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Objective: The etiology of ulcerative colitis (UC) is complex and involves multiple factors, with exposure to environmental toxins potentially contributing greatly to its pathogenesis. Therefore, this study was carried out with the purpose of delving into the associations between single and combined exposures to environmental phenols and UC among American adults., Methods: Survey data from the 2009-2010 National Health and Nutrition Examination Survey were selected for our research. The associations between single and combined exposures to environmental phenols and the prevalence of UC were analyzed using weighted multivariate logistic regression models as well as Bayesian kernel machine regression (BKMR)., Results: A total of 1,422 adults aged 20 years old and above were included in this study, 17 of whom had UC. The correlation matrix showed strong associations between 2,4-dichlorophenol (2,4-DCP) and 2,5-dichlorophenol (2,5-DCP) (R = 0.81), as well as between 2,4,5-trichlorophenol (2,4,5-TCP) and 2,4,6-trichlorophenol (2,4,6-TCP) (R = 0.73). The logistic regression model revealed that, after adjusting for confounders, exposure to environmental phenols was positively associated with the prevalence of UC, with 2,4,6-TCP showing a significant association (OR = 2.37, 95 % CI = 1.10, 5.09, P = 0.037). The BKMR analysis indicated an upward trend in the overall effect of combined exposures to environmental phenols on UC. All five phenols contributed to this effect, with 2,4,6-TCP exhibiting the most pronounced effect. When other compounds were fixed at the 50th percentile, the impact of the five phenols on UC demonstrated a positive association, without any noteworthy interaction among the compounds., Conclusion: Our findings suggested that exposure to environmental phenols may contribute to the occurrence of UC among American adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs., Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs., Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged., Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy., (© 2024. The Author(s).)

Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy., Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses., Results: A total of 236 subjects with a median age of 38 (Q 1 -Q 3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q 1 -Q 3  = 2.50-4.47) at baseline to 2.50 (Q 1 -Q 3  = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel., Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: Cenobamate (CNB) is a new antiseizure medication (ASM) to treat drug-resistant, focal-onset seizures. Data on its use in early therapy lines are not yet available, and clinicians frequently consider CNB to be a later ASM drug choice. We investigated the efficacy and safety of CNB as an early adjunctive treatment in drug-resistant, focal-onset seizures., Methods: The study population were patients with drug-resistant, focal-onset seizures who were initiated with CNB after they did not respond to two or three lifetime ASMs, including all prior and concomitant ASMs. These patients were matched (1:2) by sex, age, and seizure frequency to controls who were initiated with any ASM other than CNB. All participants participated in the Mainz Epilepsy Registry. We evaluated the retention rate after 12 months of CNB and after each new adjunctive ASM in the control group. In addition, seizure freedom and the response rate (reduction of seizure frequency by ≥ 50% from baseline) after 12 months were estimated., Results: We included 231 patients aged 44.4 ± 15.8 years. Of these, 33.3% (n = 77) were on CNB, 19.0% (n = 44) on valproate (VPA), 17.3% (n = 40) on lacosamide (LCS), 16.4% (n = 38) on levetiracetam (LEV), and 13.9% (n = 32) on topiramate (TPM). The highest retention rate after 12 months since the beginning of the early adjunctive therapy was observed on CNB (92.0%), compared with LCS (80.0%), LEV (73.3%), VPA (68.2%), or TPM (62.5%) (p < 0.05). Seizure freedom and response rate were also the best on CNB (19.5% and 71.4%, respectively) compared with other ASMs (8.3% and 52.5%, respectively; p < 0.05). No significant differences in adverse events between CNB and other ASMs were observed., Conclusions: Our study provides evidence that CNB is an effective ASM with a good safety profile in the early therapy lines of drug-resistant, focal-onset seizures. This data should support medical decision making in the management of patients with refractory epilepsy., Clinical Trial Id: NCT05267405., (© 2024. The Author(s).)

