabatrin could be repurposed to block tumor cells utilization of GABA as a metabolite, thereby decreasing metastatic outgrowth.…”

Section: Resultsmentioning

confidence: 99%

“…Vigabatrin acts a suicide inhibitor of the enzyme directly downstream of GAD1, GABA transaminase (GABA-T), leading to an accumulation of GABA. For patients suffering from epilepsy, the increased pool of GABA results in a decrease in epileptic seizures(40). At the same time, inhibiting GABA-T also prevents GABA flux into the TCA cycle in tumor cells, suggesting that repurposing this neurological drug for brain metastasis may inhibit tumor GABA metabolism.…”

Section: Discussionmentioning

confidence: 99%

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GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

et al. 2017

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The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

et al. 2017

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“…But it was first marketed in Europe in the late 1980s and was approved in Australia in 1993 and in Canada in 1994. Although vigabatrin is available in many countries, it has not previously been available in the US, because it has been associated with irreversible peripheral vision loss in many patients (27). It is an irreversible GABA transaminase inhibitor thereby increasing GABA levels in brain.…”

Section: Recent Fda Approved Aedsmentioning

confidence: 99%

Innovations in Epilepsy Management – An Overview

Abraham

Shaju

2013

J Pharm Pharm Sci

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-In the past twenty years, thirteen new antiepileptic drugs (AEDs) have been introduced, each differing in their efficacy spectrum, mechanism of action, pharmacokinetics, safety and tolerability profiles. These newer AEDs symbolize a welcoming future in the management of epilepsy because they are able to produce a remarkable reduction in seizure frequency in up to 40% to 50% of the patients who had been refractory to old generation drugs. Despite the current availability of these new drugs, only a few patients with truly refractory seizures can be made seizure free. Although the newer agents are not superior to that of the older drugs, some have been shown to be non-inferior in terms of their efficacy. They offer additional advantages like better tolerability, ease of use, reduced interaction profile. Even though in most situations the older generation drugs still represent the best choice, advancing studies show that in many conditions, new generation drugs may be entirely vindicated for initial therapy. This urges a need for the search of novel and more efficacious new antiepileptic drugs in the management of uncontrollable seizures. More direct comparisons of newer versus newer and newer versus older drugs in clinical trials, both for monotherapy and adjunctive therapy must be conducted. More than 20 compounds with promising antiepileptic and neuroprotective properties have been discovered and are under various stages of drug development.

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“…Vigabatrin reduces GABA catabolism. It irreversibly inhibits GABA transaminase (Tolman and Faulkner 2009).…”

mentioning

confidence: 99%

“…Taking into account that the need for providing drugs for treatment of stereotypies (Ghanizadeh 2010(Ghanizadeh , 2011, the role of GABAergic neurons for stereotypies (Chao et al 2010), the hypofunction of GABA system in autism in brain (Harada et al 2011), the role of GABA transaminase in catabolizing GABA (Tolman and Faulkner 2009), it seems reasonable to hypothesize that GABA transaminase inhibitors such as Vigabatrin may improve stereotypies in autism and Rett syndrome. It is worthwhile to conduct clinical experimental studies on animal models of autism.…”

mentioning

confidence: 99%

May GABA transaminase inhibitors improve stereotyped behaviors in Rett syndrome?

Ghanizadeh

2011

Amino Acids

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Vigabatrin: a comprehensive review of drug properties including clinical updates following recent FDA approval

Abstract: The recent approval of vigabatrin makes a significant addition to antiepileptic drug options. The FDA implemented a Risk Evaluation and Mitigation Strategy to control for the possibility of severe adverse drug events.

Cited by 46 publications

References 79 publications

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

Innovations in Epilepsy Management – An Overview

May GABA transaminase inhibitors improve stereotyped behaviors in Rett syndrome?

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