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BACKGROUND: In a flare of osteoarthritis (OA) pain, increasing the dose of standard anti-inflammatory or routine analgesic drugs may not be practical because of an increased incidence of side effects. In patients achieving inadequate pain relief from traditional non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2-selective inhibitors, it may be appropriate to add an analgesic agent with a different mechanism of action, thereby targeting multiple components of the pain pathway. OBJECTIVE: The addition of tramadol/acetaminophen tablets to existing therapy was compared with the addition of placebo in the treatment of OA flare pain. METHODS: This was a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Patients received 1 or 2 tramadol/acetaminophen (37.5 mg/325 mg) tablets QID or matching placebo for 10 days in addition to ongoing NSAID or COX-2-selective inhibitor therapy. The primary outcome measures were average daily pain intensity and average daily pain relief scores from days 1 through 5. RESULTS: Three hundred eight patients were randomized to tramadoUacetaminophen (n = 197) or placebo (n = 111) and were followed for up to 10 days. Patients had a mean (+/-SD) age of 60.1 +/- 9.87 years, and were predominantly female (71.8%) and white (87.7%). Their mean (+/- SD) pain visual analog score at baseline was 73.2 +/- 11.8 mm, and their mean pain intensity score was 2.4 +/- 0.5 (on a scale from 0 = none to 3 = severe). Average daily pain intensity and pain relief scores were significantly improved with tramadol/acetaminophen compared with placebo on the primary assessment of efficacy from days 1 through 5 (both, P < 0.001) and on the assessment of efficacy from days I through 10 (both, P < 0.001) Tramadol/acetaminophen was significantly superior to placebo on the patients' and physicians' overall assessments of medication (both, P < 0.001) and on 3 of 4 subscales (pain [P = 0.004], physical function [P = 0.013], and overall [P = 0.008]) of the Western Ontario and McMaster Universities Osteoarthritis Index Questionnaire. The most common treatment-emergent adverse events with tramadol/acetaminophen were nausea, vomiting, and dizziness. No serious adverse events were reported in the tramadol/acetaminophen group. CONCLUSION: In this study, addition of tramadol/acetaminophen to NSAID or COX-2-selective inhibitor therapy was well tolerated and effective in the treatment of OA flare pain. [ABSTRACT FROM AUTHOR]

African American HIV+ and HIV- recent mothers were compared on levels of psychosocial functioning. Participants included 82 HIV+ and 122 HIV- women. HIV risk behaviors, stressors, coping resources, close relationships, coping responses, and psychological distress were examined. There were fewer statistically significant differences than expected, indicating that psychosocial functioning was relatively well preserved for the HIV+ women. There were no statistically significant differences in social support, close relationships or psychological distress. Statistically significant differences indicated that HIV- women perceived greater control over present health and sexual behaviors than HIV+ women, although HIV+ women used more sexual protection than did the HIV- women. HIV+ women also used avoidant as well as support coping more than their HIV- counterparts. These differences were also apparent in a discriminant function analysis, implying that they are independent of each other. Implications of the findings for future efforts to address HIV/AIDS in this community are discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Tramadol and acetaminophen (APAP) have both shown efficacy in the treatment of lower back pain. The combination of these 2 agents has demonstrated synergistic analgesic action in animal models at specific ratios. OBJECTIVE: This study assessed the long-term (3-month) efficacy and safety of tramadol 37.5 mg/APAP 325 mg combination tablets in the treatment of chronic lower back pain. METHODS: Patients with at least moderate lower back pain (pain visual analog [PVA] score >/=40 mm on a 100-mm scale) were randomized to receive up to 8 tablets of tramadol/APAP per day or placebo for 91 days. Medication was titrated from 1 to 4 tablets/d by day 10. The primary efficacy measure was PVA score at the final visit. Secondary measures included scores on the Pain Relief Rating Scale (PRRS), Short-Form McGill Pain Questionnaire (SF-MPQ), Roland Disability Questionnaire (RDQ), and 36-Item Short-Form Health Survey (SF-36); the incidence of discontinuation due to insufficient pain relief (Kaplan-Meier analysis); and overall assessments of medication by the patients and investigators. RESULTS: Three hundred eighteen patients (161 tramadol/APAP, 157 placebo) were included in the intent-to-treat population, defined as all patients who took >/=1 dose of study medication and had >/=1 postrandomization efficacy measurement. The mean age of the study population was 53.9 years, 63.2% were female, 90.3% were white, and the mean baseline PVA score was 70.0 mm. There were no significant differences between groups at baseline. Tramadol/APAP significantly improved final PVA scores (P = 0.015) and final PRRS scores (P < 0.001) compared with placebo. Tramadol/APAP also significantly improved RDQ scores (P