Objective: 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., Methods: 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)., Results: 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., Significance: 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., Plain Language Summary: 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., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Although most people with epilepsy achieve complete seizure cessation, approximately one-third of those with the condition continue experiencing seizures despite the use of antiseizure medications (ASMs) given as monotherapy or polytherapy. In this review, we summarised the evidence from randomised controlled trials (RCTs) about cenobamate as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant ASMs., Objectives: To assess the efficacy and tolerability of add-on oral cenobamate for the treatment of drug-resistant focal-onset seizures, defined as seizures persisting despite treatment with one or more ASMs., Search Methods: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (September 2022). In addition, we contacted the manufacturer of cenobamate and experts in the field to enquire after any ongoing or unpublished studies., Selection Criteria: RCTs comparing add-on cenobamate to placebo or another ASM in people with focal epilepsy uncontrolled by one or more concomitant ASMs., Data Collection and Analysis: Two review authors independently selected trials for inclusion, extracted data, performed risk of bias assessment, and assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were at least a 50% reduction in total seizure frequency, seizure freedom, and the occurrence of adverse events. We used an intention-to-treat approach for our primary analyses. For each outcome we estimated summary risk ratios (RRs) with their 95% confidence intervals (CIs). We summarised the estimates of effects and certainty of the evidence for each outcome in a summary of findings table., Main Results: We included two studies (659 adult participants, 442 allocated to cenobamate and 217 to placebo). The overall RR for at least a 50% reduction in seizure frequency for add-on cenobamate at any dose compared to placebo was 2.17 (52% versus 24%, 95% CI 1.66 to 2.84; 2 studies, 605 participants; moderate-certainty evidence). The RR for seizure freedom for add-on cenobamate at any dose compared to placebo was 4.45 (16% versus 5%, 95% CI 2.25 to 8.78; 2 studies, 605 participants; moderate-certainty evidence). The RR for the occurrence of adverse events for add-on cenobamate at any dose compared to placebo was 1.14 (77% versus 67%, 95% CI 1.02 to 1.27; 2 studies, 659 participants; moderate-certainty evidence). We judged the two included RCTs as at low or unclear risk of bias. Both studies were sponsored by the drug company that produces cenobamate., Authors' Conclusions: Add-on cenobamate is probably better than placebo in reducing the frequency of seizures by at least 50% and in achieving seizure freedom in adults with focal epilepsy uncontrolled by one or more concomitant ASMs (moderate level of certainty). Its use is probably associated with an increased risk of adverse events (moderate level of certainty). Further prospective, controlled trials are required to evaluate the efficacy and tolerability of add-on cenobamate compared to other ASMs. The efficacy and tolerability of cenobamate as adjunctive treatment for focal epilepsy in children should be further investigated. Finally, the long-term efficacy and tolerability of add-on cenobamate treatment in people with other epilepsy types (e.g. generalised epilepsy) or specific epilepsy syndromes, as well as its use as monotherapy, require additional study., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: To compare the efficacy, safety, and tolerability of cenobamate with other newer anti-seizure medications (ASMs) including brivaracetam, eslicarbazepine, lacosamide, perampanel, and zonisamide, approved for adjunctive treatment of drug-resistant focal-onset seizures (FOS) in adults with epilepsy., Methods: A systematic literature review (SLR) was conducted to obtain relevant efficacy, safety, and tolerability data for ASMs for the treatment of drug-resistant FOS. All studies were thoroughly assessed for potential sources of heterogeneity and analysed via Bayesian network meta-analyses (NMAs). Efficacy outcomes were ≥50 % responder rate and seizure freedom during the maintenance period, which were modelled simultaneously using a multinomial Bayesian NMA. Safety and tolerability outcomes were the proportion of patients who experienced at least one treatment-emergent adverse event (TEAE) and the proportion who experienced at least one TEAE leading to discontinuation., Results: The SLR identified 76 studies, of which 23 were included in the Bayesian NMAs. Cenobamate was associated with statistically significant higher rates for the ≥50 % responder rate and seizure freedom outcomes compared with all ASMs analysed. The point estimates indicated that cenobamate was associated with higher rates of experiencing at least one TEAE and at least one TEAE leading to discontinuation compared with brivaracetam, lacosamide, and zonisamide; however, no results were statistically significant., Conclusion: Cenobamate was associated with increased efficacy compared with all ASMs analysed. There were no statistically significant differences in the safety and tolerability outcomes. The results presented corroborate the conclusions drawn from previous published NMAs, which also highlight the notable efficacy of cenobamate in comparison with other ASMs., Competing Interests: Declaration of competing interest SM is an employee of Angelini Pharma (Market Access). TPL, MMcS, and RD are employees of Putnam LLC. ND has served as a paid advisor and / or speaker for Angelini Pharma, Eisai, Jazz Pharma, Radius Pharma, and UNEEG Medical. ND has been compensated for his time and expertise in the preparation of this manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Adjunctive cenobamate was effective and safe for the treatment of uncontrolled focal onset seizures in a randomized, double-blind, placebo-controlled, phase 2 study (YKP3089C017; NCT01866111). This post-hoc analysis assessed the efficacy of adjunctive cenobamate in the treatment of patients with different epileptic etiologies during the study., Methods: Adult patients with uncontrolled focal seizures who previously received 1 to 3 antiseizure medications (ASMs) were randomly assigned in a ratio of 1:1:1:1 to receive placebo or cenobamate 100, 200 or 400 mg/day. Patients were further stratified based on their etiologic causes as genetic/presumed genetic, unknown cause, structural cause, and not reported (NR) groups. The frequency per 28 days for an 18-week double-blind treatment period, responder rates (≥50 %, ≥75 %, ≥90 %, and 100 %) during the maintenance phase (12 weeks), and safety were assessed., Results: A total of 394 patients were categorized into the genetic/presumed genetic (n = 9; 2.28 %), unknown cause (n = 199; 50.51 %), structural cause (n = 177; 44.92 %), and NR (n = 13; 3.30 %) groups, with 4 patients were classified into either of the two etiological causes each. The baseline characteristics were comparable. The percentage of reduction in seizure frequency per 28 days was significantly higher in the cenobamate-treated structural (p = 0.01) and unknown cause (p = 0.0003) groups compared with the placebo group. Responder rates of ≥50 %, ≥75 %, ≥90 %, and 100 % were also higher with cenobamate therapy. Notably, no serious treatment-emergent adverse events (TEAEs) were observed in the genetic/presumed genetic group treated with cenobamate. The most common TEAEs (≥10 %) occurring in patients treated with cenobamate were nervous system disorders by system organ class, and somnolence was the most commonly reported TEAE., Conclusion: Cenobamate reduces seizures in adult patients previously treated with ASMs, with high responder rates and acceptable safety, regardless of underlying causes., Competing Interests: Declaration of competing interest All authors have read and approved the manuscript. Yutong Liu and Hui Ye are employees of Ignis Therapeutics (Shanghai) Limited, China. The other authors report no other potential conflicts of interest in this work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Trichlorophenols (TCPs) are metabolites of several organochlorine chemicals, including chlorobenzene, hexachlorocyclohexane, and chlorophenoxy acid, present in air, surface water, soil, and sediment. Many studies have shown that endocrine disruptors (EDs)may contribute to decreased bone mass and the increased risk of osteoporosis. However, the relationship between TCP and bone mineral density (BMD) has not been studied yet., Methods: We conducted a cross-sectional study by using data from the 2005-2010 National Health and Nutrition Examination Survey (NHANES). TCP levels were measured in urine samples from 3385 participants and bone mineral density was obtained by dual X-ray absorptiometry (DXA) lumbar spine and femur scanning. Multiple regression analysis, stratified analysis, curve fitting analysis, and trend tests were used to assess the relationship between TCP and BMD., Result: After adjusting for confounding factors, the results of multiple regression analysis only showed that ln-2,4,5-TCP was negatively associated with BMD of lumbar spine. In stratified analyses, Male, Menstruating Female and Menopausal Female were divided into three groups for analysis. The results showed that ln-2,4,5-TCP and ln-2,4,6-TCP were not statistically associated with BMD in total femur, femoral neck, femoral tuberosity, intertrochanteric femur and lumbar spine, which was also confirmed by curve fitting analyses and trend tests., Conclusion: This study demonstrated that 2,4,5-TCP and 2,4,6-TCP in urine samples were not significantly associated with BMD in the US population. Therefore, 2,4,5-TCP and 2,4,6-TCP may not be detrimental to BMD., (© 2023. The Author(s).)

