Gotowa bibliografia na temat „Lacosamide”

Object The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. Methods The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. Results The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. Conclusions This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

(2R)-N-Benzyl-2-acetamido-3-methoxypropionamide (lacosamide) is an anticonvulsant (Choi et al., 1996); under the brand name "Vimpat" this small molecule has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration for the treatment of epilepsy. The purpose of the research reported here is to develop and apply mass spectrometry approaches to the determination of protein targets of this novel therapeutic. The general strategy involves selecting potential target proteins using lacosamide analogues incorporating an 'affinity bait' to enable covalent modification binding to target proteins, and a 'chemical reporter' for the selective recovery of modified proteins. Lacosamide analogues are incubated with biological samples (primarily mouse brain extracts) and the modified proteins are recovered by introduction of a biotin tag (via the chemical reporter group). Streptavidin affinity chromatography is then used to enrich for bound molecules. The enriched proteins are subjected to tryptic digestion and the resultant peptides analysed by reversed phase liquid chromatography coupled with tandem MS, enabling recognition of proteins via database searching. Firstly, mass spectrometric characterisation of the biotinyl (R)-lacosamide analogue bound to model compounds was performed. Adducts with protected lysine, neurotensin and enolase were analysed. The data showed that ESI was more suitable for ionisation of modified peptides and proteins than MALDI. The biotin enrichment strategy was applied to mouse brain lysate to identify putative candidate target proteins. Twenty-eight candidate target proteins were identified. Moreover, the 14-3-3 protein family, CRMP2 and the sodium/potassium-transporting ATPase family showed preference for the biologically active(R)- isomer over the (S)- lacosamide analogue using a fluorescence tag. Three more biotinyl lacosamide analogues containing different affinity baits were used to enrich candidate target proteins of lacosamide. Most of the identified target proteins supported the findings of the analogue A. To indicate the binding sites, a method was developed for enriching peptides modified by the biotinyl (R)-lacosamide analogue, using streptavidin beads and subsequently analysed these biotinylated peptides using CID and ETD fragmentation methods. Neither fragmentation technique was optimal for elucidation of the sequence or site of modification of unknown target peptides. Purified recombinant proteins were therefore adducted with an AB-(R)-lacosamide analogue lacking the biotinprobe. This smaller (R)-lacosamide analogue underwent less fragmentation than the biotin analogue during CID and could be used for sequence and site identification of the modified peptides. In summary, the studies illustrated the power of MS to study drug mechanisms via the discovery of candidate protein targets.

Lacosamide (LCM) is a new antiepileptic drug with a previously unknown mode of action. Using electrophysiological recording techniques in a range of in vitro preparations I have determined a mechanism of action of the new drug. In a 4-aminopyridine model of tonic-clonic seizures in rat visual cortex in vitro, LCM stereoselectively reduced maximal frequency and duration of tonic activity with EC[50�s] of 71 and 41 [mu]M respectively. LCM (100 [mu]M) significantly reduced excitability in whole cell patch clamped neurons producing non-selective reduction in the incidence of excitatory/inhibitory postsynaptic currents (EPSCs; LCM: 46.1 � 15.5 %, P <0.01, n = 4, IPSCs; LCM: 24.9 � 9.6 %, P <0.01, n = 4) and block of spontaneous action potentials (EC₅₀ 61 [mu]M). The inhibitory effects of LCM did not result from changes in passive membrane properties (including resting membrane potential or input resistance) as assessed by application of voltage ramps between -70 to +20 mV. LCM did not mimic the effects of diazepam as an allosteric modulator of GABA[A] receptor currents, nor did it inhibit evoked excitatory currents mediated by AMPA or NMDA receptors. Unlike phenytoin (DPH), carbamazepine (CBZ) or lamotrigine (LTG) that blocked sustained action potential firing evoked by brief depolarising steps (750 ms) or ramps (-70 to 20 mV, 90 mV.sec⁻�), LCM could weakly reduce the frequency of action potentials evoked by brief depolarisation suggesting a potential interaction with VGSCs. In accordance with this, the effect of LCM upon neurotransmission was negated in the presence of tetrodotoxin (200 nM, TTX). The frequency of miniature EPSCs was not altered by the drug (100 [mu]M). These results discounted some crucial potential anticonvulsant targets for LCM but implied a potential interaction with electrogenic VGSCs. When SRF duration was prolonged (10 s) LCM produced significant (P <0.01, n = 4-10, EC₅₀: 48 [mu]M) inhibition, but not within the first second of the burst EC₅₀: 640 [mu]M). Evoked TTX sensitive sodium currents in N1E-115 neuroblastoma cells were significantly reduced by LCM, CBZ, LTG and DPH when V[h]: -60 mV. Hyperpolarizing pulses (500 ms) to -100 mV could reverse block by CBZ, LTG and DPH but not LCM. The V₅₀ for steady state fast inactivation was more hyperpolarized by CBZ (-79.45 � 2.64 mV, n = 5, P < 0.001), LTG (-72.30 � 1.70 mV, n = 6, P <0.05) and DPH (-77.17 � 2.32 mV, n = 6, P <0.05) but not by LCM (-65.02 � 1.75 mV, n = 6, CONTROL: -65.84 � 0.86 mV). In contrast to CBZ, LCM did not slow recovery from fast inactivation or produce frequency dependent facilitation of block of a 3 s, 10 Hz pulse train. LCM (100 [mu]M) did produce a (V₅₀: CONTROL ~64 mV, LCM -57.47 � 4.53 mV, P <0.001, n = 4-8) hyperpolarizing shift in the voltage dependence of slow sodium channel inactivation and promoted channel entry into the slow inactivated state (P <0.001, n = 6) but did not alter the rate of recovery. I therefore conclude that LCM produces inhibition of epileptiform cellular activity, at least in part, via enhancement of voltage gated sodium channel slow inactivation and represents a molecule possessing a unique anticonvulsant mechanism of action.

Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

En esta Tesis Doctoral se han explorado y optimizado nuevas metodologías enantioselectivas y directas de formación de enlaces carbono-carbono catalizadas por complejos quirales de níquel(ll). Esencialmente, se han estudiado procesos asimétricos que involucran Ia formación in situ de enolatos quirales que participan en reacciones de alquilación con ortoésteres y acetales, en reacciones aldólicas con aldehidos aromaticos y en adiciones de Michael con compuestos carbonílicos α,β−insaturados. En el Capítulo I, después de evaluar seis catalizadores quirales y cinco scaffolds heterocíclicos, se ha desarrollado una reacción de alquilación directa, enantioselectiva y catalitica de Ia N-azidoacetil- 1,3-tiazolidin-2-tiona con ortoformiato de trimetilo. De acuerdo con Ia optimización llevada a cabo, empleamos Ia 1,3-tiazolidin-2-tiona como plataforma aquiral y el [(S)-ToiBINAP]NiCI2 como catalizador con el fin de obtener el mejor rendimiento (82%) y exceso enantiomérico (96% ee). Ademas, como el scaffold posee Ia capacidad de actuar como éster activo, en el Capítulo II se ha descrito Ia preparación de diferentes amidas en una sola etapa con excelentes rendimientos (60- 94%). Estas amidas se transformaron de forma facil y rapida en compuestos con potencial interes biol6gico como Ia (R)-Iacosamida y un amplio abanico de análogos. Los resultados descritos en ambos Capítulos han sido publicados recientemente en el artículo: " Direct, Enantioselective, and Nickel(//) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orlhoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives." Teloxa. s. F.; Kennington, S. C. D.; Camats, M.; Romea, P.; Urpi, F.; Aull6n, G.; Font-Bardia, M. Chem. Eur. J. 2020, 26, 11540. En el Capítulo Ill se ha descrito el proceso para generar dos centros estereogénicos en una única etapa. Para conseguirlo, se ha optimizado Ia reacción del enolato de nlquel(ll) de Ia N-azidoacetil-1,3-tiazolidin-2-tiona con el acetal dimetílico del p-anisaldehído, de nuevo en una reacción directa, catalítica y enantioselectiva que ha permitido obtener un aducto de tipo α-azido-β-metoxicarboxílico con buen rendimiento (68%), aceptable diastereoselectividad (r. d. 81:19) y excelente exceso enantiomérico (99% ee). Siguiendo Ia misma linea, en el Capítulo IV se ha estudiado Ia reacción directa y catalitíca de Ia N­ azidoacetil-1,3-tiazolidin-2-tiona con aldehídos. De este estudio, se han diseñado dos metodologías directas, enantioselectivas y catalíticas. La primera implica las reacciones aldólicas con aldehidos aromáticos y Ia segunda con aldehídos α,β−insaturados que permite obtener los aductos de Michael. Los aldehídos alifáticos quedaron excluídos ya que solo generaron mezclas complejas o, en el mejor de los casos, se recuperó el material de partida inalterado. En el caso de los aldehídos propargílicos fue necesario cobaltar el triple enlace para obtener únicamente un 15% de rendimiento del aldol. A excepción de las reacciones de adición Michael en Ia que se obtienen compuestos 1,5- dicarbonílicos, en todas las estrategias desarrolladas, se consiguen estructuras tipo β-hidroxi o β-alcoxi-α-aminocarboxilicas que, como se demuestra en el Capítulo II, pueden ser transformadas fácilmente a sistemas más complejos ya sea reduciendo Ia azida o desplazando el scaffold con diferentes agentes nucleofílicos. Finalmente, y siguiendo este contexto, en el Capítulo V se ha detallado un conjunto de transformaciones en las que elscaffold actúa como éster activo y permite preparar muchos derivados de Ia anti β -hidroxifenilalanina. La estrategia desarrollada implica principalmente el tratamiento con α-aminoesteres, aminas primarias y secundarias, con enolatos y con agentes reductores del aldol sililado obtenido en el Capítulo IV: el N-[(2R,3R)-2-azido-3-fenil-3-triisopropilsililoxipropanoil]-1,3- tiazolidin-2-tiona. En todos los casos, los rendimientos fueron de buenos a excelentes.
In this Doctoral dissertation new enantioselective and direct methodologies for the construction of carbon-carbon bonds through catalyzed reactions by chiral nickel(ll) complexes have been explored and optimized. In Chapter I, a direct, enantioselective and catalytic alkylation reaction of N-azidoacetyl-1,3- thiazolidine-2-thione with trimethyl orthoformate has been developed. According to the carried out optimization, we used 1,3-thiazolidine-2-thione as an achiral scaffold and [(R)-ToiBINAP]NiCI2 as a chiral catalyst in order to afford the best yield (82%) and enantiomeric excess (96%). Furthermore, as the scaffold has also the ability to act as an active ester, in Chapter II has been described the preparation of different amides in one pot processes with excellent yields (60-94%). These amides were easily transformed into potential biologically active compounds such as (R)-Iacosamide and analogues.In Chapter Ill, a one pot process to generate two stereogenic center have been described. In this methodology, the reaction of the nickel(ll) enolate derived from N-azidoacetyl-1,3-thiazolidin- 2-thione with p-anisaldehyde dimethylacetal has been optimized in a direct, catalytic and enantioselective reaction too. This protocol gave access in good yield (68%), highly diastereoselectivity (dr. 81:19), and excellent enantiomeric excess (99%) to anti α-azido- ­ methoxycarboxylic adduct type. In Chapter IV, a new aldol and Michael type reactions methodologies have been developed from the reaction between N-azidoacetyl-1,3-thiazolidin-2-thione with aromatic aldehydes or α, β unsaturated aldehydes through direct, enantioselective and catalytic processes. Finally, in Chapter IV, a set of transformations has been detailed in which the scaffold act as an active ester giving access to a different β -hydroxyphenylalanine derivatives. The strategy involves the treatment with α-aminoesteres, primary and secondary amines, with enolates and reducing agents of some sililated aldols previously obtained in Chapter IV. In all the cases, the products were obtained in good to excellent yields.

