Rational Polytherapy Research Articles

Treatment simplification to optimize cenobamate effectiveness and tolerability: A real-world retrospective study in Spain.

This study aimed to explore the impact of co-antiseizure medication (co-ASM) optimization on the effectiveness and tolerability of adjunctive cenobamate (CNB) in patients with drug-resistant epilepsy in a real-world setting. This unicentric, retrospective, observational study included adults with focal-onset seizures who had received ≥2 previous ASMs. The main effectiveness endpoints included responder rates and seizure frequency reduction at 3, 6, and 12-month visits. The number of co-ASMs and defined daily dose (DDD) were analyzed at every visit. Safety endpoints included adverse drug reactions (ADRs). Thirty-four patients with a median epilepsy duration of 22 years and a median of 15.5 seizures/month were analyzed. The median number of prior ASMs was 12, and the mean number of co-ASMs was 2.9 (SD 1). There was a reduction in seizure frequency/month from baseline to the last visit (p < 0.0001). Between baseline and the end of the study, the mean number of co-ASMs in the per-protocol (PP) population was reduced from 2.9 to 1.6 (p < 0.0001), and DDD was reduced from 3.6 to 1.4 (p < 0.0001). Sodium channel blockers (carbamazepine and lacosamide) and GABAergic drugs (clobazam) were the agents with the most significant reductions in DDD after 12 months. The percentage of patients in the PP population with ≥3 co-ASMs was reduced from 61.8% at baseline to 14.3% at 12 months; 1 patient was receiving CNB as monotherapy at the last visit. At the last visit, 85.7% of the PP population were ≥50% responders, and 33.3% were seizure-free. The percentage of patients with ADRs in the PP population was 71.9% at 3 months and 52.3% at 12 months. Following rational polytherapy, optimization of co-ASM management during CNB treatment allowed high seizure freedom rates despite meaningful reductions in co-medication, while also achieving both good tolerability and patient satisfaction scores in a highly drug-resistant population. Many patients with epilepsy still have seizures, even after being treated with several different epilepsy drugs. In this study of 34 patients from a Spanish clinic, we show that the epilepsy drug cenobamate can reduce the number of seizures in these patients, even after many other epilepsy drugs have failed. We also show that patients treated with cenobamate can reduce the dose or even stop taking certain other epilepsy drugs. This allows them to simplify their treatment and reduce adverse effects while still keeping control of their epilepsy.

DIAGNOSIS AND TREATMENT OF STATUS EPILEPTICUS : AN UPDATE SYSTEMATIC REVIEW

Background: Status epilepticus (SE) is a condition resulting from the failure of the mechanisms involved in termination or the initiation of mechanisms responsible for seizure prolongation. The aim: The aim of this study to show about diagnosis and treatment of status epilepticus. Methods: By the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. This search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed, SagePub, and Google Scholar were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search get 110 articles, whereas the results of our search on SagePub get 163 articles, on Google Scholar 8200 articles. Records remove before screening are 7182, so we get 2761 articles fos screening. After we screened based on record exclude, we compiled a total of 10 papers. We included five research that met the criteria. Conclusion: There are increasingly more drug options to treat SE, but rational polytherapy should consider the pharmacodynamics and kinetics of established and new antiepileptic drugs. When seizures cannot be controlled with conventional medical therapy, non-conventional treatments, including early surgical evaluation can be considered; however, high-quality evidence for these strategies are lacking. Neurointensivists are challenged to reduce secondary brain injury by managing common complications.

Is thalamic deep brain stimulation synergistic with vagus nerve stimulation in drug-resistant genetic generalized epilepsy?

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a "rational polytherapy" may exist in some patients with GGE undergoing dual neuromodulation.