Purpose: To assess how efficacy and safety outcomes were affected when cenobamate was co-administered with antiseizure medications (ASMs) that use either sodium channel blocker (SCB) or non-sodium channel blocker (non-SCB) mechanisms of action (MoAs) in patients with uncontrolled focal seizures., Methods: An exploratory post-hoc analysis of a randomized, double-blind, placebo-controlled clinical study (YKP3089C017) was conducted. Baseline concomitant ASMs were grouped as either those that employed an SCB or non-SCB MoA. Efficacy was examined by cenobamate dose (100 mg, 200 mg, and 400 mg/day) and concomitant ASM group using responder rates (≥50%, ≥75%, ≥90% seizure reduction; 100% seizure reduction/seizure freedom) during the maintenance phase and median percentage seizure reduction during the double-blind period. Treatment-emergent adverse events (TEAEs) were examined in the double-blind period., Results: When co-administered with SCBs or non-SCBs, significantly higher percentages of patients achieved ≥50%, ≥75%, and ≥90% responder rates with cenobamate 200 mg/day and/or 400 mg/day versus placebo. Additionally, significantly higher percentages of patients achieved seizure freedom with cenobamate 400 mg/day versus placebo (SCB group, 17.5% versus 1.2%; non-SCB group, 40.0% versus 0.0%). Patients receiving 200 mg/day and 400 mg/day and concomitant SCBs and all patients taking cenobamate combined with non-SCB concomitant ASMs had significantly greater median percentage reductions in focal seizure frequency versus placebo. TEAEs were similar across groups; however, dizziness was more frequently reported in the SCB group., Conclusion: Cenobamate is a highly effective new treatment option for patients with uncontrolled focal seizures when co-administered with SCB or non-SCB ASMs., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: The efficacy and safety of cenobamate relative to other antiseizure medications (ASMs) has not been evaluated. An indirect treatment comparison (network meta-analysis) was performed to determine if adjunctive cenobamate increases the odds ratio (OR) for ≥50% responder rate or for withdrawals due to treatment-emergent adverse events (TEAEs) leading to ASM discontinuation versus adjunctive therapy with other ASMs., Methods: A systematic literature review was conducted to identify randomized, double-blind, placebo-controlled trials (maintenance phase ≥ 12 weeks) assessing adjunctive ASMs in adults with uncontrolled focal seizures. Cenobamate was compared to a group of seven other ASMs, and to subgroups of branded (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel) and older (lamotrigine, levetiracetam, and topiramate) ASMs at FDA-recommended daily maintenance doses (FDA-RDMD), at all doses, and at maximum and minimum daily doses. Statistical significance was set at p < 0.05., Results: Twenty-one studies were eligible for analysis. The placebo-adjusted ≥ 50% responder rate for FDA-RDMD of cenobamate was superior (OR 4.200; 95% CI 2.279, 7.742) to FDA-RDMD of all seven assessed (OR 2.202 95% CI 1.915, 2.532; p = 0.044) and branded ASMs (OR 2.148; 95% CI 1.849, 2.494; p = 0.037). There was no significant difference for ≥50% responder rate between FDA-RDMD of cenobamate and FDA-RDMD of older ASMs (OR 2.617; 95% CI 1.767, 3.878; p = 0.202). No significant differences were identified for ≥50% responder rate when comparing all doses and maximum/minimum doses of cenobamate to all seven, branded, and older ASMs. Cenobamate demonstrated comparable TEAE withdrawal rates to all seven ASMs, branded ASMs, and older ASMs across each of the four dose ranges (all p > 0.05)., Significance: Patients receiving FDA-RDMD of cenobamate were more likely to have ≥50% seizure reduction compared with FDA-RDMD of the seven assessed ASMs and branded ASMs, without an increase in treatment discontinuation due to TEAEs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Different textile constituents may act as allergens and/or irritants and provoke textile contact dermatitis (TCD)., Objectives: To report a case of TCD caused by ethylene glycol monododecyl ether and 2,4-dichlorophenol, present in a bikini., Methods: A woman presented with an eczematous, pruritic rash in the area of the bikini straps and back. Patch testing was performed with the European baseline, textile, sunscreen, and photo-patch series, the bikini "as is", and ethanol and acetone extracts of the bikini. Thin-layer chromatography (TLC) of the extracts and gas chromatography-mass spectrometry (GC-MS) analysis were used to elucidate the culprit agents., Results: Positive reactions were found to the bikini "as is" and to the ethanol and acetone extracts. Patch testing with TLC strips showed a strong reaction to spots-fractions 3 and 4. GC-MS was performed to identify substances in each fraction and those suspected to be skin sensitisers were patch tested. On day (D) 4 positive reactions to ethylene glycol monododecyl ether (irritant reaction) and 2,4-dichlorophenol (++) were observed., Conclusion: A myriad of chemical compounds can be found in clothing. Ethylene glycol monododecyl ether and 2,4-dichlorophenol were identified as the potential culprits of this bikini TCD., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the efficacy and safety of adjunctive cenobamate for treatment of uncontrolled focal seizures., Methods: We performed a systematic search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE and Google Scholar to identify eligible studies. We included randomized placebo-controlled trials (RCTs) for uncontrolled focal seizures. We calculated the risk ratio (RR) of ≥50%, ≥75% and 100% reduction in seizure frequency from baseline, as well as dropout and serious adverse events related to treatment. Quality of included trials was assessed using the Cochrane Collaboration's tool., Results: Two RCTs with a total of 658 patients were included. A significantly larger proportion of patients allocated to cenobamate achieved 50% seizure reduction (RR 2.06, 95% CI 1.70-2.51, p < 0.001) as compared to placebo, subgroup analysis demonstrated that the most effective dose was at 400 mg (RR 2.28, 95% CI 1.57-3.32, p < 0.001). Patients achieving seizure-freedom during the treatment period were 14.9% with cenobamate and 4.5% with placebo (RR 5.32, 95% CI 2.94-9.62, p < 0.001). Dropouts (RR 1.40, 95% CI 1.01-1.94, p = 0.05) and incidence of serious adverse events (RR 1.48, 95% CI 0.93-2.33, p = 0.1) were not significantly higher in patients receiving cenobamate. However, subgroup analyses based on doses suggested that patients exposed to 400 mg cenobamate were more likely to dropout than placebo (RR 2.09, 95% CI 1.17- 3.71, p = 0.012)., Conclusion: Cenobamate demonstrated favourable efficacy for treatment of uncontrolled focal seizures and showed a dose-related fashion. Cenobamate could be well tolerated, the most common adverse events associated with cenobamate were dizziness, somnolence, fatigue, headache and nausea. Nevertheless, majority of them were mild to moderate in severity., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. The recommended starting dose is 12.5 mg/day, titrated gradually to the target daily dose of 200 mg, which may be increased to a maximum of 400 mg/day based on clinical response. Although the high rate of seizure freedom observed in randomized, placebo-controlled clinical trials has resulted in exciting expectations, further clinical studies are needed to better define its clinical profile. Cenobamate is characterized by a peculiar pharmacology regarding both pharmacodynamics and pharmacokinetics. The mechanism of action has only partly been described, with the drug acting on voltage-gated sodium channels through a pronounced action on persistent rather than transient currents. Cenobamate also acts as a positive allosteric modulator of GABA A receptors independently from the benzodiazepine binding site. The bioavailability of cenobamate is not influenced by other drugs, except phenytoin; it can inhibit cytochrome P450 (CYP) 2C19 and induce CYP3A4 and 2B6, and hence can potentially interact with many drugs (e.g. dose adjustments may be required for lamotrigine, carbamazepine and clobazam). The pharmacokinetics of cenobamate are not linear and dosage increases imply a disproportional increase in plasma levels, particularly at doses higher than 300 mg. The most common and dose-related adverse effects associated with cenobamate include central nervous system-related symptoms, mainly somnolence, dizziness, diplopia, and disturbances in gait and coordination. A somewhat higher incidence of adverse events has been observed in patients concomitantly treated with sodium channel blockers. The most relevant safety issues are currently represented by the risk of severe skin reactions (apparently avoidable by a slow titration) and QT shortening (the drug is contraindicated in patients with familial short QT syndrome or taking QT-shortening drugs). Overall, cenobamate is a promising ASM with an intriguing and not fully understood mechanism of action; pharmacokinetic issues need to be considered in clinical practice.

Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life-threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ-aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl-carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABA A receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl-carbamates have been shown to interact with voltage-gated ion channels. Flupirtine and retigabine share an ability to activate K + currents mediated by KCNQ (Kv7) K + channels, and felbamate, carisbamate, and cenobamate have been shown to block Na + channels. In contrast to other alkyl-carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na + current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl-carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABA A receptor and on persistent Na + currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction : Despite the introduction of numerous new antiseizure medications (ASMs) still about one-third of epilepsies remain drug-resistant. Therefore, new compounds with advanced efficacy are urgently needed. Cenobamate (CNB) is a new ASM that has been recently introduced in the United States for the treatment of adults with focal-onset seizures. The approval in Europe is under way. Areas covered : This review covers the pharmacological profile of CNB, the proof-of-concept trial, the two double-blind, placebo-controlled phase 2 trials investigating adjunct CNB in adults with focal-onset seizures, one open-label safety trial, and a variety of published abstract material that provided additional post hoc data. Expert opinion : In two placebo-controlled randomized multicenter phase 2 trials adjunct CNB showed unusually high efficacy with rates of seizure-free people with epilepsy (PWE) partially beyond 20%. However, during the clinical program cases of drug-related reactions with eosinophilia and systemic symptoms (DRESS syndrome) occurred. Therefore, an open-label safety study was performed in more than 1300 PWE with particularly slower titration schedules which did not add more cases with similar reactions. Taking into consideration the promising efficacy and the safety experience from the open-label trial, CNB applied according to the meanwhile recommended titration strategy, might offer a new prospect.

