Effectiveness and tolerability of brivaracetam in patients with epilepsy stratified by comorbidities and etiology in the real world: 12-month subgroup data from the international EXPERIENCE pooled analysis.

OBJECTIVE: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies. METHODS: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE]). RESULTS: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively. CONCLUSIONS: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.

Prevention of epileptogenesis - are we there yet?

PURPOSE OF REVIEW: To review recent progress in preventing epileptogenesis in patients with epilepsy. RECENT FINDINGS: The recent success of epilepsy prevention and disease modification in tuberous sclerosis using simple EEG biomarkers to guide treatment initiation, and the identification of biomarkers to enrich the targeted patient population has made clinical trials of epilepsy prevention after acquired central nervous system (CNS) insults such as traumatic brain injury, stroke or infection both feasible and timely. Two such trials are currently on-going to prevent poststroke epilepsy. SUMMARY: No disease-modifying or preventive treatments exist for epilepsy, and their development remains a major unmet need.. We have entered though the era of change in the treatment of epilepsy from symptomatic only to disease prevention. In this review, we summarize developments and review opportunities, challenges, and potential solutions to develop preventive treatment for acquired epilepsies in humans. The 'Holy Grail' of epilepsy is within our reach.

Sudden Unexpected Death in Epilepsy During Ambulatory Video-EEG Monitoring at Home.

BACKGROUND AND OBJECTIVES: We report the recording of sudden unexpected death in epilepsy (SUDEP) in a 68-year-old man with recent onset cryptogenic epilepsy, captured by video-EEG monitoring, at home in the company of his wife while sitting in a chair. This was only the third seizure of his life, the first 2 occurring 19 days previously. This rare event is a novel case of SUDEP recorded with ambulatory video EEG at home. The video is included by permission. METHODS: Electroclinical seizure and cardiorespiratory analysis was ascertained using a combination of video, EEG (Natus, standard 10-20 electrode), ECG, and sound. Respiratory rate was ascertained based on chest, abdominal, and facial respiratory movements, together with video and audio. RESULTS: The unique video-EEG recording illustrates the time course of apnea and bradycardia leading to terminal apnea in conjunction with prolonged postictal generalized EEG suppression. DISCUSSION: This case is illustrative of a wide spectrum of SUDEP cases, ranging from the highly intractable to the patient with newly diagnosed epilepsy with very few seizures. It illustrates that patients can succumb to SUDEP while awake and in the sitting position (1) very early in their epilepsy course, (2) without recognized risk factors other than generalized convulsive seizures, (3) even when accompanied.

Patterns of antiseizure medication utilization in the Human Epilepsy Project.

OBJECTIVE: This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. METHODS: The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy. RESULTS: A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients. SIGNIFICANCE: Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

Effectiveness and Tolerability of 12-Month Brivaracetam in the Real World: EXPERIENCE, an International Pooled Analysis of Individual Patient Records.

BACKGROUND AND OBJECTIVE: Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population. METHODS: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥ 6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥ 16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤ 200 mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥ 50% seizure reduction. All outcomes were summarised using descriptive statistics. RESULTS: Analyses included 1644 adults. At baseline, 72.0% were 16-49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥ 50% seizure reduction was achieved by 32.1% (n = 619), 36.7% (n = 867), and 36.9% (n = 822) of patients; seizure freedom rates were 22.4% (n = 923), 17.9% (n = 1165), and 14.9% (n = 1111); and continuous seizure freedom rates were 22.4% (n = 923), 15.7% (n = 1165), and 11.7% (n = 1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n = 1542), 14.2% (n = 1376), and 9.3% (n = 1232) of patients at 3, 6, and 12 months, respectively. CONCLUSIONS: This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population.

The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented?

Despite the many therapeutic options for epilepsy available today, a third of patients still have poorly controlled epilepsy. Over the years, their transition through lines of treatment exposes them to increased risk of disease progression, mortality, morbidity, mental distress, and not least significantly impaired quality of life (QoL). The present review explores the multiple factors contributing to the impairment of health-related QoL in PWE-including both seizure-related and non seizure-related. The analysis aims to identify potential areas of intervention and strategies for a more holistic approach to epilepsy care and inform policy-makers and healthcare providers in their approach to this condition.

Failure to use new breakthrough treatments for epilepsy.

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one-third of epilepsy patients experience seizures despite therapy. Drug-resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3-13.4 times higher mortality rate than in seizure-free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic-clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long-term, open-label studies, 10%-36% of patients were seizure-free for a median duration of ~30-45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open-label extension studies. Mortality was reduced 5-fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post-launch information about the efficacy and safety of these ASMs.

