Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat

Doheny, Helen C.; Ratnaraj, Neville; Whittington, Miles A.; Jefferys, John G. R.; Patsalos, Philip N.

doi:10.1016/s0920-1211(98)00104-1

Cited by 89 publications

(73 citation statements)

References 18 publications

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“…This may reflect a suboptimal SE treatment approach with insufficient doses of newer AEDs, or their prescriptions without or with underdosed benzodiazepines as first line treatment (34). However, in animal studies levetiracetam has shown a relatively slow penetration into the central nervous system, with latencies of more than 1 hour to achieve maximum concentrations in the cerebrospinal or in the brain extra-cerebral fluid (35)(36)(37). Animal studies with phenytoin, on the other side, shows maximum concentrations in cerebrospinal and brain extra-cerebral fluids within 9-13minutes and 39-34minutes, respectively (38).…”

Section: Discussionmentioning

confidence: 99%

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

2017

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Section: Discussionmentioning

confidence: 99%

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

2017

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“…Pharmacokinetic research indicates that LEV levels in cerebrospinal fluid peak within a few hours after initial oral administration (Doheny et al 1999;Patsalos 2004), similar to other AEDs. Yet the onset of LEV's anticonvulsant effect can take up to 2 days after treatment initiation (Stefan et al 2006), far longer than benzodiazepines, which clearly act extracellularly (Riss et al 2008).…”

Section: Synaptic Activity Modulates the Efficacy Of Levmentioning

confidence: 99%

“…The high concentrations of LEV used in these experiments were chosen to allow us to observe significant differences between control and drug-treated slices. Although the drug concentration required to induce a readily quantifiable electrophysiological change in single patched neurons is almost certainly greater than the concentration required for seizure control, the LEV concentration we most frequently employed (300 M) is within the range of CSF concentrations in rats treated with anticonvulsive doses of LEV (100 -500 M) (Doheny et al 1999). In support of our proposed LEV mechanism of action, we have recently replicated all of our LEV results with much lower concentrations of a LEV derivative with higher SV2A affinity (unpublished observations).…”

Section: Synaptic Activity Modulates the Efficacy Of Levmentioning

confidence: 99%

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam

Meehan¹,

Yang²,

McAdams³

et al. 2011

Journal of Neurophysiology

114

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A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227-1239, 2011. First published June 8, 2011 doi:10.1152/jn.00279.2011 is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.epilepsy; synaptic vesicle protein 2A; synaptic vesicle release; hippocampal slice LEVETIRACETAM (LEV) IS AN antiepileptic drug (AED) with a unique mode of action and efficacy against focal and generalized seizures. The exact mechanism by which this drug reduces seizures is still under investigation. LEV does not inhibit voltage-gated Na ϩ channels (Zona et al. 2001), nor does it modulate GABA receptors (Margineanu and Klitgaard 2003), two common AED mechanisms. It is established that LEV binds to a presynaptic protein, synaptic vesicle protein 2A (SV2A), located in the membrane of synaptic vesicles (Lynch et al. 2004). The precise function of SV2A is also unknown, but studies of cultured neurons from SV2A knockout mice show a reduced postsynaptic response, due to a lower initial vesicle release probability (Custer et al. 2006) and a decrease in the total amount of neurotransmitter release during a stimulus train compared with controls (Chang and Sudhof 2009).Because SV2A plays a modulatory, but not essential, role in neurotransmission, it is unclear how a ligand binding to SV2A might alter neurotransmitter release.The cellular mechanism of action of LEV remains paradoxical. While it seems to do nothing to normal synaptic transmission, i...

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“…In the rat, cerebrospinal fluid concentrations of LEV reached concentrations of 300 mM by 30 min after a dose of 80 mg/kg i.p. (Doheny et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

Robinson

Chen

Stamatakis

et al. 2013

Neuropsychopharmacol

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The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol-and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial selfstimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/ kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol-and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.

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Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat

Cited by 89 publications

References 18 publications

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam

Levetiracetam Has Opposite Effects on Alcohol- and Cocaine-Related Behaviors in C57BL/6J Mice

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