A validated bioanalytical HPLC method for pharmacokinetic evaluation of 2‐deoxyglucose in human plasma

Gounder, Murugesan; Lin, Huan; Stein, Mark N.; Goodin, Susan; Bertino, Joseph R.; Kong, Ah‐Ng Tony; DiPaola, Robert S.

doi:10.1002/bmc.1710

Cited by 10 publications

(15 citation statements)

References 29 publications

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“…However, we could not measure the absolute concentrations of 2DG in the blood and DLN after in vivo administration, and it is well known that 2DG is rapidly metabolized in vivo (40). Another perplexing issue was the observation that 2DG could inhibit the effects of glucose in vitro when the later was far in excess of 2DG concentrations.…”

Section: Discussionmentioning

confidence: 99%

Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects

Varanasi

Donohoe

Jaggi

et al. 2017

The Journal of Immunology

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This report deals with physiological changes and their implication following ocular infection with herpes simplex virus (HSV). This infection usually results in a blinding inflammatory reaction in the cornea orchestrated mainly by pro-inflammatory CD4 T cells and constrained in severity by regulatory T cells (Treg). In the present report, we make the unexpected finding that blood glucose levels change significantly during the course of infection. Whereas levels remained normal during the early phase of infection when the virus was actively replicating in the cornea, they increased around two fold during the time when inflammatory responses to the virus was occurring. We could show that glucose levels influenced the extent of induction of the inflammatory T cell subset in vitro that mainly drives lesions, but not regulatory T cells. Additionally, if glucose utilization was limited in vivo as a consequence of therapy in the inflammatory phase with the drug 2DG, lesions were diminished compared to untreated infected controls. In addition, lesions in 2DG treated animals contained less pro-inflammatory effectors. Glucose metabolism also influenced the acute phase of infection when replicating virus was present in the eye. Thus, therapy with 2DG to limit glucose utilization caused mice to become susceptible to the lethal effects of HSV infection, with virus spreading to the brain causing encephalitis. Taken together, our results indicate that glucose metabolism changed during the course of HSV infection and that modulating glucose levels can influence the outcome of infection, being detrimental or beneficial according to the stage of viral pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects

Varanasi

Donohoe

Jaggi

et al. 2017

The Journal of Immunology

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“…In this regard, the relative safety profile of 2DG has already been established in cancer trials (Pelicano et al, 2006), and epilepsy clinical trials are in progress (Bialer et al, 2017). The half-life of 2DG in humans is estimated to be 5–7 h, so this therapy would be potentially useful with twice-daily dosing (Gounder et al, 2012). With respect to BHB, ketone esters have been investigated preclinically as potential therapeutic agents, primarily due to their ability to produce prolonged elevations in blood ketone bodies (D’Agostino et al, 2013).…”

Section: -Deoxyglucose Versus/plus Ketone Bodiesmentioning

confidence: 99%

2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control

Rho

Shao

Stafstrom

2019

Front. Cell. Neurosci.

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Current anti-seizure drugs (ASDs) are believed to reduce neuronal excitability through modulation of ion channels and transporters that regulate excitability at the synaptic level. While most patients with epilepsy respond to ASDs, many remain refractory to medical treatment but respond favorably to a high-fat, low-carbohydrate metabolism-based therapy known as the ketogenic diet (KD). The clinical effectiveness of the KD has increasingly underscored the thesis that metabolic factors also play a crucial role in the dampening neuronal hyperexcitability that is a hallmark feature of epilepsy. This notion is further amplified by the clinical utility of other related metabolism-based diets such as the modified Atkins diet and the low-glycemic index treatment (LGIT). Traditional high-fat diets are characterized by enhanced fatty acid oxidation (which produces ketone bodies such as beta-hydroxybutyrate) and a reduction in glycolytic flux, whereas the LGIT is predicated mainly on the latter observation of reduced blood glucose levels. As dietary implementation is not without challenges regarding clinical administration and patient compliance, there is an inherent desire and need to determine whether specific metabolic substrates and/or enzymes might afford similar clinical benefits, hence validating the concept of a “diet in a pill.” Here, we discuss the evidence for one glycolytic inhibitor, 2-deoxyglucose (2DG) and one metabolic substrate, β-hydroxybutyrate (BHB) exerting direct effects on neuronal excitability, highlight their mechanistic differences, and provide the strengthening scientific rationale for their individual or possibly combined use in the clinical arena of seizure management.

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“…In patients with prostate cancer, a 2‐week dose‐escalation study revealed dose‐limiting asymptomatic QTc prolongation at 60 mg/kg, but doses of 45 mg/kg were well tolerated . The serum half‐life of 2DG in humans has recently been established to be in the 5 to 7 h range, similar to that in several animal species including rodents and dogs . The half‐life is one parameter used to determine the optimal clinical dosing schedule.…”

Section: Dg As a Potential Clinical Agentmentioning

confidence: 99%

Glycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures

2018

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SUMMARYConventional antiseizure medications reduce neuronal excitability through effects on ion channels or synaptic function. In recent years, it has become clear that metabolic factors also play a crucial role in the modulation of neuronal excitability. Indeed, metabolic regulation of neuronal excitability is pivotal in seizure pathogenesis and control. The clinical effectiveness of a variety of metabolism-based diets, especially for children with medication-refractory epilepsy, underscores the applicability of metabolic approaches to the control of seizures and epilepsy. Such diets include the ketogenic diet, the modified Atkins diet, and the low-glycemic index treatment (among others). A promising avenue to alter cellular metabolism, and hence excitability, is by partial inhibition of glycolysis, which has been shown to reduce seizure susceptibility in a variety of animal models as well as in cellular systems in vitro. One such glycolytic inhibitor, 2-deoxy-D-glucose (2DG), increases seizure threshold in vivo and reduces interictal and ictal epileptiform discharges in hippocampal slices. Here, we review the role of glucose metabolism and glycolysis on neuronal excitability, with specific reference to 2DG, and discuss the potential use of 2DG and similar agents in the clinical arena for seizure management.

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A validated bioanalytical HPLC method for pharmacokinetic evaluation of 2‐deoxyglucose in human plasma

Cited by 10 publications

References 29 publications

Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects

Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects

2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control

Glycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures

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