Binding Site For Levetiracetam Research Articles

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.

Despite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [(18)F]UCB-H: First-in-Human Study.

[(18)F]UCB-H is a novel radiotracer with a high affinity for synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a "first-in-class" antiepileptic drug with a distinct but still poorly understood mechanism of action. The objective of this study was to determine the biodistribution and radiation dosimetry of [(18)F]UCB-H in a human clinical trial and to establish injection limits according to biomedical research guidelines. Additionally, the clinical radiation dosimetry results were compared to estimations in previously published preclinical data. Dynamic whole body positron emission tomography/X-ray computed tomography (PET/CT) imaging was performed over approximately 110min on five healthy male volunteers after injection of 144.5 ± 7.1MBq (range, 139.1-156.5MBq) of [(18)F]UCB-H. Major organs were delineated on CT images, and time-activity curves were obtained from co-registered dynamic PET emission scans. The bladder could only be delineated on PET images. Time-integrated activity coefficients were calculated as area under the curve using trapezoidal numerical integration. Urinary excretion data based on PET activities including voiding was also simulated using the dynamic bladder module of OLINDA/EXM. The radiation dosimetry was calculated using OLINDA/EXM. The effective dose to the OLINDA/EXM 70-kg standard male was 1.54 × 10(-2) ± 6.84 × 10(-4)millisieverts (mSv)/MBq, with urinary bladder wall, gallbladder wall, and the liver receiving the highest absorbed dose. The brain, the tracer's main organ of interest, received an absorbed dose of 1.89 × 10(-2) ± 2.32 × 10(-3)mGy/MBq. This first human dosimetry study of [(18)F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672MBq for US practice and 649MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.

The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

SV2A is a synaptic vesicle membrane protein expressed in neurons and endocrine cells and involved in the regulation of neurotransmitter release. Although the exact function of SV2A still remains elusive, it was identified as the specific binding site for levetiracetam, a second generation antiepileptic drug. Our sequence analysis demonstrates that SV2A has significant homology with several yeast transport proteins belonging to the major facilitator superfamily (MFS). Many of these transporters are involved in sugar transport into yeast cells. Here we present evidence showing, for the first time, that SV2A is a galactose transporter. We expressed human SV2A in hexose transport-deficient EBY.VW4000 yeast cells and demonstrated that these cells are able to grow on galactose-containing medium but not on other fermentable carbon sources. Furthermore, the addition of the SV2A-binding antiepileptic drug levetiracetam to the medium inhibited the galactose-dependent growth of hexose transport-deficient EBY.VW4000 yeast cells expressing human SV2A. Most importantly, direct measurement of galactose uptake in the same strain verified that SV2A is able to transport extracellular galactose inside the cells. The newly identified galactose transport capability of SV2A may have an important role in regulating/modulating synaptic function.

SV2A in Epilepsy: The Plot Thickens

Decreased Expression of Synaptic Vesicle Protein 2A, the Binding Site for Levetiracetam, during Epileptogenesis and Chronic Epilepsy. van Vliet EA, Aronica E, Redeker S, Boer K, Gorter JA. Epilepsia 2009;50(3):422–433. PURPOSE: We previously showed that gene expression of synaptic vesicle protein 2A (SV2A), the binding site for the antiepileptic drug levetiracetam, is reduced during epileptogenesis in the rat. Since absence of SV2A has been associated with increased epileptogenicity, changes in expression of SV2A could have consequences for the progression of epilepsy. Therefore, we investigated hippocampal SV2A protein expression of temporal lobe epilepsy (TLE) patients and in rats during epileptogenesis and in the chronic epileptic phase. METHODS: SV2A immunocytochemistry and Western blot analysis were performed on the hippocampus of autopsy controls, patients that died from status epilepticus (SE), and pharmacoresistant TLE patients. In addition, in epileptic rats, SV2A expression was determined after SE during the acute, latent, and chronic epileptic phase. RESULTS: In control tissue, presynaptic SV2A was expressed in all hippocampal subfields, with strongest expression in mossy fiber terminals. SV2A positive puncta were distributed in a patchy pattern over the somata and dendrites of neurons. SV2A decreased throughout the hippocampus of TLE patients with hippocampal sclerosis (HS), compared to autopsy control, SE, and non-HS tissue. In most rats, SV2A was already decreased in the latent period especially in the inner molecular layer and stratum lucidum. Similarly as in humans, SV2A was also decreased throughout the hippocampus of chronic epileptic rats, specifically in rats with a progressive form of epilepsy. DISCUSSION: These data support previous findings that reduced expression of SV2A could contribute to the increased epileptogenicity. Whether this affects the effectiveness of levetiracetam needs to be further investigated.

Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy

We previously showed that gene expression of synaptic vesicle protein 2A (SV2A), the binding site for the antiepileptic drug levetiracetam, is reduced during epileptogenesis in the rat. Since absence of SV2A has been associated with increased epileptogenicity, changes in expression of SV2A could have consequences for the progression of epilepsy. Therefore we investigated hippocampal SV2A protein expression of temporal lobe epilepsy (TLE) patients and in rats during epileptogenesis and in the chronic epileptic phase. SV2A immunocytochemistry and Western blot analysis were performed on the hippocampus of autopsy controls, patients that died from status epilepticus (SE), and pharmacoresistant TLE patients. In addition, in epileptic rats, SV2A expression was determined after SE during the acute, latent, and chronic epileptic phase. In control tissue, presynaptic SV2A was expressed in all hippocampal subfields, with strongest expression in mossy fiber terminals. SV2A positive puncta were distributed in a patchy pattern over the somata and dendrites of neurons. SV2A decreased throughout the hippocampus of TLE patients with hippocampal sclerosis (HS), compared to autopsy control, SE, and non-HS tissue. In most rats, SV2A was already decreased in the latent period especially in the inner molecular layer and stratum lucidum. Similarly as in humans, SV2A was also decreased throughout the hippocampus of chronic epileptic rats, specifically in rats with a progressive form of epilepsy. These data support previous findings that reduced expression of SV2A could contribute to the increased epileptogenicity. Whether this affects the effectiveness of levetiracetam needs to be further investigated.

Behavioural phenotyping reveals anxiety-like features of SV2A deficient mice

Synaptic vesicle protein 2A (SV2A) is involved in neurotransmitter release and has been identified as the binding site for levetiracetam (Keppra ®), a novel antiepileptic drug. Homozygous SV2A (−/−) mice are not viable beyond a few weeks. In contrast, heterozygous SV2A (+/−) mice have a normal lifespan. We performed a behavioural phenotyping on SV2A (+/−) mice in a battery of tests: gross behavioural observation, spontaneous locomotor activity, sensori-motor coordination, acute pain sensitivity, exploration in an elevated plus-maze and an assessment of learning abilities in an inhibitory avoidance procedure. SV2A (+/−) mice were compared to age-matched, 2-month-old wild type controls. Overall, gross behaviour, spontaneous locomotor activity, sensori-motor coordination and acute pain sensitivity were comparable between wild type and SV2A (+/−) mice. When tested in a plus-maze, SV2A (+/−) mice displayed significant increased avoidance of open elevated arms whereas locomotor activity was not altered. Finally, both SV2A (+/−) and wild type mice showed comparable memory performance at the end of a multi-trial passive avoidance procedure. Interestingly, SV2A (+/−) mice exhibited increased avoidance of the lit area during the first sessions without foot shock. These results suggest an anxiety-like phenotype for SV2A (+/−) mice indicated by increased open-arm avoidance in the elevated plus-maze test as well as a shorter latency to escape from a lit area in the inhibitory avoidance procedure.

Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein

A specific binding site for the antiepileptic drug levetiracetam (2 S-(oxo-1-pyrrolidinyl)butanamide, Keppra®) in rat brain, referred to as the levetiracetam binding site, was discovered several years ago. More recently, this binding site has been identified as the synaptic vesicle protein 2A (SV2A), a protein present in synaptic vesicles [Lynch, B., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S.M., Matagne, A., Fuks, B., 2004. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. USA, 101, 9861–9866.]. In this study, we characterized the binding properties of levetiracetam in post-mortem human brain and compared them to human SV2A expressed in Chinese hamster ovary (CHO) cells. The results showed that the binding properties of levetiracetam and [ 3H]ucb 30889, an analogue that was previously characterized as a suitable ligand for levetiracetam binding site/SV2A in rat brain [Gillard, M., Fuks, B., Michel, P., Vertongen, P., Massingham, R. Chatelain, P., 2003. Binding characteristics of [ 3H]ucb 30889 to levetiracetam binding sites in rat brain. Eur. J. Pharmacol. 478, 1–9.], are almost identical in human brain samples (cerebral cortex, hippocampus and cerebellum) and in CHO cell membranes expressing the human SV2A protein. Moreover, the results are also similar to those previously obtained in rat brain. [ 3H]ucb 30889 binding in human brain and to SV2A was saturable and reversible. At 4 °C, its binding kinetics were best fitted assuming a two-phase model in all tissues. The half-times of association for the fast component ranged between 1 to 2 min and represent 30% to 36% of the sites whereas the half-times for the slow component ranged from 20 to 29 min. In dissociation experiments, the half-times were from 2 to 4 min for the fast component (33% to 49% of the sites) and 20 to 41 min for the slow component. Saturation binding curves led to K d values for [ 3H]ucb 30889 of 53 ± 7, 55 ± 9, 70 ± 11 and 75 ± 33 nM in human cerebral cortex, hippocampus, cerebellum and CHO cells expressing SV2A respectively. B max values around 3–4 pmol/mg protein were calculated in all brain regions. Some of the saturation curves displayed curvilinear Scatchard plots indicating the presence of high and low affinity binding sites. When this was the case, K d values from 25 to 30 nM for the high affinity sites (24% to 34% of total sites) and from 200 to 275 nM for the low affinity sites were calculated. This was observed in all brain regions and in CHO cell membranes expressing the SV2A protein. It cannot be explained by putative binding of [ 3H]ucb 30889 to SV2B or C isoforms but may reflect different patterns of SV2A glycosylation or the formation of SV2A oligomers. Competition experiments were performed to determine the affinities for SV2A of a variety of compounds including levetiracetam, some of its analogues and other molecules known to interact with levetiracetam binding sites in rat brain such as bemegride, pentylenetetrazol and chlordiazepoxide. We found an excellent correlation between the affinities of these compounds measured in human brain, rat brain and CHO cells expressing human SV2A. In conclusion, we report for the first time that the binding characteristics of native levetiracetam binding sites/SV2A in human brain and rat brain share very similar properties with human recombinant SV2A expressed in CHO cells.

Translational Research: Human Tissue & Pathology

Abstract 1 Andreas V. Alexopoulos, 1 Cristiane Q. Tilelli, 1 Roger O. Oghlakian, 2 Jorge Gonzalez-Martinez, 2 William E. Bingaman, and 1 Imad M. Najm ( 1 Neurology, Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH ; and 2 Neurosurgegy, Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH ) Rationale: The synaptic vesicle protein 2A (SV2A) has been recently identified as the specific binding site for levetiracetam (LEV) in the brain and as a potential target for future antiepileptic drug (AED) therapy. LEV belongs to a new generation of AEDs with a novel mechanism of action seemingly unrelated to traditional AED targets. The objective of our study is to investigate the expression of the SV2A protein in the neocortex of patients with pharmacoresistant epilepsy. We hypothesize that surgically resected epileptic tissue shows a differential expression of the SV2A protein. Methods: Human neocortical tissue specimens from seven patients with histopathologically proven focal cortical dysplasia (FCD) were used for this set of experiments. All patients underwent chronic extraoperative electrocorticographic (ECoG) recordings using subdural grids. “Epileptic areas” exhibiting ictal activity on ECoG (with or without interictal spiking) were identified and separated during surgery from resected “non-epileptic” cortical regions (n = 7). Additional controls consisted of “non-epileptic” tissue acquired from lateral temporal neocortex of patients with hippocampal sclerosis and normal neocortical MRI (n = 3), and human neocortical tissue obtained from autopsy patients without a known history of neurological disease (n = 5). Immunocytochemical staining was performed using polyclonal antibodies against SV2A to study SV2A protein expression in the human tissue specimens. The extent, density and distribution of SV2A protein immunoreactivity were visually analyzed by three independent and blinded observers. Results: Immunocytochemical analysis revealed two main staining patterns: Autopsy controls were characterized by clusters of punctate, “terminal-like” SV2A labeling in the presence of a lightly stained background seen throughout all layers of cortex. In contrast, tissue identified by ECoG as “epileptic” showed intense and diffuse staining of the neuropil with disruption or absence of punctate labeling in all cortical layers. Finally, an intermediate mixed pattern was seen in tissue obtained from “non-epileptic” and lateral temporal neocortex. Conclusions: These distinct SV2A immunoreactivity patterns provide evidence for redistribution of the SV2A protein in the neocortex of patients with FCD and pharmacoresistant epilepsy. Further studies to elucidate the mechanism and functional significance of SV2A redistribution in these patients are currently underway in our laboratory. These findings may have implications for the pathogenesis and treatment of pharmacoresistant epilepsy in patients with focal cortical dysplasia. (Supported by Investigator-initiated study grant to A.V.A. sponsored by UCB-Pharma.)