The Gradual Release of Alendronate for the Treatment of Critical Bone Defects in Osteoporotic and Control Rats.

Purpose: Osteoporosis is a severe health problem with social and economic impacts on society. The standard treatment consists of the systemic administration of drugs such as bisphosphonates, with alendronate (ALN) being one of the most common. Nevertheless, complications of systemic administration occur with this drug. Therefore, it is necessary to develop new strategies, such as local administration. Methods: In this study, emulsion/dispersion scaffolds based on W/O emulsion of PCL and PF68 with ALN, containing hydroxyapatite (HA) nanoparticles as the dispersion phase were prepared using electrospinning. Scaffolds with different release kinetics were tested in vitro on the co-cultures of osteoblasts and osteoclast-like cells, isolated from adult osteoporotic and control rats. Cell viability, proliferation, ALP, TRAP and CA II activity were examined. A scaffold with a gradual release of ALN was tested in vivo in the bone defects of osteoporotic and control rats. Results: The release kinetics were dependent on the scaffold composition and the used system of the poloxamers. The ALN was released from the scaffolds for more than 22 days. The behavior of cells cultured in vitro on scaffolds with different release kinetics was comparable. The difference was evident between cell co-cultures isolated from osteoporotic and control animals. The PCL/HA scaffold show slow degradation in vivo and residual scaffold limited new bone formation inside the defects. Nevertheless, the released ALN supported bone formation in the areas surrounding the residual scaffold. Interestingly, a positive effect of systemic administration of ALN was not proved. Conclusion: The prepared scaffolds enabled tunable control release of ALN. The effect of ALN was proved in vitro and in in vivo study supported peri-implant bone formation.

Recent advances in pharmacotherapy for epilepsy.

PURPOSE OF REVIEW: Epilepsy affects 70 million people worldwide and is a significant cause of morbidity and early mortality. The mainstay of therapy is oral medications. Epilepsy drug development is escalating, driven by continued drug resistance in up to a third of epilepsy patients. Treatment development now focuses on discovery of novel mechanisms of action and syndrome-specific therapies. RECENT FINDINGS: Difficult-to-treat epilepsy related to conditions including tuberous sclerosis complex (TSC), Lennox Gastaut syndrome (LGS) and Dravet syndrome (DS) have been the target of recent developments. Disease-modifying therapy for epilepsy related to TSC with vigabatrin at onset of first electroencephalographic epileptiform changes, rather than after first clinical seizure, has demonstrated strongly positive seizure and developmental outcomes. Fenfluramine, approved for DS and, more recently, LGS, has robust data supporting efficacy, safety/tolerability, as well as mortality, quality of life and cognitive function. Rescue therapy has expanded to include better tolerated benzodiazepines in the form of nasal midazolam and valium. Cenobamate, a first-in-class inactivator of the persistent voltage-gated sodium channel and approved for adult partial onset epilepsy, has exceptional efficacy and tolerability and will be expanded to children and to generalized onset epilepsy in adults. SUMMARY: The repertoire of available and developmental therapies for epilepsy is rapidly expanding, and now includes disease-modifying vigabatrin in TSC and agents with extraordinary efficacy, fenfluramine and cenobamate.

Preclinical pharmacokinetics and tolerability of a novel meglumine-based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus.

OBJECTIVE: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy-to-use and easy-to-prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)-approved excipient meglumine. METHODS: During formulation development, we compared the solubility of TPM in bi-distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine-based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine-induced SE. RESULTS: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether-ß-cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co-administered with another ASM for SE treatment. The tolerability studies of the meglumine-based TPM solution and meglumine-based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine-induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. SIGNIFICANCE: In conclusion, the novel meglumine-based solution of TPM presented here may be well suited for clinical development.

Retention, efficacy, tolerability, and quality of life during long-term adjunctive brivaracetam treatment by number of lifetime antiseizure medications: A post hoc analysis of phase 3 trials in adults with focal seizures.