Perampanel in adjunctive therapy of patients with brain tumor-related epilepsy: real-world data

Background. Brain tumor-related epilepsy (BTRE) is an important and insufficiently studied interdisciplinary problem. In a significant part of brain tumor patients, the disease onsets with epileptic seizures. The course of tumor-associated epilepsy is often pharmacoresistant and requires rational polytherapy. To date, there are no uniform recommendations on the choice of an antiepileptic drug (AED) for the initial therapy of BTRE.Objective: retrospective analysis of the efficacy/tolerability of adjunctive therapy with perampanel in relation to epileptic seizures in patients with epilepsy associated with glial brain tumors and metastases.Material and methods. The analysis included 51 patients with glial tumors and brain metastases who were prescribed perampanel as part of adjunctive therapy. Its effectiveness against focal seizures (FS) and bilateral tonic-clonic seizures (BTCS) was evaluated at follow-up periods of &gt;1≥3≥6 months. A decrease in the frequency of seizures by 50% or more (responders) or by 100% (seizure freedom) was analyzed. An analysis of the influence of intervening factors in a multifactorial model, an assessment of the effectiveness of perampanel as a whole and a stratified assessment of intervening factors were carried out. The frequency and profile of adverse events (AEs) were also evaluated, including their possible association with the use of other AED.Results. In the multifactorial model, independent predictors of the clinical effect were the onset of the disease in the form of FS at &gt;1≥3≥6 months follow-up. None of AEDs used in the first line of therapy demonstrated an impact on the clinical effect. There were no predictors of clinical effect in patients with BTCS during the entire follow-up period. Out of 51 patients, 48 (94.1%) were responders, and in 36 of them (70.6%) the seizure freedom was registered. Among patients with FS, the proportion of responders was 83.3–90.9% at different follow-up periods, including 31.2–50.0% who showed seizure freedom. Among patients with BTCS, 86.7–92.3% became responders, including 56.1–88.5% who achieved seizure freedom. AEs were noted in 7 (13.7%) patients, the most common was aggression – 4 patients (7.8%). There were no cases required reduction the dose or discontinuation the treatment with perampanel due to AEs. In most patients at &gt;1≥3≥6 months follow-up, the median was 6 mg/day.Conclusion. The study performed in real-world practice confirmed the high efficiency and safety of perampanel in the adjunctive therapy of epileptic seizures associated with glial brain tumors and metastases, which together with the low potential of drug interactions allow us recommend the drug to this contingent of patients.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II.

Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

Unanticipated improvement in seizure control in drug-resistant epilepsy- real world observations

ObjectivesTo determine the clinical features and anti-seizure medication (ASM) strategies associated with an unanticipated substantial improvement in seizure control in patients with drug-resistant epilepsy (DRE). MethodsThis retrospective analysis of patients attending a tertiary care epilepsy clinic between 2008 and 2017 identified all patients with active DRE (at least 1 seizure per month for 6 months, despite treatment with 2 different ASMs). All treatment interventions were recorded from when DRE was first identified to the end of the study. The primary end points were seizure freedom or meaningful reduction in seizure frequency (greater than 75 %) sustained for at least 12 months after a treatment intervention. ResultsThree hundred and twenty-two patients were included in the analysis. Overall, 10 % became seizure free following ASM adjustment and an additional 10 % had a greater than 75 % improvement in seizure control (median follow-up, 4 years). An ASM introduction was ten times more likely than an ASM dose increase to improve seizure control. Combined focal and generalized epilepsy, intellectual disability and prior treatment with more than 5 ASMs were more frequently observed in those with continued pharmacoresistance. ASM responders were more likely to have primary generalized epilepsy. Rational polytherapy (combining ASMs with different mechanisms of action) was almost ubiquitous amongst ASMs responders (95 % taking at least 2 drugs with different mechanistic targets). Of the ASM additions that heralded improved seizure control, 85 % were maintained at submaximal doses. ConclusionsThis retrospective analysis of a large number of ‘real-world’ patients provides evidence to persist with ASM trials in DRE. Early rotation of ASMs if a clinical response is not observed at a substantial dose and rational ASM polytherapy may yield better clinical outcomes in patients with DRE, although a prospective study would need to be conducted to validate these findings.