Characterization of [3H]ucb 30889 binding to synaptic vesicle protein 2A in the rat spinal cord

The novel antiepileptic drug levetiracetam ((2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA®) possesses a specific binding site in brain, which has very recently been identified as the synaptic vesicle protein SV2A. The aim of this study was to evaluate the presence of a levetiracetam binding site in the spinal cord and compare its properties to that in rat brain. We used [3H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analogue, to perform binding assays, photoaffinity labelling and autoradiography experiments, and revealed the presence of SV2A by Western-blot analysis. [3H]ucb 30889 binding kinetics at 4 °C were biphasic and saturation binding curves were compatible with the labelling of a homogenous population of binding sites with a Kd similar to that in brain. Competition curves with ligands known to interact with levetiracetam binding sites and photolabelling experiments indicated that [3H]ucb 30889 labels the same 90 kDa protein in both spinal cord and brain. Levetiracetam binding site was localised in the grey matter of the spinal cord and its expression was not modified in a model of neuropathic pain. This study demonstrates the presence of a specific levetiracetam binding site in the rat spinal cord, which is similar to that found in rat brain.

The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.

Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies.

Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity.

(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.

Binding characteristics of [ 3H]ucb 30889 to levetiracetam binding sites in rat brain

Levetiracetam (2 S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA®), a novel antiepileptic drug, has been shown to bind to a specific binding site located in brain (levetiracetam binding site [Eur. J. Pharmacol. 286 (1995) 137]). However, [ 3H]levetiracetam displayed only micromolar affinity for these sites making it an unsuitable probe for further characterization. The present study describes the binding properties of an analogue of levetiracetam: [ 3H]ucb 30889, (2 S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide. [ 3H]ucb 30889 binds reversibly to specific binding sites in rat brain. Kinetics at 4 °C were biphasic with half-times of association and dissociation of, respectively, 3 and 4 min for the fast component and 47 and 61 min for the slow component. [ 3H]ucb 30889 saturation binding curves were compatible with the labelling of a homogenous population of binding sites having a B max of 4496±790 fmol/mg protein (mean±S.D., n=5) and a K d of 62±20 nM (mean±S.D., n=5), a 20-fold increase in affinity compared to [ 3H]levetiracetam. Competition binding curves with ligands known to interact with levetiracetam binding sites and tissue distribution restricted to the brain indicated that [ 3H]ucb 30889 and [ 3H]levetiracetam bind to the same site. Although levetiracetam binding sites and GABA A (γ-aminobutyric acid) receptors share some ligands such as pentobarbital and pentylenetetrazol, experiments performed with [ 35S]TBPS ( tert-butyl-bicyclo[2.2.2]phosporothionate), a probe for the GABA A Cl − channel do not support the hypothesis that levetiracetam binding sites are part of the GABA A receptor complex. Preliminary autoradiography studies in rat brain revealed that [ 3H]ucb 30889 labels specific sites in all brain regions and that this binding is concentration-dependently displaced by levetiracetam.

Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines

Levetiracetam (2 S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA®), a novel antiepileptic drug, has been shown to bind to a specific binding site located in the brain (Eur. J. Pharmacol. 286 (1995) 137). To identify the protein constituent of the levetiracetam binding site in situ, we synthesized the photoaffinity label [ 3H]ucb 30889 ((2 S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analog with higher affinity for the levetiracetam binding site. This radioligand was used to map the levetiracetam binding site within the brain and to study its cellular and subcellular distribution. Autoradiography experiments using [ 3H]ucb 30889 in rat brain revealed a unique distribution profile that did not match that of classical receptors known to be involved in the generation of epileptic seizures. There was a high level of binding in the dentate gyrus, the superior colliculus, several thalamic nuclei, the molecular layer of the cerebellum and to a lesser extent in the cerebral cortex, the striatum and the hypothalamus. The levetiracetam binding site was restricted to neuronal cell types, undifferentiated PC12 cells and was highly enriched in synaptic vesicles. [ 3H]ucb 30889 was also used in photoaffinity labelling studies and shown to bind covalently to a membrane protein with a molecular weight of approximately 90 kDa.

Levetiracetam: The Preclinical Profile of a New Class of Antiepileptic Drugs?

Levetiracetam is a new antiepileptic drug (AED) devoid of anticonvulsant activity in the two classic screening models for AEDs, the maximal electroshock and pentylenetetrazol seizure tests in both mice and rats. This contrasts a potent seizure suppression in genetic and kindled mice and rats and against chemoconvulsants inducing partial seizures in rats. The highly selective action in "epileptic" animals distinguishes levetiracetam from classic and other new AEDs that have nearly equipotent effects in normal and "epileptic" animals. Levetiracetam induces minor behavioral alterations in normal and in kindled mice and rats. This results in an unusually high safety margin in animal models reflecting both partial and primary generalized epilepsy. Furthermore, experiments in the kindling model suggest that levetiracetam may possess antiepileptogenic properties due to a potent ability to prevent the development of kindling in mice and rats at doses devoid of adverse effects. Electrophysiologic recordings from different experimental models suggest that levetiracetam exerts a selective action against abnormal patterns of neuronal activity, which probably explains its selective protection in epileptic animals and its unique tolerability. This effect appears to derive from one or more novel mechanisms of action that do not involve a conventional interaction with traditional drug targets implicated in the modulation of inhibitory and excitatory neurotransmission. Instead, ligand-binding assays have disclosed a brain-specific binding site for levetiracetam. These studies reveal a unique preclinical profile of levetiracetam, distinct from that of all known AEDs, suggesting that levetiracetam could represent the first agent in a new class of AEDs.

An assessment of levetiracetam as an anti-epileptic drug

A brief review of epilepsy as a disease, anti-epileptic drugs (AEDs) and methods of evaluation of AEDs are presented as a background for the assessment of levetiracetam which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. The exact mechanism of action of levetiracetam is not known but its action differs from that of other anti-epileptic drugs. A specific binding site for levetiracetam has been identified and is possibly related to anticonvulsant activity. Levetiracetam offers an effective and broad spectrum treatment of epileptic seizures, partial as well as generalised epilepsy. Levetiracetam has been shown to be effective in genetic and kindled animal models of epilepsy and against chemoconvulsant-induced partial epileptic seizures. Levetiracetam has a near perfect pharmacokinetic profile, with rapid absorption following oral administration, excellent bioavailability, quick attainment of steady-state concentrations, linear kinetics and minimal plasma protein binding. Levetiracetam does not interact with commonly used drugs and other AEDs. In recent Phase III clinical trials, the responder rate was 39.4 - 42.1% on 3000 mg dose, compared with placebo rates of 10.9 - 16.7%. Levetiracetam has a favourable safety profile and the most frequently reported adverse events were somnolence, asthenia and dizziness. Overall, levetiracetam is considered to have several advantages over current AEDs.