Cenobamate is approved for the treatment of focal seizures in adults and is currently available as an oral tablet. Alternative methods of drug administration are needed for patients who are unable to swallow whole intact tablets. This phase 1, open-label, randomized, single-dose, three-way crossover (3-period, 3-treatment, 6-sequence) study (NCT05572255), conducted in healthy volunteers, assessed the relative bioavailability of a crushed 200-mg cenobamate tablet administered orally or via nasogastric (NG) tube compared with an intact 200-mg tablet. Each treatment was separated by a 13-day washout period. Plasma samples for cenobamate concentration analysis were collected pre-dose and at multiple time points up to 264 h post-dose. Standard bioequivalence study criteria were applied to the relative bioavailability assessments. All 90% confidence intervals of test-to-reference geometric mean ratios for cenobamate pharmacokinetic parameters (C max , AUC last , and AUC inf ) were within 85-110% (predefined limit, 80-125%), suggesting no difference in cenobamate exposures following administration of an intact tablet orally or a crushed tablet orally or via NG tube. All treatment-emergent adverse events (TEAEs) were classified as mild and resolved. There were no deaths or other serious AEs (SAEs), and no TEAEs led to discontinuation. Our results indicate that the administration of cenobamate as a crushed tablet taken orally or via an NG tube can provide additional flexibility when patients cannot swallow intact tablets. Based on the results of this study, cenobamate is now approved by FDA to be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy., Methods: A population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8-1.25., Results: In the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816-0.925) for adjunctive carbamazepine and 1.24 (1.147-1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8-1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam., Conclusions: Based on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Even though the prevalence of VSR after MI is only 1%-3%, the mortality associated with the condition is more than 80%. Very few studies in the literature have described in detail the treatment options for delayed VSR repair. This systematic review was conducted to evaluate the outcomes of delayed ventricular septal rupture (VSR) repair following acute myocardial infarction (AMI). Digital databases were searched systematically to identify studies reporting the outcomes of delayed VSR repair. Detailed study and patient-level baseline characteristics including the type of study, sample size, follow-up, number of delayed repairs, time to repair, outcomes (in terms of major adverse cardiovascular events), and predictors of outcome were abstracted. A total of 12 studies, recruiting 8,579 patients were included in the final analysis. Male gender, young age (<60 years), and delayed VSR repair were reported as predictors of survival along with left ventricular assist devices (LVADs) and extracorporeal membrane oxygenation (ECMO), and the use of inotropes before surgery. Postoperative renal failure, higher New York Heart Association (NYHA) score, early repair, and history of heart failure (HF) were demonstrated as predictors of mortality. This study demonstrated that delayed VSR repair can reduce mortality in patients who develop VSR after AMI. Furthermore, the use of LVADs can prolong the time of surgery, and the use of inotropes can predict survival benefits in this patient cohort., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To report post-hoc efficacy data by focal seizure subtypes from 10 US study sites from a large, global, open-label, phase 3 study of adjunctive cenobamate., Methods: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals (target dose 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments every other week were allowed., Results: 240 patients were evaluated; 27 (11.3%), 224 (93.3%), and 56 (23.3%) patients had focal aware motor (FAM), focal impaired awareness (FIA), and focal to bilateral tonic-clonic (FBTC) seizures, respectively (patients may have had ≥ 1 seizure subtype). Median baseline seizure frequencies/28 days were 10.5, 2.3, and 0.9 for FAM, FIA, and FBTC seizure subtypes. Reductions in median percent seizure frequency/28 days from baseline were observed during Months 1-3 (55.0%, 52.4%, and 94.1% for FAM, FIA, and FBTC). Greater reductions were observed during Months 4-5 (88.2%, 81.0%, and 100%) and during Months 25-27 (98.1%, 100%, and 100%). The percentage of patients achieving 100% seizure reduction in the FAM, FIA, and FBTC seizure subtypes was 22.2% (6/27), 21.5% (48/223), and 50% (28/56) during Months 1-3 and increased to 47.8% (11/23), 54.3% (88/162), and 90.5% (38/42) during Months 25-27, respectively. The most common treatment-emergent adverse events (≥ 20%) were fatigue, dizziness, and somnolence. No cases of DRESS were reported., Conclusions: Seizure reductions occurred in all focal seizure subtypes with cenobamate over time through Months 25-27, with the earliest onset in the FBTC group. Results from this subset analysis of the phase 3 study support the long-term efficacy of cenobamate across focal seizure types., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1-63) up-titrated by 50-mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo-moxifloxacin (days -1 and 64); (B) moxifloxacin 400 mg (day -1; positive control), placebo-cenobamate (days 1-63), and placebo-moxifloxacin (day 64); and (C) placebo-moxifloxacin (day -1), placebo-cenobamate (days 1-64), and moxifloxacin 400 mg (day 64). The primary end point was baseline-adjusted, placebo-corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, -10.8 milliseconds; day 63, -18.4 milliseconds). Based on concentration-QTc analysis, ∆∆QTcF effect was predicted as -9.85 and -17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose-related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc-prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short-QT syndrome and caution should be used when coadministering with drugs that shorten QT interval., (© 2022, The American College of Clinical Pharmacology.)