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients because the majority require anticonvulsant treatment for an extended period of time. Due to the fact that 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Cenobamate is the latest approved antiepileptic drug in focal epilepsy, and its mode of action is thought to be mediated by blocking voltage-gated sodium channels and interaction with the GABAergic system., Areas Covered: This article reviews animal studies, pharmacokinetics, pharmacodynamics, and the phase 1 to 3 trials and open-label extension data on cenobamate., Expert Opinion: Cenobamate has the potential to perform as an important ASD because trial data are indicative of remarkable responder and seizure freedom rates so far not seen with other ASDs. Cenobamate demonstrated significant efficacy at a dosage between 100 and 400 mg per day. The side-effect profile of this drug is comparable to other ASDs and is mainly CNS related; in particular, somnolence, dizziness, headache, diplopia, and nystagmus. However, slow titration is mandatory to decrease the risk of drug rash with eosinophilia and systemic symptoms (DRESS) that was observed in several patients with fast uptitration schemes.

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA A receptors, binding at a non-benzodiazepine site., Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques., Methods: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome., Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia., Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Introduction: Uncontrolled epilepsy has persisted despite development of numerous antiseizure medications (ASMs) over the past 25 years, and more effective treatments are needed. Cenobamate is a new ASM approved in the US for treatment of adults with focal onset seizures., Areas Covered: This review outlines cenobamate study results from preclinical animal models through phase 2 and 3 clinical studies. Topics include mechanisms of action, pharmacokinetics, efficacy, and safety of cenobamate. Information on dosing, tolerability, and special populations are included to help healthcare providers understand this new ASM., Expert Opinion: Adjunctive cenobamate shows a high level of efficacy in patients with refractory focal epilepsy compared to that reported for other ASMs. Most notable are reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%) with cenobamate in patients with refractory epilepsy despite the concomitant use of 1-3 ASMs. Cenobamate was generally safe and well-tolerated, with a safety profile similar to other ASMs. Due to 3 early cases of DRESS, however, the cenobamate starting dose was lowered and titration rate slowed; no additional cases occurred. If efficacy responses in real-world use reflect what have been observed in clinical studies, cenobamate would be a welcome new treatment option.

Cenobamate (YKP3089) is an antiepileptic drug recently approved by the Food and Drug Administration for the treatment of focal (partial-onset) seizures in adults. The objectives of a first-in-human single-ascending-dose study and 3 multiple-ascending-dose studies were to characterize the pharmacokinetics, safety, and tolerability of cenobamate after single-dose and multiple-dose administration in healthy subjects. The 4 randomized, placebo-controlled, double-blind studies were conducted in 210 healthy subjects receiving single (5 to 750 mg) or multiple (50 to 600 mg/day) oral doses of cenobamate or placebo using capsule formulation. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory evaluations. Maximum plasma concentrations of cenobamate were observed between 0.8 and 4.0 hours after oral administration. C max increased in a dose-proportional manner for single- and multiple-dose administration across all tested doses. Although the AUC of cenobamate increased in a more than dose-proportional manner after single-dose administration, a dose-proportional increase in cenobamate AUC τ was observed after multiple dosing from 50 to 500 mg/day. Cenobamate exhibited low oral clearance (decreasing from approximately 1.4 to 0.50 L/h with dose increase) and long terminal half-life (range, approximately 30 to 76 hours with increasing dose). Steady-state was attained after approximately 2 weeks, and the accumulation ratio was approximately 5 over the 50 to 300 mg/day range. The pharmacokinetic characteristics of cenobamate are consistent with once-daily dosing. Most TEAEs were mild in severity, 2 serious TEAEs were reported, and no deaths occurred across all studies. Except for multiple daily doses of 600 mg, all doses were generally well tolerated., (© 2020, The American College of Clinical Pharmacology.)

Focal-onset or partial seizures are localized to a specific brain area or areas of the cerebral hemisphere. Cenobamate (CNB, Xcopri, YKP-3089; SK Life Science) is a recent U.S. Food and Drug Administration (FDA)-approved drug for the treatment of focal-onset seizures in the adult population. CNB has demonstrated broad-spectrum efficacy in alternative preclinical models of epilepsy. The molecule exerts an antiseizure effect due to its dual mechanism of action: besides inhibiting the voltage-gated persistent component of the sodium currents, CNB is additionally an allosteric GABA(A) channel modulator in a non-benzodiazepine fashion. The superior clinical effect of this molecule over placebo in reducing seizure frequency may be observed after 2 weeks following a starting oral dose of 50 mg/day. The drug can be titrated up to a maximum daily maintenance dose of 400 mg/day. CNB has mild to moderate side effects. During initial development, a critical drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome was noticed in 3 patients. However, the DRESS effect was not observed in the large C021 safety study involving 1,347 patients, suggesting a maximum potential risk of no more than 0.3%. The present monograph describes the background, preclinical and clinical pharmacology, indication and safety of CNB for the treatment of partial/focal seizures., (Copyright 2020 Clarivate Analytics.)