A small natural molecule CADPE kills residual colorectal cancer cells by inhibiting key transcription factors and translation initiation factors

Residual disease is the major cause for colorectal cancer (CRC) relapse. Herein, we explore whether and how a natural molecule CADPE killed heterogenic populations in a panel of CRC cell lines with KRAS/BRAF mutations that are natively resistant to EGFR- or VEGFR-targeted therapy, without sparing persistent cells, a reservoir of the disease relapse. Results showed that CADPE killed the tumor bulk and residual cells in the panel of CRC cell lines, rapidly inactivated c-Myc, STAT3, and NF-κB, and then decreased the protein levels of key signaling molecules for CRC, such as β-catenin, Notch1, and the nodes of mTOR pathways; eukaryotic translation initiation factors (eIF4F); anti-apoptotic proteins (Bcl-xl, Mcl-1, and survivin); and stemness-supporting molecules (CD133, Bim-1, and VEGF). In terms of mechanism of action, concurrent downregulation of Mcl-1, Bcl-xl, and survivin was necessary for CADPE to kill CRC bulk cells, while additional depletion of CD133 and VEGF proteins was required for killing the residual CRC cells. Moreover, the disabled c-Myc, STAT3, NF-κB, and eIF4F were associated with the broadly decreased levels of anti-apoptosis proteins and pro-stemness proteins. Consistently, CADPE suppressed CRC tumor growth associated with robust apoptosis and depleted levels of c-Myc, STAT3, NF-κB, eIF4F, anti-apoptotic proteins, and pro-stemness proteins. Our findings showed the promise of CADPE for treating CRC and suggested a rational polytherapy that disables c-Myc, STAT3, NF-κB, and eIF4F for killing CRC residual disease.

Pharmacotherapy for Pediatric Convulsive Status Epilepticus.

Convulsive status epilepticus (CSE) is one of the most common pediatric neurological emergencies. Ongoing seizure activity is a dynamic process and may be associated with progressive impairment of gamma-aminobutyric acid (GABA)-mediated inhibition due to rapid internalization of GABAA receptors. Further hyperexcitability may be caused by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartic acid) receptors moving from subsynaptic sites to the synaptic membrane. Receptor trafficking during prolonged seizures may contribute to difficulties treating seizures of longer duration and may provide some of the pathophysiological underpinnings of established and refractory SE (RSE). Simultaneously, a practice change toward more rapid initiation of first-line benzodiazepine (BZD) treatment and faster escalation to second-line non-BZD treatment for established SE is in progress. Early administration of the recommended BZD dose is suggested. For second-line treatment, non-BZD anti-seizure medications (ASMs) include valproate, fosphenytoin, or levetiracetam, among others, and at this point there is no clear evidence that any one of these options is better than the others. If seizures continue after second-line ASMs, RSE is manifested. RSE treatment consists of bolus doses and titration of continuous infusions under continuous electro-encephalography (EEG) guidance until electrographic seizure cessation or burst-suppression. Ultimately, etiological workup and related treatment of CSE, including broad spectrum immunotherapies as clinically indicated, is crucial. A potential therapeutic approach for future studies may entail consideration of interventions that may accelerate diagnosis and treatment of SE, as well as rational and early polytherapy based on synergism between ASMs by utilizing medications targeting different mechanisms of epileptogenesis and epileptogenicity.

Antiepileptic Drug Therapy in Patients with Drug-Resistant Epilepsy.

Antiepileptic drug (AED) therapy starts with an accurate diagnosis of epilepsy and is followed by sequential drug trials. Seizure freedom is largely achieved by the first two drug trials; thus, epilepsy that cannot be controlled after appropriately conducted trials of the first two drugs is defined as drug-resistant epilepsy (DRE). It is still unclear which mode of pharmacotherapy, among monotherapy and polytherapy, shows better outcomes in cases of DRE. However, in a recent large hospital cohort study over past two decades, combination therapy was associated with a progressive increase in seizure-free rate than monotherapy in DRE. The benefits of polytherapy in the management of DRE might be related to the recent introduction of many new AEDs with different and novel mechanisms of action and better pharmacokinetic and tolerability profiles. These new AEDs were introduced to the market after they have proven their superiority over placebos in randomized controlled trials (RCTs) on add-on therapy in patients with DRE. Therefore, polytherapy including these new AEDs in the regimen is the approved mode of treatment for cases of DRE; this has prompted physicians to try various combinations of polytherapy to optimize the clinical outcomes. In addition, the significant discrepancies in AED responder rates between RCTs and real-world practice may support the importance of judicious use of new drugs in polytherapy by experienced epileptologists. Most experts now agree to the concept of “rational polytherapy” consisting of mechanistic combinations of AEDs exerting synergistic interactions and to the importance of continuing trials of different rational polytherapy regimens to improve the outcome of the core population of epilepsy patients in the long term.