碩士
國立臺灣大學
生理學研究所
107
It has been shown that the genesis of nerve excitation and action potential conduction is mainly controlled by voltage-gated sodium channels. Abnormal neuronal excitation may lead to neurological disorders like epilepsy. The sodium channel inhibitors such as carbamazepine, phenytoin, lamotrigine, have been the mainstay of medical treatment of epilepsy. These prototypical anticonvulsants have been shown to bind to the fast-inactivated state rather than resting state of the sodium ion channel. Lacosamide (LCM) is a new generation anticonvulsant, which also inhibits sodium channel but is different from the prototypical ones. The molecular actions of LCM on sodium channels are not clear, although selective binding to the slow-inactivated state of the sodium channel was proposed. We found that LCM dose-dependently inhibits sodium currents at more depolarized holding potentials, and the inhibitory effect could be described by different one-to-one binding curves at different holding potentials, giving an apparent dissociation constant (KI) of ~ 150 μM at -70mV for LCM binding to the inactivated sodium ion channels. The apparent dissociation constant derived from the ratio between the binding rate constant of LCM and the unbinding rate from the sodium channel is ~155 μM (at -70mV). In addition, a KI of ~156 μM is derived from the LCM concentration-dependent shift of the inactivation curve. The apparent dissociation constant of LCM for the sodium channel of the inactive state is therefore about 150-156 μM, which is much smaller than that for the resting sodium channels (>10mM). On the other hand, different inactivation curves are constructed with 100 milliseconds or 18 seconds inactivating pulses at various voltages (fast inactivation curves, slow inactivation curves and “combined’’ inactivation curves) to show that the very slow kinetics of LCM action on the inactivated sodium channels. Furthermore, LCM slows recovery from the inactivated to the resting state. The slowing effect is much more manifest with inactivating pulse at -10 than -80 mv, indicating that the effect of LCM on the slow-inactivated sodium channels is greater than on the fast-inactivated state. Last but not the least, we also explored the effect of concomitant LCM and phenytoin & LCM and lidocaine on sodium currents, and found that the LCM and phenytoin have a different action on the fast inactivation and slow inactivation of sodium channels; however, LCM and lidocaine have a synergistic inhibitory action on fast inactivation of the sodium channels.

ABSTRACT INTRODUCTION. Epilepsy is one of the most common chronic neurological disorders characterized by the presence of spontaneous and recurrent seizures and it affects 1% of the population worldwide. Up to 30% of patients continue to have seizures despite an adequate and well-tolerated treatment with antiepileptic drugs (ASMs), used singularly or in combination. These individuals are regarded as having refractory or drug- resistant epilepsy. In 2010, an Internationally accepted definition of refractory epilepsy was proposed by a Task Force of International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules to achieve sustained seizure freedom”. Regardless of the advances in the field of epilepsy and the acquisition of new antiepileptic drugs, the proportion of drug-resistant patients remain unchanged. Dravet syndrome (DS) is a rare, drug-resistant, developmental epileptic encephalopathy with onset in infancy characterized by multiple types of frequent, disabling epileptic seizures, developmental delay/cognitive impairment and an increased risk of sudden unexpected death in epilepsy (SUDEP). In more than 80% of patients, a sodium voltage-gated channel alpha subunit 1 gene (SCN1A) genetic variant can be demonstrated, although diagnosis is based on clinical criteria. Idiopathic generalized epilepsies (IGEs) are the most common group of epilepsies in children and adolescents and include four well-characterized epilepsy syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and IGE with generalized tonic–clonic seizures only. Distinctive features of IGE syndromes are typical age of onset, specific generalized seizures type, normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion and with normal developmental skills. Lacosamide (LCM) is a third generation ASM approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as both monotherapy and adjunctive therapy in treatment