Objective: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy., Methods: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed., Results: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 μg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence., Conclusions: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy., Clinicaltrialsgov Identifier: NCT00616148., Classification of Evidence: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Chlorophenols (CPs), suspected as endocrine disrupting chemicals, exposure during early life may contribute to body size. However, limited human data with inconsistent findings have examined the developmental effects of CPs exposure., Objective: To explore associations between prenatal and postnatal CPs exposure and anthropometric parameters in children aged 3 years., Methods: A subset of 377 mother-child pairs with urinary five CP concentrations were enrolled from a prospective birth cohort. Generalized linear models were conducted to evaluate associations of CPs exposure with children's anthropometric measures., Results: Maternal urinary 2,4,6-trichlorophenol (2,4,6-TCP) concentrations were significantly negatively associated with weight z scores [regression coefficient (β) = -0.51, 95% confidence interval (CI): -0.96, -0.05; p = 0.01], weight for height z scores (β = -0.54, 95% CI: -1.02, -0.06; p = 0.01) and body mass index (BMI) z scores (β = -0.53, 95% CI: -1.03, -0.03; p = 0.01) of children aged 3 years, after adjustment for potential confounders and postnatal CPs exposure. In the sex-stratified analyses, these inverse associations remained among boys, while in girls, positive associations of prenatal 2,4,6-TCP exposure with weight for height z scores and BMI z scores were observed. Postnatal exposure to 2,5-diclorophenol (2,5-DCP) was positively associated with weight z scores (β = 0.26, 95% CI: 0.02, 0.50; p = 0.04), after controlling for possible confounders and maternal CPs exposure during pregnancy. Considering potential sex-specific effects, these associations were only observed in girls., Conclusions: Our findings indicate that prenatal 2,4,6-TCP exposure and postnatal 2,5-DCP exposure may have adverse and sex-specific effects on children's physical development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To test cross-sectional associations between urinary concentrations of 2,5-dichlorophenol (2,5-DCP) and 2,4-dichlorophenol (2,4-DCP) with the prevalence of cardiovascular disease (CVD), cancer, lung disease, thyroid problems and liver conditions., Methods: Logistic regression was used to evaluate associations of urinary concentrations of 2,5-DCP and 2,4-DCP with prevalence of various medical conditions among 3617 National Health and Nutrition Examination Survey participants from 2007-2008 and 2009-2010. ORs and 95% CIs for each disease were estimated. All regression models were adjusted for urinary creatinine., Results: We observed a monotonically increasing association between quartiles of 2,5-DCP and prevalence of CVD. After adjustment for sociodemographic and lifestyle characteristics, participants with the highest versus lowest quartile of urinary 2,5-DCP had an OR=1.84 (95% CI 1.26 to 2.70) (p linear trend=0.006). The association was similar with further adjustment for established clinical CVD risk factors. Higher 2,5-DCP was also associated with prevalence of all cancers combined (OR Q4 vs Q1 =1.50 (95% CI 1.00 to 2.26); p trend=0.05) and, in exploratory analyses, with gynaecological cancers (OR Q4 vs Q1 =4.15 (95% CI 1.51 to 11.40; p trend=0.01)). No associations were detected between 2,5-DCP and lung diseases, thyroid problems or liver conditions, nor between 2,4-DCP and prevalent disease., Conclusion: In this nationally representative study, higher urinary 2,5-DCP concentrations were associated with greater prevalence of CVD and all cancers combined. Further examination may be warranted to assess whether chronic exposure to 2,5-DCP is associated with incidence of adverse health outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Evidence of bisphenols' obesogenic effects on humans is mixed and inconsistent. We aimed to explore the presence of bisphenol A (BPA), bisphenol F (BPF) and chlorinated BPA (ClBPA), collectively called the bisphenols, in different brain regions and their association with obesity using post-mortem hypothalamic and white matter brain material from twelve pairs of obese (body mass index (BMI) >30 kg/m 2 ) and normal-weight individuals (BMI <25 kg/m 2 ). Mean ratios of hypothalamus:white matter for BPA, BPF and ClBPA were 1.5, 0.92, 0.95, respectively, suggesting no preferential accumulation of the bisphenols in the grey matter (hypothalamic) or white matter-enriched brain areas. We observed differences in hypothalamic concentrations among the bisphenols, with highest median level detected for ClBPA (median: 2.4 ng/g), followed by BPF (2.2 ng/g) and BPA (1.2 ng/g); similar ranking was observed for the white matter samples (median for: ClBPA-2.5 ng/g, BPF-2.3 ng/g, and BPA-1.0 ng/g). Furthermore, all bisphenol concentrations, except for white-matter BPF were associated with obesity (p < 0.05). This is the first study reporting the presence of bisphenols in two distinct regions of the human brain. Bisphenols accumulation in the white matter-enriched brain tissue could signify that they are able to cross the blood-brain barrier.

We investigated in this study the relationship between exposure to para-dichlorobenzene (p-DCB), measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), and metabolic syndrome in non-diabetic adult participants. A nationally representative subsample of 1706 non-diabetic adult participants aged 20-79 years randomly selected for measurement of urinary concentrations of 2,5-DCP in the 2007-2010 US National Health and Nutrition Examination Survey was analyzed. A dose-dependent increase in the prevalence of metabolic syndrome was observed in the study participants across quartiles of urinary 2,5-DCP (p-trend = 0.0025). After adjusting for potential confounders, individuals in the third and fourth quartile of urinary 2,5-DCP had 1.47 (95% CI 1.02, 2.14) and 1.56 (95% CI 1.10, 2.23) increased odds of metabolic syndrome, respectively, compared with individuals with the lowest quartile. Of the five components of metabolic syndrome, waist circumference and HDL-cholesterol showed a significant and monotonic association with urinary 2,5-DCP. Participants with the highest quartile of 2,5-DCP had 3.18 cm (95% CI 1.34, 5.02) higher mean waist circumference and 2.83 mg/dL (95% CI -4.68, -0.98) lower mean HDL-cholesterol than the participants in the lowest quartile. This study suggests a potential relationship between p-DCB exposure and metabolic syndrome in non-diabetic adults. Prospective epidemiological and mechanistic studies are needed to further explore these interactions.

Accumulating evidence from recent studies has suggested a possible link between exposure to environmental pesticides and obesity. In this study, we assessed the potential associations between exposure to dichlorophenol pesticides and obesity in adults. Study participants aged 20-85 years were selected from the 2005 to 2006 and 2007 to 2008 U.S. National Health and Nutrition Examination Survey, and were categorized as obese and non-obese based on body mass index. Creatinine-corrected urinary concentrations of dichlorophenols were determined to assess level of exposure to environmental pesticides. Multivariate logistic regression was performed using SAS 9.3 to assess the association between 2,4-dichlorophenol (2,4-DCP) and 2,5-dichlorophenol (2,5-DCP) levels in urine and obesity with adjustment for potential confounders. Significantly higher geometric means of urinary concentrations of both 2,5-DCP (p<0.0001) and 2,4-DCP (p=0.0170) were seen in obese adults, compared to that in non-obese adults. A dose-dependent increase in the prevalence of obesity was observed in the study participants across increasing levels of urinary 2,5-DCP (p-trend<0.0001). Urinary concentrations of 2,5-DCP were significantly associated with obesity among the second (AOR: 1.47, 95% CI: 1.12, 1.93), third (AOR: 1.41, 95% CI: 1.07, 1.87), and fourth (AOR: 1.62, 95% CI: 1.21, 2.17) inter-quartiles after adjustment for age, gender, race, education, total fat intake, and physical activity. A statistically significant association was not seen between urinary 2,4-DCP and obesity. Our findings suggest a potential relationship between exposure to the fumigant insecticide paradichlorobenzene, measured as urinary concentrations of 2,5-DCP, and obesity in adults. Because we cannot rule out the possibility of reverse causality in our study, prospective studies measuring exposure during etiologically relevant periods are warranted., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Chlorophenols (CPs) and related phenoxyacetic acids (PAs) are pesticide groups contaminated with highly toxic 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) during production. PAs and CPs exposure is associated with risk of cancer, but the situation regarding lung cancer has not been clearly defined. We proposed a meta-analysis of published researches to evaluate relationship between chronic exposure to PAs and CPs in pesticide production workplaces and the risk of lung cancer., Materials and Methods: After searching PubMed, Scopus, Scholar Google, Web of Sciences until August 2013, the association between chronic PAs and CPs exposure in production workplace and lung cancer was studied in 15 cohort studies. The standardized mortality rate (SMR) and 95% confidence intervals (CI) were collected from the papers. We used random or fixed-effects models, Egger test, funnel plot and meta regression in our analysis., Results: Five papers with six reports were included in the final analysis. The standardized mortality rate for lung cancer from the random model was 1.18 (95% CI: 1.03-1.35, p=0.014) with moderate heterogeneity. Publication bias was not found for included studies in meta-analysis (p=0.9)., Conclusions: Our findings has strengthen the evidence of lung cancer from chronic exposure to chlorophenol related compounds (PAs, CPs).