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no-effect interval (0.80-1.25). When co-administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC 0-last ) GMR (90% CIs) for midazolam was 0.734 (0.647-0.832). When co-administered with cenobamate 200 mg/day, AUC 0-last GMRs (90% CI) for midazolam, bupropion, S-warfarin, and omeprazole were 0.277 (0.238-0.323), 0.615 (0.522-0.724), 1.14 (1.10-1.18), and 2.07 (1.44-2.98), respectively. Co-administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co-administration of cenobamate led to omeprazole values which were outside and above the no-effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co-administration of cenobamate with these probes drugs was well-tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose-dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9., (© 2021 SK Life Science, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Our objective was to ascertain the efficacy and safety of once weekly Dulaglutide among patients with Type 2 diabetes of Pakistani origin., Methods: This prospective cohort study was conducted at the Endocrinology Clinics of Shifa International Hospital, Islamabad and Umar Diabetes and Foot Care Centre, Islamabad, Pakistan during the period from July 2020 to December 2020. Dulaglutide at the dose of 1.5 mg once weekly was initiated in patients with BMI >28 and suboptimal glucose control in the background of Type 2 Diabetes who were also taking one or more of oral anti-diabetic and/or insulin therapy., Results: Mean age of patient cohort (n = 148) was 49.51 years (SD +/- 12.15) with 53.5% (n = 85) having type 2 diabetes for a duration of over 10 years. Mean weight was 93.2 kg at baseline with end of study mean weight being 90.7 kg. Mean HbA1c at baseline was 9.2%, which improved to 8.05% at the end of study. The main side-effects were nausea in 32%, vomiting in 8%, and diarrhea in 7% with 19% discontinuation rate due to cost and side-effects., Conclusion: Dulaglutide as a therapy demonstrated favorable HbA1c and weight reduction in obese type 2 diabetes patients of Pakistani origin., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Endocrinology and Metabolism.)

Objective: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968)., Methods: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis., Results: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity., Significance: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background The treatment of primary hypothyroidism with thyroxine is weight-based or body mass index (BMI)-based. However, significant variation in the dose and the consequent delay in achieving euthyroid state is observed along the spectrum of patient body weights. Objectives To determine the weight and BMI-based dosing of thyroxine in primary hypothyroidism to achieve euthyroidism . Material and methods It was a retrospective review of the patient records conducted in the department of endocrinology, Shifa International Hospital, Islamabad, from July 1, 2014, to June 30, 2019 (five-year period) . Patients with clinical and biochemical hypothyroidism were enrolled and initiated on thyroxine replacement to achieve euthyroid status. A total of 504 patients were included in the study. Results The mean age was 44.5 ±13.6 standard deviation. Females were 83.5%. The mean dose of thyroxine to achieve euthyroid status was 107.7 ± 39.3 mean standard deviation mcg/day, i.e. 1.4 (0.5) mcg/kg/day. Euthyroid status was achieved in 264 (52.4%) of patients at three months. The mean TSH level after treatment was 2.09 (1.2) mU/L. The linear regression model showed that BMI and weight are independent predictors of the required thyroxine dose (R and Rsquare values are .274 and 0.075 for BMI and .319 and .102 for weight, respectively (P-value <.0001). There was no impact of age, gender, height, and duration of disease on achieving euthyroid at six months after treatment (P values: .85, .394, .827, and .105, respectively). Conclusion The optimum dose in primary hyperthyroidism can be determined with body weight and BMI-based calculations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Raashid et al.)