of focal seizures, with or without bilateral tonic-clonic seizures, in patient older than 16 (EMA) or 17 (FDA) years old. Stiripentol (STP) is a third generation ASM indicated as adjunctive therapy in Dravet syndrome, whose seizures are not adequately controlled with clobazam and valproate. Fenfluramine (FFA) Hydrochloride is fourth generation ASMs, recently noticed as effective for the treatment of convulsive seizures and non-convulsive SE in DS. In the 2019, Zogenix supported an EAP of FFA in patients with a clinical diagnosis of DS, without echocardiographic signs of cardiac valve disfunction and pulmonary arterial hypertension and in June 2020 FDA approved FFA for the treatment of seizures in DS. Levetiracetam (LEV) is one of the most widely used ASMs for both adults and children. It is approved by EMA and FDA as adjunctive therapy in IGEs with myoclonic or tonic-clonic seizures in patients >12 years, as monotherapy in focal seizures in patients >16 years and as add-on therapy in focal or focal to bilateral tonic- clonic seizures in children and adults. AIM OF THE STUDY. To evaluate efficacy, long-term efficacy and tolerability of LCM, STP, FFA, or LEV in a cohort of children, adolescents and young adults with different types of refractory epilepsies, including focal and generalized forms and epileptic encephalopathies such as DS. METHODS. Patients treated with Study Drugs as therapy for different, refractory, types of epilepsy and seen at the Neuroscience Center of Excellence-Meyer Children Hospital in different period time were included in our studies. Data were retrospectively reviewed. Responder rate, relapse free survival and retention rate were calculated. Tolerability was assessed by reporting adverse events. RESULTS. Lacosamide: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11). Stiripentol first study: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with DS. The median follow-up was 14.8 months (range=4 months-18 years, interquartile range=25.72). Twenty-nine individuals (22%) received more than two ASMs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. Stiripentol second study: We expanded our analysis to a larger cohort of 196 patients with long-term follow-up. We observed a responder rate of 53% including seizure freedom in 9%. Etiology was associated with sustained response over time, with DS being the etiology with the highest responder rate (64%) at 48 months compared with syndromes with other genetic causes (13%) or unknown etiology (38%). A higher responder rate over time was also observed in patients with generalized (44%) and combined focal and generalized epilepsies (28%) than in patients with focal epilepsies (20%). The highest relapse free-survival was observed when STP was initiated at the youngest age (0-4 years) or in adulthood. Fenfluramine: Levetiracetam: A total of 88 patients with IGEs aged from 3.4 to 33.8 years, started LEV as monotherapy or add-on therapy. The median follow-up was 7.3 months (range=0.5-106 months). Thirty-four individuals (46.6%) received more than two ASMs. Thirty-five patients (39.8%) were responders, and 26 of them (29.5%) were seizure-free. The median time to LEV failure was 42 months and the median retention time was 10 months in all 88 individuals. A higher retention time was observed in patient older than 14 years. Fifty- Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. seven patients changed their therapy regimen by replacing LEV with another ASMs. Fourty-two (73.4%) remained responders at the last evaluation. About patients that replaced LEV with VPA or ETS, 23/27 (85.2%) or 9/12 (75%) were responders, respectively (p=0.19). neurological/psychiatric (17/18). CONCLUSIONS. Lacosamide: This study documents a real-world progressive and significant loss Stiripentol: suggest that STP is an effective and well-tolerated therapeutic option not only in DS but also in other epilepsy syndromes with or without an established genetic etiology, with sustained response over time. Fenfluramine: Levetiracetam: This study suggests that LEV did not result in a satisfactory clinical response in IGEs, considering their known good prognosis The most frequent adverse events were of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time. These studies In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated. Further confirmations based on prospectively or controlled designed studies with larger population are required to confirm our data.