OBJECTIVE: To evaluate long-term retention, reasons for discontinuation, efficacy, tolerability, and health-related quality of life (HRQOL) during adjunctive brivaracetam (BRV) treatment in adults with focal seizures by number of lifetime antiseizure medications (ASMs). METHODS: Post hoc analyses of a randomized, double-blind, placebo-controlled trial (N01358; NCT01261325) and corresponding open-label extension (OLE) (N01379; NCT01339559) of adjunctive BRV in adults (16-80 years of age) with focal seizures. Outcomes were assessed from the first day of BRV treatment in the double-blind (patients randomized to BRV) or open-label trial (patients randomized to placebo) by number of lifetime ASMs (1-2, 3-4, 5-6, or ≥ 7). Lifetime ASMs were defined as previous (stopped before BRV initiation) and concomitant ASMs at BRV initiation. RESULTS: Seven hundred and forty patients received adjunctive BRV (safety set [SS]; median modal dose: 200 mg/day [N = 737]; median treatment duration: 2.67 years), of whom 13.8 % had 1-2, 20.8 % had 3-4, 21.1 % had 5-6 and 44.3 % had ≥7 lifetime ASMs. Patients with a higher number of lifetime ASMs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. Kaplan-Meier estimated retention on BRV at 12 (83.2-65.9 %) and 36 months (63.0-44.1 %) was highest in patients with 1-2 lifetime ASMs and decreased with the number of lifetime ASMs. The estimated proportions of patients who discontinued BRV due to lack of efficacy or treatment-emergent adverse events (TEAEs) increased with the number of lifetime ASMs. Efficacy analyses included seven hundred and thirty eight patients (intention-to-treat set [ITT]). Median percentage reductions from baseline in focal seizure frequency/28 days (76.3-39.6 %), 50 % responder rates (66.7-39.8 %), 75 % responder rates (51.0-19.6 %), and continuous seizure freedom for ≥12 months at any time during BRV treatment (35.3-6.1 %) were highest in patients with 1-2 lifetime ASMs and decreased by the number of lifetime ASMs. The overall incidence of TEAEs (SS) was generally similar in each lifetime ASM subgroup (84.4-90.5 %). Discontinuations due to TEAEs increased with the number of lifetime ASMs (7.8-20.1 %). The greatest improvements in QOLIE-31-P scores occurred in the Seizure Worry and Daily Activities/Social Function subscales, with no clear pattern by the number of lifetime ASMs at 12 months and with the highest improvement in patients with 1-2 lifetime ASMs at 24 months. At 24 months, the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale scores improved in patients (SS) with 1-2 and 3-4 lifetime ASMs. HADS Depression subscale scores were generally stable independent of the number of lifetime ASMs. CONCLUSIONS: The balance between efficacy, tolerability, and HRQOL was most favorable in patients with focal seizures who had been exposed to one or two ASMs before BRV initiation. However, patients exposed to ≥7 ASMs before BRV initiation also benefitted from long-term adjunctive BRV treatment.

Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity.

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

EEG parameters as endpoints in epilepsy clinical trials - An expert panel opinion paper.

INTRODUCTION: The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development. METHODS: A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues. RESULTS: Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by > 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting. DISCUSSION & CONCLUSION: Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts.

Gut microbiome diversity of porcine peritonitis model of sepsis.

Animal models are essential in understanding of the mechanisms of sepsis moreover the development and the assessment of emerging therapies. In clinically relevant porcine model, however, a significant variability in the host response has been observed among animals. Thus, there is a strong demand to better understand the potential sources of this heterogeneity. In this study, we compared faecal microbiome composition of 12 animals. Three samples were collected at different time points from each animal. Bacteriome was subjected to 16S rDNA profiling. A significant difference in bacterial composition was associated with the season (p < 0.001) but not with the sex of the pig (p = 0.28), the timing of sample collection (p = 0.59), or interactions thereof (all p > 0.3). The season batch explained 55% of the total variance in the bacteriome diversity. The season term was highly significant from the high-resolution level of the bacterial amplicon sequencing variants up to the level of phylum. The diversity of the microbiome composition could significantly influence experimental model of sepsis, and studies are warranted to demonstrate the effects of gut microbiome diversity on the host-response. If confirmed, control of the gut microbiome should become a standard part of the pre-clinical sepsis experiments.

Effect of Bisphenol S on testicular tissue after low-dose lactation exposure.

Exposure to endocrine disruptors such as bisphenols, can lead to and be the explanation for idiopathic infertility. In our study, we assessed the effect of exposure to bisphenol S (BPS) via breast milk on the testicular tissue health of adult male mice. Lactating dams were exposed to BPS through drinking water (0.216 ng g bw/day and 21.6 ng g bw/day) from post-natal day 0-15. Although there was no significant difference in testicular histopathology between the control and experimental groups, we observed an increase in the number of tight and gap junctions in the blood-testis barrier (BTB) of adult mice after lactation BPS exposure. Moreover, there was an increase in oxidative stress markers in adult testicular tissue of mice exposed via breast milk. Our lactation model indicates that breast milk is a route of exposure to an endocrine disruptor that can be responsible for idiopathic male infertility through the damage of the BTB and weakening of oxidative stress resistance in adulthood.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

INTRODUCTION: Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. METHODS: A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. RESULTS: We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. CONCLUSION: The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate's dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control. Video Abstract: Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Efficacy of cenobamate for uncontrolled focal seizures in patients with previous epilepsy-related surgery: Post hoc analysis of a phase 3, multicenter, open-label study.