Background and Objectives Liraglutide, an analog of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes mellitus in Pakistan since 2016. It is a GLP-1 receptor agonist that has shown promising results in terms of not only glycemic control but also weight loss. Our study aimed to provide evidence regarding the safety and effectiveness of liraglutide in Pakistan and to look at the adherence rate and treatment satisfaction of patients using liraglutide. Methods This is an observational retrospective study that recruited patients who were treated with liraglutide. Data were collected at the first visit and follow-up. Morisky Green Levine Adherence Scale and Treatment Satisfaction Questionnaire for Medication (TSQM-9) were used for the determination of adherence and satisfaction with the treatment. Results A total of 70 patients were recruited in the study, The mean difference in weight, body mass index, glycated hemoglobin (HbA1C), systolic blood pressure, and diastolic blood pressure from baseline to follow-up was -5.36 kg, -2.14 kg/m 2 , -1.76%, -12.38 mmHg, and 5.55 mmHg, respectively. Nausea was the main side effect reported. TSQM-9 scores were compared from baseline, and it was found that patients are satisfied with the treatment and its effectiveness. Conclusions Our study has demonstrated the effectiveness of liraglutide as a monotherapy or combination therapy in the Pakistani population. Liraglutide led to reduction in HbA1C and weight. This is associated with high treatment satisfaction rate and adherence rate. Thus, liraglutide remains an effective though expensive treatment option in a country like Pakistan., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Zameer et al.)

Introduction Dapagliflozin is a member of a novel class of drugs (sodium-glucose cotransporter-2 inhibitors) used to treat type 2 diabetes mellitus and licensed in Pakistan in 2017. This retrospective observational study evaluated the effects of dapagliflozin on glycated hemoglobin (HbA1c) concentrations in patients treated at endocrinology clinics in Islamabad, Pakistan. The secondary objectives included assessing the effects of dapagliflozin on weight reduction and blood pressure control and to determining its safety. Methodology Patients with type 2 diabetes who were treated with dapagliflozin were identified by screening the electronic medical records at tertiary care hospitals in Islamabad. Data were collected at the first visit and at follow-up. Categorical variables were recorded as frequencies and percentages and compared by McNemar's tests, and continuous variables were recorded as means and standard deviations and compared by paired sample t-tests. Results Mean HbA1C concentration was significantly lower at follow-up than at the first visit (7.57%±0.98% vs. 9.07%±2.07%, respectively; p<0.001). Bodyweight (85.09±15.92 kg vs. 87.07±16.11 kg, respectively; p<0.001) and diastolic blood pressure (80.34±7.12 mmHg vs. 82.34±9.61 mmHg, respectively; p<0.001) were also significantly lower at follow-up than at the first visit, whereas systolic pressure showed a marginally significant reduction (123.5±16.57 mmHg vs. 126.83±19.97 mmHg, p=0.048). Conclusion This first observational study of patients in Pakistan treated with dapagliflozin found that HbA1c concentration, weight, and blood pressure were reduced after initiation of dapagliflozin treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Kamin et al.)

Objective: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs., Methods: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment., Results: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo ( p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%)., Conclusion: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated., Clinicaltrialsgov Identifier: NCT01397968., Classification of Evidence: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital., Methods: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%-33%., Results: At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ≥1 treatment dose (median modal dose = 200 mg). The most common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline., Significance: No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start-low (12.5 mg/d), go-slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%-33%), when needed during cenobamate titration, maintained stable plasma levels., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)