Indiana University-Purdue University Indianapolis (IUPUI)
Posttraumatic epilepsy, the development of temporal lobe epilepsy (TLE) following traumatic brain injury, accounts for 20% of symptomatic epilepsy. Reorganization of mossy fibers within the hippocampus is a common pathological finding of TLE. Normal mossy fibers project into the CA3 region of the hippocampus where they form synapses with pyramidal cells. During TLE, mossy fibers are observed to innervate the inner molecular layer where they synapse onto the dendrites of other dentate granule cells, leading to the formation of recurrent excitatory circuits. To date, the molecular mechanisms contributing to mossy fiber sprouting are relatively unknown. Recent focus has centered on the involvement of tropomycin-related kinase receptor B (TrkB), which culminates in glycogen synthase kinase 3β (GSK3β) inactivation. As the neurite outgrowth promoting collapsin response mediator protein 2 (CRMP2) is rendered inactive by GSK3β phosphorylation, events leading to inactivation of GSK3β should therefore increase CRMP2 activity. To determine the involvement of CRMP2 in mossy fiber sprouting, I developed a novel tool ((S)-LCM) for selectively targeting the ability of CRMP2 to enhance tubulin polymerization. Using (S)-LCM, it was demonstrated that increased neurite outgrowth following GSK3β inactivation is CRMP2 dependent. Importantly, TBI led to a decrease in GSK3β-phosphorylated CRMP2 within 24 hours which was secondary to the inactivation of GSK3β. The loss of GSK3β-phosphorylated CRMP2 was maintained even at 4 weeks post-injury, despite the transience of GSK3β-inactivation. Based on previous work, it was hypothesized that activity-dependent mechanisms may be responsible for the sustained loss of CRMP2 phosphorylation. Activity-dependent regulation of GSK3β-phosphorylated CRMP2 levels was observed that was attributed to a loss of priming by cyclin dependent kinase 5 (CDK5), which is required for subsequent phosphorylation by GSK3β. It was confirmed that the loss of GSK3β-phosphorylated CRMP2 at 4 weeks post-injury was likely due to decreased phosphorylation by CDK5. As TBI resulted in a sustained increase in CRMP2 activity, I attempted to prevent mossy fiber sprouting by targeting CRMP2 in vivo following TBI. While (S)-LCM treatment dramatically reduced mossy fiber sprouting following TBI, it did not differ significantly from vehicle-treated animals. Therefore, the necessity of CRMP2 in mossy fiber sprouting following TBI remains unknown.