КЛИНИЧЕСКИЕ ПРЕДИКТОРЫ НЕЭФФЕКТИВНОСТИ СТАРТОВОЙ МОНОТЕРАПИИ ЭПИЛЕПСИИ У ДЕТЕЙ

Actuality. Effectiveness of epilepsy treatment in children is determined by the possibility of achieving clinical remission at initial monotherapy. The spectrum of anticonvulsants recommended for initial treatment of epilepsy in children is relatively known, but the analysis of their prescription indicates the influence of other non-pharmacologic factors on the possibility of achieving adequate control over epileptic seizures. Objective of the study: to find the frequency of achieving clinical remission in children with epilepsy while taking initial anticonvulsant and to define a combination of independent clinical factors which determine ineffectiveness of initial anticonvulsant monotherapy. Material and methods. Using the method of target selection there was performed a cohort retrospective-prospective comparative study of 447 children with epilepsy aged from birth to 17 years old. The frequency of clinical remission at initial anticonvulsant therapy was analyzed; a comparative study of clinical parameters was made within the frames of mono-factor analysis in order to find significant differences with consideration of age of epilepsy onset and effectiveness of initial treatment. Results. The study found the influence of a child’s age at epilepsy debut on achieving clinical remission at initial monotherapy: the younger the child, the lower is the possibility of its acheving, pllat<0.001. The highest frequency of absence of remission was noted in children under 1 year (72.5%) and those aged 1-3 years (71.4%) in comparison to children of older age groups (33.0%-59.5%), pFisher<0.001.The factors which define the prognosis of initial treatment of epilepsy in children were determined: in case of chronic somatic comorbidity ineffectiveness of therapy was noted in 69.8% of cases (pFisher<0.001) and chances of remission absence raised by 2.5 times (ОR=2.480; S=0.201; 95% CI [1.672; 3.681]; in case of psychic comorbidity therapy was ineffective in 87.6% of cases (pFisher<0.001) with a 7-fold increase of chances of remission absence (ОR=7.06; S=0.283; 95% CI [4.054; 12.291]; in case of neurologic comorbidity monotherapy was ineffective in 76.3% of cases (pFisher<0.001) and chances of remission absence increased by 3.9 times (ОR=3.925; S=0.206; 95% CI [2.62; 5.88]. For the first time the combination of independent factors in patients with epilepsy was stated – age at disease onset less than 6 years, presence of neurologic disorders, focal or combined types of epilepsy, presence of chronic somatic comorbidity. The set of these factors validly defines prognosis of effectiveness of initial anticonvulsant therapy with precision of 78.5% (AUC = 0.785; 95% CI [0.742; 0.828]) (p<0.001) by the results of ROC-analysis and with precision of 72.5% by the results of logistic regression (0.725 with 95% CI [0.680; 0.765]), which proves the tactics of fast correction of anticonvulsant dosage, its change and using rational polytherapy at initial stage of epilepsy treatment in children. Conclusions. New data regarding prognosis of effectiveness of initial anticonvulsant momotherapy in children were received; they allow defining the possibility of achieving clinical remission at prescribing the first anticonvulsant with a probability of more than 70%.

Rational polytherapy: Myth or reality?

Rational polytherapy: Myth or reality?

Abstract B27: Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib

Abstract The RAS-RAF-MEK-ERK pathway is a major player in initiation and progression of multiple cancers where it can be hyperactivated by upstream regulatory proteins, such as tyrosine kinases, phosphatases, and GTPases. Several inhibitors targeting the RAS-MAPK pathway exhibit anticancer activity and are approved as single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK, EGFR, and K-RAS mutant lung cancer and neuroblastoma containing hyperactivating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, and NF1 genes, leading to hyperactivation of RAS-MAPK signaling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors, since monotreatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacologic inhibition of the MEK-ERK pathway in ALK-positive neuroblastoma cells results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by the mTORC2 complex protein SIN1. Taken together, our results indicate that blocking MEK-ERK leads to increased activation of AKT signaling core in ALK-positive neuroblastoma, intensifying survival signals in these cells. Our results contraindicate use of MEK inhibitors as an effective single- and polytherapeutic strategy in ALK-positive neuroblastoma. Citation Format: Bengt Hallberg, Ganseh Umapathy, Jikui Guan, Dan Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djoos, Tommy Martinsson, Ruth Palmer. Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B27.