Background: Fentichlor elicits high rates of positive photopatch test reactions despite its currently unknown clinical relevance., Objectives: The aims of this study were to provide a comprehensive review of fentichlor, to investigate the characteristics of patients with photosensitivity to fentichlor, and to explore the current uses of fentichlor., Methods: A review of photopatch test studies involving fentichlor was performed. A retrospective chart review was conducted in patients with positive photopatch test reactions to fentichlor at our institution. Product inquiries were placed to manufacturers of fentichlor to elicit the current uses of fentichlor., Results: In selected photopatch test studies, positive reactions to fentichlor occurred in 0.0% to 11.8% of subjects. We found that 25 companies distribute or manufacture fentichlor worldwide, which includes 2 companies that sell 25-kg drums of fentichlor. The most common current uses of fentichlor are in research, in high throughput screening, and in antibacterial and antifungal creams., Conclusions: Our review of selected photopatch test studies demonstrates that fentichlor remains a potent photosensitizing allergen worldwide. The bulk quantities of fentichlor available for sale and the current uses of fentichlor suggest that fentichlor may be currently incorporated into consumer products. We recommend that fentichlor remain in the standard series of photopatch test allergens.

Background: We recently reported increased risks for all cancers and urinary cancers in workers exposed to chlorophenoxy herbicides using data from the Dutch herbicide cohort study. These risks could not be linked to the qualitative exposure proxies available. Here, we re-investigate exposure-response relationships using a (semi)quantitative measure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure., Methods: Plasma TCDD levels of 187 workers were used to develop a predictive model for TCDD exposure. Cox proportional hazards model was used to investigate associations between time-varying TCDD exposure and cause-specific mortality. Sensitivity analyses were performed to assess the impact of key assumptions in exposure assessment., Results: Predicted TCDD levels were associated with mortality from all causes (HR 1.08; 95% CI 1.03 to 1.13), ischaemic heart disease (IHD; HR 1.19; 95% CI 1.08 to 1.32) and non-Hodgkin's lymphoma (NHL; HR 1.36; 95% CI 1.06 to 1.74). No relationships were found between TCDD exposure and mortality from all cancers, respiratory or urinary cancers, which were previously linked to qualitative proxies of TCDD exposure in this cohort. Sensitivity analyses showed that results were relatively robust to slight changes in exposure estimation., Conclusions: Modelled TCDD exposure does not explain the previously reported increased risks for cancer mortality in this cohort except for a possible association with NHL. A small increase in ischaemic heart disease was observed, however we cannot exclude that this finding was due to residual confounding. Although risk estimates for some of the rarer outcomes were still rather imprecise, we do not expect more precise estimates from longer follow-up of this cohort due to the long time-span since last exposure to TCDD.

Objective: We examined the overall mortality rates of 1599 workers employed between 1969 and 1988 at a New Zealand site, which manufactured trichlorophenol., Methods: We developed exposure estimates for 2,3,7,8-tetrachlorodibenzo-p-dioxin from a serum dioxin evaluation and used standardized mortality ratios (SMR) and proportional hazards models to evaluate risk from exposure., Results: Among exposed workers, deaths from total cancers (SMR = 1.1, 95% confidence intervals [CI]: 0.9-1.4), non-Hodgkin lymphoma (SMR = 1.6, 95% CI: 03-4.7), and ischemic heart disease (SMR = 1.1, 95% CI: 0.9-1.5) were slightly greater than expected, whereas deaths from lung cancer (SMR = 0.8, 95% CI: 0.4-1.5) were less than expected. We observed no significant trends with exposure levels., Conclusions: Although this study is small, we found no increasing trend of cancer or disease risk with increasing 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure with the possible exception of all cancers combined.

The authors examined 1,615 workers exposed to dioxins in trichlorophenol production in Midland, Michigan, to determine if there were increased mortality rates from exposure. Historical dioxin levels were estimated by a serum survey of workers. Vital status was followed from 1942 to 2003, and cause-specific death rates and trends with exposure were evaluated. All cancers combined (standardized mortality ratio (SMR) = 1.0, 95% confidence interval (CI): 0.8, 1.1), lung cancers (SMR = 0.7, 95% CI: 0.5, 0.9), and nonmalignant respiratory disease (SMR = 0.8, 95% CI: 0.6, 1.0) were at or below expected levels. Observed deaths for leukemia (SMR = 1.9, 95% CI: 1.0, 3.2), non-Hodgkin lymphoma (SMR = 1.3, 95% CI: 0.6, 2.5), diabetes (SMR = 1.1, 95% CI: 0.6, 1.8), and ischemic heart disease (SMR = 1.1, 95% CI: 0.9, 1.2) were slightly greater than expected. No trend was observed with exposure for these causes of death. However, for 4 deaths of soft tissue sarcoma (SMR = 4.1, 95% CI: 1.1, 10.5), the mortality rates increased with exposure. The small number of deaths and the uncertainty in both diagnosis and nosology coding make interpretation of this finding tenuous. With the exception of soft tissue sarcoma, the authors found little evidence of increased disease risk from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Aim: The focus of this study was to examine the staining potential of calcium hydroxide (Ca(OH)2) on tooth structure following the removal of AH26 root canal sealer., Methods and Materials: Fifty maxillary anterior teeth were prepared and obturated with AH26 and gutta percha. The sealers were then removed 24 hours later and the teeth were randomly divided into two groups. Ca(OH)2 was then placed in the root canals of the first group of teeth as a medicament and camphorated monochlorophenol (CMCP) was placed in the second group of teeth after the filling material was removed. The color of the external tooth surfaces was determined before tooth preparation and two weeks after the placement of the medicaments. The Z test was used for statistical analysis., Results: All experimental teeth showed varying degrees of coronal discoloration with the Ca(OH)2 group showing more discoloration than the CMCP group (p<0.05)., Conclusion: Using Ca(OH)2 as a medicament after removing AH26 caused progressive discoloration of the teeth, whereas using CMCP caused only slight discoloration., Clinical Significance: To avoid staining of the treated tooth, AH26 root canal sealer must be completely removed from the dentin walls before using a medicament.

Objective: To determine if surface disinfectants cause a change in the shade perception of a standard Classic Vitapan shade guide., Method and Materials: Consistency in shade selection for dental restorations involves many factors, and one of the most important is the shade tabs used in the selection process. Ten shade tabs each of shades B2, D2, C1, and A3.5 were selected from the Classic Vitapan shade guide (Vident). All tabs were measured with the EasyShade shade device (Vident) at baseline. Three tabs of each shade were set aside as controls. The other 7 tabs of each shade were treated with the surface disinfectant Cavicide (Metrex Research) for 480 cycles to simulate a year's usage. After each 480 cycles, all the tabs were again measured with the EasyShade. This process was repeated to simulate 2 and 3 years of use., Results: The data were analyzed to calculate the delta E 2000 for any change. A statistically significant increase was observed in the value (L*) and chroma (C*) after 2 and 3 years of simulated treatments. These changes were not perceptible to the clinician., Conclusions: The authors suggest that 1 standard shade guide be set aside to compare against those in clinical use to determine when they should be replaced.