Rufinamide, lacosamide, and perampanel are third-generation agents licensed for use as antiepileptic drugs in recent years. Clinical experience is still limited, and little is known about their positive and negative psychotropic properties or their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of anxiety, depression, irritability, and agitation in patients with epilepsy treated with rufinamide, whereas depression, irritability, agitation, and psychotic symptoms have been reported during lacosamide treatment. There are initial reports of behavioural disturbances (especially depression, anxiety, irritability, and psychosis) in patients with epilepsy treated with perampanel. These effects seem to be dose-related and tend to appear within the first weeks of treatment. Overall, these antiepileptic drugs have no indications for the treatment of psychiatric disorders and there is insufficient experience to draw any conclusion regarding their psychotropic profiles.

Seizures are a common problem in intensive care units (ICU) and the advent of continuous electroencephalography is demonstrating that the incidence of seizures is still underestimated. Many patients considered encephalopathic from any cause are now found to be in non-convulsive status epilepticus. While the significance of non-convulsive seizures remains unclear, there is little disagreement that these seizures should be treated with antiseizure agents and prevention of any type of seizure is a reasonable therapeutic goal. Many antiseizure agents have been studied in ICU populations and extensive experience exists with drugs such as phenytoin, valproate, or pentobarbital. Since the previous edition of this textbook, several new antiseizure agents have been introduced. Levetiracetam, topiramate, and lacosamide have been established as reasonable pharmacologic options, in particular for treatment of status epilepticus. Patients with seizures in the ICU often present with challenging clinical scenarios, which influence the choice of antiseizure agents. For example, reduced liver or renal function, especially if needing continuous renal replacement therapy or intermittent haemodialysis, has an impact on drug level variability and susceptibility to seizure development. ICU patients will typically require a multitude of pharmacological agents for their specific clinical situation and drug–drug interactions must be considered. Additionally, many medications used in ICUs are associated with seizures, in particular, certain antibiotics. Overall, the development of new drugs and better monitoring methods will undoubtedly improve our ability to control seizures in ICU patients, but currently no treatment has been shown to be universally effective for challenges, such as refractory status epilepticus.

Background: Epilepsy is a complex neurological disorder, that affects 0.5 to 1% of the population, with a diversified etiology, but with emphasis on its relation with genetics. Despite there are several therapies to treat it, in some cases, this variety is still insuficiente, featuring refractory epilepsy, frequent in people with intelectual disabilities (ID). Objectives: To analyze the scientific production about refractory epilepsy and ID. Methods: Integrative literature review that searched for international articles in the Virtual Health Library (VHL), using the keywords “Intellectual disability” AND “Refractory epilepsy” with the filter: “full text”. Results: From the 27 articles found, 2 were excluded for escaping the theme, having 25 articles as a final corpus and 2 thematic axes identified: (I) Genetic aspects related to ID and refractory epilepsy and (II) Therapeutic interventions in these patients. According to studies, refractory epilepsy in people with ID is related to mutations in some genes, such as: PCDH19, FMR1, TDP2, GABRB2 and SLC9A6. As for therapies for these patients, drugs such as stiripentol, lacosamide and benzodiazepines have been used, in addition to other interventions such as vagus nerve therapies, responsive neural stimulation, ketogenic diet, immunotherapy and resection surgery. Conclusions: The ID association with refractory epilepsy is strongly linked to genetic mutations, being essencial the genetic diagnosid to individualize the treatment and overcome insuficiente therapies for this epilepsy, especially in patients with associated ID, who tend to have a reduced life quality, having as primary objective the improvement of it.