PO-181 Anaplastic lymphoma kinase addictive neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib

Introduction The RAS-MAPK pathway is a major player in initiation and progression of multiple cancers where it can be hyper-activated by upstream regulatory proteins, such as receptor tyrosine kinases, phosphatases and GTPase’s. Several inhibitors targeting the RAS-MAPK pathway exhibit anti-cancer activity and are approved as a single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK, EGFR and K-RAS mutant lung cancer and neuroblastoma containing hyper activating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, NF1 genes, leading to hyperactivation of RAS-MAPK signalling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors since mono-treatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Material and methods In order to determine which signalling core should be blocked for combinatorial treatment, we treated a panel of neuroblastoma cell lines using Trametinib, a MEK inhibitor. Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. Results and discussions Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacological inhibition of MEK-ERK pathway results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by SIN1 of mTORC2. Taken together, our results indicate that blocking MEK-ERK leads to ‘super-activation’ of AKT signalling core in ALK-positive neuroblastoma, increasing survival signals of these cells. Conclusion Our results contraindicate the use of MEK inhibitors as an effective therapeutic strategy in ALK-positive neuroblastoma.

Abstract B038: Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib

Abstract The RAS-RAF-MEK-ERK pathway is a major player in initiation and progression of multiple cancers where it can be hyper-activated by upstream regulatory proteins, such as tyrosine kinases, phosphatases, and GTPases. Several inhibitors targeting the RAS-MAPK pathway exhibit anticancer activity and are approved as single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational poly therapy strategy for treating EML4-ALK, EGFR, and K-RAS mutant lung cancer and neuroblastoma containing hyper-activating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, NF1 genes, leading to hyper-activation of RAS-MAPK signaling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors, since monotreatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacologic inhibition of the MEK-ERK pathway in ALK-positive neuroblastoma cells results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by the mTORC2 complex protein SIN1. Taken together, our results indicate that blocking MEK-ERK leads to "increased activation" of AKT signalling core in ALK-positive neuroblastoma, intensifying survival signals in these cells. Our results contraindicate use of MEK inhibitors as effective single and poly-therapeutic strategy in ALK-positive neuroblastoma. Citation Format: Bengt Hallberg, Ganesh Umapathy, Diana Cervantes-Madrid, Jikui Guan, Dan E. Gustafsson, Ruth H. Palmer. Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B038.

Аnalysis of antiepileptic therapy of epilepsy patients in Bishkek

Background: Most patients with epilepsy can achieve seizure freedom with adequate and timely appointed single AED. Need for rational polytherapy may occur in 30-50% of patients who failed to achieve a reduction in seizure frequency with monotherapy.

Status Epilepticus and Beyond: A Clinical Review of Status Epilepticus and an Update on Current Management Strategies in Super-refractory Status Epilepticus.

Status epilepticus and refractory status epilepticus represent some of the most complex conditions encountered in the neurological intensive care unit. Challenges in management are common as treatment options become limited and prolonged hospital courses are accompanied by complications and worsening patient outcomes. Antiepileptic drug treatments have become increasingly complex. Rational polytherapy should consider the pharmacodynamics and kinetics of medications. When seizures cannot be controlled with medical therapy, alternative treatments, including early surgical evaluation can be considered; however, evidence is limited. This review provides a brief overview of status epilepticus, and a recent update on the management of refractory status epilepticus based on evidence from the literature, evidence-based guidelines, and experiences at our institution.

A Long-Term Treatment with Arachidonyl-2'-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy.

Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC.

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non–small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma

The advent of genomics has led to the identification of specific “driver” mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance.

Monotherapy or polytherapy for childhood epilepsies?

Antiepileptic drugs (AEDs) were frequently used as polytherapy until evidence from a series of studies in the late 1970s and early 1980s suggested that patients derive as much benefit from...