A new reactor system was designed for an integrated process involving photoelectrocatalytic oxidation (PECO) and electro-Fenton (E-Fenton) oxidation. Its efficiency was evaluated in terms of 2,4-dichlorophenol (2,4-DCP) degradation in aqueous solution. In this process, a TiO2 electrode and an iron (Fe) electrode were used as anodes in parallel, while graphite felt (GF) was used as a cathode. When an electrical current is applied between the anodes and the cathode, the iron anode can release Fe2+ and the GF cathode can generate H2O2 continuously in the reaction solution. Under UV-A illumination, while a H2O2-assisted PECO reaction occurs on the surface of the TiO2 photo anode, an E-Fenton reaction takes place in the solution. The experimental results demonstrated that 2,4-DCP degradation in aqueous solution was greatly enhanced because of the interaction between the two types of reactions. Moreover, the effect of pH as an important factor was investigated. It was found that the combined reaction becomes less pH sensitive than the typical E-Fenton reaction and may be suitable for application in a wide pH range.

Background: Exposure misclassification may occur when nonspecific exposure indicators are used. Developing estimates of more specific measures may be difficult due to sampling limitations or a paucity of historical measurements and, thus, often requires substantial effort. We examine the impact on exposure-response relationships of moving from 2 measures of exposure mixtures (dust, chlorophenols) to more specific exposure indicators (wood dust, pentachlorophenol, tetrachlorophenol) in a retrospective cohort., Methods: The study population consisted of 26,847 male sawmill workers (> or =1 year employment between 1950 and 1995) with linkage to national cancer registries. A subcohort (n = 11,273 employed more than 1 day between 1985 and 1995) was linked to hospital discharge records. We evaluated the shape (log-linear vs log-log models), goodness of fit, precision, and expected versus observed attenuation of the exposure-response relationships., Results: The correlation between the cumulative exposure indices was moderately high (dust/wood dust, r = 0.68; total chlorophenol/pentachlorophenol, r = 0.88; total chlorophenol/tetrachlorophenol, r = 0.78). An increase in chronic obstructive pulmonary disease hospitalizations was found with wood dust but not with total dust. Stronger associations for non-Hodgkin lymphoma and kidney cancer incidence were observed with pentachlorophenol than with total chlorophenol; no association was observed with tetrachlorophenol. We observed greater attenuation than expected using total dust, but less than expected using total chlorophenol., Conclusions: The relationships between health outcomes were substantially attenuated when nonspecific exposure indicators were used. This study demonstrates the importance of developing exposure metrics as specific to the disease-causing agent as possible, particularly when the composition of mixed exposures varies by work areas.

Over the past 40 years, a substantial rise in the incidence of non-Hodgkin lymphoma (NHL) has been observed. Epidemiologic studies aimed at understanding this rise have revealed some association with occupational exposure. NHL is common among farmers, where pesticides have been described as the culprit. The association between pesticides and NHL has been demonstrated mainly in case-control studies, while retrospective cohorts have been less convincing. Pesticides including chlorphenol and phenoxyacetic acid herbicides, organochlorines, and organophosphate insecticides, carbamates, and fungicides have been associated with NHL. Although the causality has not been clearly proven, both genotoxic and nongenotoxic mechanisms for lymphomagenesis have been proposed. The leveling-off of NHL incidence in certain countries may be the result of a favorable change in pesticide usage patterns. Future studies, such as the Agricultural Health Study, may clarify the uncertainties regarding this issue., (Copyright 2006 S. Karger AG, Basel.)

Freshwater quality criteria of 2,4,6-trichlorophenol (2,4,6-TCP) were developed with particular reference to the aquatic biota in China, and based on USEPA's guidelines. Acute toxicity tests were performed on nine different domestic species indigenous to China to determine 48 h LC(50) and 96 h LC(50) values for 2,4,6-TCP. In addition, 21 d survival-reproduction test with Daphnia magna, 30 d embryo-larval test with Carassius auratus, 60 d fry-juvenile test with Ctenopharyngodon idellus, 30 d early life stage test with Bufo bufo gargarizans and 96 h growth inhibition test with Scenedesmus obliqaus were also conducted to estimate lower chronic limit and upper chronic limit values. The final acute value (FAV) was 2.01 mg/l 2,4,6-TCP. Acute-to-chronic ratios ranged from 5.01 to 12.2. The final chronic value (FCV) and the final plant value (FPV) of 2,4,6-TCP were 0.226 and 2.24 mg/l respectively. Based on FAV, FCV and FPV for 2,4,6-TCP, a criteria maximum concentration of 1.01 mg/l and a criterion continuous concentration of 0.226 mg/l were derived. The results of this study provide useful data for deriving national or local water quality criteria for 2,4,6-TCP based on aquatic biota in China.

Contact photoallergy to ketoprofen gels has been widely reported, and cross-sensitivity reactions with other compounds, such as tiaprofenic acid, fenofibrate and benzophenones, are well known. However, positive photopatch tests to other different non-benzophenone-related compounds have recently been observed. We report the results of photopatch testing in patients with contact photoallergy to ketoprofen and discuss the spectrum of cross-sensitization to ketoprofen. 18 consecutive patients with a history of photocontact dermatitis from ketoprofen were investigated. Patch and photopatch tests were performed. As expected, we observed positive photopatch tests to Ketum* gel and ketoprofen 2.5% in petrolatum in all patients (100%). However, it was remarkable to note positive photopatch tests to other unexpected and non-relevant allergens, including fentichlor (67%), tetrachlorosalicylanilide (28%), triclosan (17%), tribromsalan (11%) and bithionol (11%), with no clinical relevance. Interestingly, these agents belong to the family of halogenated salicylanilides and related compounds, which have been forbidden in Europe since the 1970s. Our results raise the question of hyper-photosusceptibility to non-relevant allergens induced by photosensitivity to ketoprofen. The mechanism may involve the high photoreactivity induced by the association of a benzene ring with an oxygen group.

Physiological and cytological responses of the marine diatom, Skeletonema costatum, to 2,4-dichlorophenol (2,4-DCP) were investigated after exposing algal cultures to 1-6 mg x l(-1) of 2,4-DCP for 96 h. Growth rate of the diatom was significantly reduced by 2,4-DCP at and above 3.0 mg x l(-1) while other biological parameters such as photosynthetic and respiration rates, carotenoid and protein content, ATP level and adenylate energy charge were unaffected. Exposure to 6.0 mg x l(-1) 2,4-DCP for 96 h resulted in the total lipid content being increased to 304%, while the RNA/DNA ratio was reduced to 31% of the control values. A parallel study by transmission electron microscopy further confirmed the increase in cellular lipid content, as evidenced by the accumulation of lipid droplets within diatom cells. A slight increase in carbohydrate (+37.8%) and decrease in chlorophyll a (-20.4%) and total chlorophyll c (-14.4%) were also found at 6.0 mg x l(-1) 2,4-DCP. Although 2,4-DCP is known to uncouple oxidative phosphorylation, our results show that energy production was not significantly inhibited at sublethal concentrations of 2,4-DCP. The observed growth inhibition in S. costatum caused by 2,4-DCP was associated with an increase in energy storage and inhibition of protein synthesis, as indicated by a reduction in RNA/DNA ratio.