OBJECTIVE: This post hoc analysis of 10 US study sites from a long-term open-label phase 3 study of adjunctive cenobamate evaluated the efficacy of cenobamate in patients with prior epilepsy-related surgery. METHODS: Patients with uncontrolled focal seizures despite taking stable doses of 1-3 concomitant antiseizure medications (ASMs) received increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals over 12 weeks (target dose, 200 mg/day). Further increases up to 400 mg/day using biweekly 50-mg/day increments were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019. RESULTS: Of the 240 eligible patients, 85 had prior epilepsy-related surgery and 155 were nonsurgical patients. Baseline focal seizure frequency per 28 days was numerically higher among prior surgery (mean=25.9/median=4.1/range=0.3-562.3) versus nonsurgical (mean=13.8/median=2.4/range=0.2-534.2) patients. Among all patients, 100 % seizure reduction ≥ 12 months at any consecutive month interval occurred in 30.6 % (26/85) prior surgery and 39.4 % (61/155; p > 0.05) nonsurgical patients (cenobamate treatment median duration=32.9 months). Among the 177 patients still receiving cenobamate at the data cutoff, 29.2 % (19/65) of prior surgery and 36.6 % (41/112; p > 0.05) of nonsurgical patients had 100 % seizure reduction ≥ 12 months at the data cutoff. Cenobamate was well tolerated. CONCLUSIONS: This post hoc analysis supports the efficacy of cenobamate in patients with refractory focal seizures despite prior surgery. These findings suggest cenobamate may be considered early in the treatment regimen, including, in some patients, before surgery is considered.

Long-Term Efficacy and Safety From an Open-Label Extension of Adjunctive Cenobamate in Patients With Uncontrolled Focal Seizures.

OBJECTIVE: Evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study. METHODS: Patients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n=360) could enter the OLE, where they underwent a 2-week blinded conversion to cenobamate (target dose, 300 mg/day; min/max, 50/400 mg/day). RESULTS: Three hundred fifty-five patients were included in the OLE safety population (265 originally randomized to cenobamate, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% (209/355) of patients were continuing cenobamate treatment and 141 had discontinued, including 16.6% (59/355) due to lack of efficacy, 8.7% (31/355) due to withdrawal by patient, and 7.6% (27/355) due to adverse events. Median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE mITT population, 10.2% (36/354) of patients achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% (72/355) of patients. CONCLUSION: Long-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of cenobamate treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of cenobamate. REGISTRATION: ClinicalTrials.gov NCT01866111. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that oral Cenobamate 50-400 mg/day is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1 to 3 ASMs.

Bevacizumab Does Not Inhibit the Formation of Liver Vessels and Liver Regeneration Following Major Hepatectomy: A Large Animal Model Study.

BACKGROUND/AIM: Patients with unresectable liver colorectal cancer metastases are treated with neoadjuvant chemotherapy often accompanied by biological therapy aimed at reducing the mass of metastases and thus increasing the chances of resectability. Bevacizumab comprises an anti-VEGF (vascular endothelial growth factor) humanized IgG monoclonal antibody that is used for biological therapy purposes. It acts to inhibit angiogenesis, thereby slowing down the growth of metastases. Due to its being administered systematically, bevacizumab also exerts an effect on the surrounding healthy liver parenchyma and potentially limits the process of neovascularization and thus regeneration of the liver. Since the remnant liver volume forms an important factor in postoperative morbidity and mortality following a major hepatectomy, we decided to study the effect of bevacizumab on vascular and biliary microarchitecture in healthy liver parenchyma and its ability to regenerate following major hepatectomy. MATERIALS AND METHODS: We performed an experiment employing a large animal model where a total of 16 piglets were divided into two groups (8 piglets in the control group and 8 piglets in the experimental group with bevacizumab). All the animals were subjected to major hepatectomy and the experimental group was given bevacizumab prior to hepatectomy. All the animals were sacrificed after 4 weeks. We performed biochemical analyses at regular time intervals during the follow-up period. Histological examination of the liver tissue was performed following sacrifice of the animals. RESULTS: No statistical difference was shown between groups in terms of the biochemical and immunohistochemical parameters. The histological examination of the regenerating liver tissue revealed the higher length density of sinusoids in the experimental group. CONCLUSION: Bevacizumab does not act to impair liver regeneration following hepatectomy.