Background: Photoallergy to ketoprofen and cross reactivity of ketoprofen with diphenylketones are well known; here are some cases of photoreaction to ketoprofen and unusual substances., Patients and Methods: Eleven photoallergic to ketoprofen patients were photo patch tested with Ketum(R), ketoprofen, oxybenzone, tiaprofenic acid, fenofibrate, and also chlorphenesin, sunscreen series, and photobiologists series (without lichen mix and benzocaine). We performed tests at day 0, we irradiated them with UVA at day 2, and control series remained closed. We performed readings at day 3 and 4 according to ICDRG's recommendations., Results: Nine tested patients had positive reactions to the irradiated tests with no expected allergens: fenticlor (9 cases), halogenated salicylanilides (4 cases), dibenzoylmethane (3 cases) and cinnamate (1 case)., Discussion: The mechanism of these unusual photosensitizations is discussed. These cases show that it is important to test sunscreen series and photobiologists series in patients photoallergic to ketoprofen.

Effects of 2,4,5-trichlorophenol (TCP) on life-cycle traits of the midge Chironomus riparius and the ability of the midge to evolve tolerance to TCP were assessed using a reference group and a group preexposed to TCP during three generations, both originating from the same laboratory culture. F1 larvae of these groups were then exposed to nominal TCP concentrations of 51, 177, 355, and 532 micromol TCP/kg dry sediment and a control sediment in a life-cycle experiment. Most studied life-cycle traits (mortality, egg production, life span, male dry wt) were fairly insensitive to TCP, and significant effects were observed only at high (> or = 355 micromol/kg) concentrations. Larval development rate was variable, and in some cases it responded more readily to low TCP concentrations than other life-cycle parameters. Some of the observed responses were attributed to changes in food availability. No clear evidence of tolerance to 2,4,5-trichlorophenol was found, but the preexposed midges produced more eggs than the reference group. They also emerged earlier and at a smaller size than the reference midges. These differences between the midge groups suggest that some changes toward tolerance induction had occurred during the preexposure.

The paper deals with the clinical trials of the anthelmintic trichlorofen. The clinical and parasitological efficacy and tolerance of the agent for hymenolepiasis and taeniarinchiasis were studied. Twelve patients with hymenolepiasis and 5 with taeniarinchiasis were examined. Trichlorofen was shown to be effective in treating these infections, fairly tolerated and convenient for outpatient treatment. Eleven of the 12 with hymenolepiasis and 5 with taeniarinchiasis were cured.

Chlorophenoxy herbicides are used both in cereal grain agriculture and in nonagricultural settings such as right-of-ways, lawns, and parks. Minnesota, North Dakota, South Dakota, and Montana grow most of the spring and durum wheat produced in the United States. More than 90% of spring and durum wheat is treated with chlorophenoxy herbicides, in contrast to treatment of approximately 30% of winter wheat. In this ecologic study I used wheat acreage as a surrogate for exposure to chlorophenoxy herbicides. I investigated the association of chlorophenoxy herbicides with cancer mortality during 1980-1989 for selected counties based on level of agriculture ([greater and equal to] 20%) and rural population ([greater and equal to] 50%). Age-standardized cancer mortality rates were determined for grouped counties based on tertiles of wheat acreage per county or for individual counties for frequently occurring cancers. The cancer sites that showed positive trends of increasing cancer mortality with increasing wheat acreage were esophagus, stomach, rectum, pancreas, larynx, prostate, kidney and ureter, brain, thyroid, bone, and all cancers (men) and oral cavity and tongue, esophagus, stomach, liver and gall bladder and bile ducts, pancreas, cervix, ovary, bladder, and other urinary organs, and all cancers (women). Rare cancers in men and women and cancers in boys and girls were studied by comparing counties above and below the median of wheat acreage per county. There was increased mortality for cancer of the nose and eye in both men and women, brain and leukemia in both boys and girls, and all cancers in boys. These results suggest an association between cancer mortality and wheat acreage in counties of these four states.

The objective of this study was to determine whether paternal occupational exposure to chlorophenol fungicides and their dioxin contaminants is associated with childhood cancer in the offspring of sawmill workers. We used data from 23,829 British Columbian sawmill workers employed for at least 1 continuous year between 1950 and 1985 in 11 sawmills that used chlorophenates. Probabilistic linkage of the sawmill worker cohort to the provincial marriage and birth files produced an offspring cohort of 19,674 children born at least 1 year after the initiation of employment in the period 1952-1988. We then linked the offspring cohort to the British Columbia Cancer Registry. We included all malignancies in cases younger than 20 years of age that appeared on the cancer registry between 1969 and 1993. We calculated standardized incidence ratios (SIRs) using the British Columbia population as a reference. A nested case-control analysis assessed the effects of paternal cumulative exposure and windows of exposure on the risk of developing cancer in the offspring. We identified 40 cases of cancer during 259,919 person-years of follow-up. The all-cancer SIR was 1.0 [95% confidence interval (CI), 0.7-1.4]; the SIR for leukemia was 1.0 (CI, 0.5-1.8); and the SIR for brain cancer was 1.3 (CI, 0.6-2.5). The nested case-control analysis showed slightly increased risks in the highest categories of chlorophenol exposure, although none was statistically significant. Our analyses provide little evidence to support a relationship between the risk of childhood cancer and paternal occupational exposure to chlorophenate fungicides in British Columbian sawmills.

Background: Elevated rates of nasal and nasopharyngeal cancers have been associated with wood-related occupational exposures, including chlorophenols, formaldehyde, and wood dust., Methods: Occupational information was obtained from 43 nasal carcinoma cases, 92 nasopharyngeal carcinoma cases, and 1909 controls, by interview. Exact conditional logistic regression was used to evaluate the association of these cancers with chlorophenol exposure, estimated from a review of verbatim responses., Results: Both nasal and nasopharyngeal cancers were significantly associated with estimated duration of chlorophenol exposure. For nasopharyngeal cancer, elevated risk was observed among those who held jobs assigned medium or high intensity chlorophenol exposure (n(exposed)=18, OR=1.94, 95% CI=1.03-3.50) and among those with 10+ years in jobs assigned high intensity with high certainty (n(exposed)=3, OR=9.07, 95% CI=1.41-42. 9). Controlling for estimated formaldehyde and wood dust exposure did not alter these findings, as much of the estimated chlorophenol exposure was among machinists., Conclusions: These findings support the hypothesis that occupational exposure to chlorophenol is a risk factor for nasal and nasopharyngeal cancer, although the role of machining-related exposures warrants further assessment., (Copyright 2000 Wiley-Liss, Inc.)

Background: The association between maternal occupational exposure to specific chemical substances (organic solvents, carbon tetrachloride, herbicides, chlorophenols, polychlorinated biphenyls, aromatic amines, lead and lead compounds, mercury and mercury compounds) and birth of small-for-gestational-age (SGA) infants was evaluated using data from a prospective cohort study of 3,946 pregnant women in West Germany from 1987 to 1988., Methods: Occupational, medical, and psychosocial information was gathered through a questionnaire from pregnant women who were recruited between 15 and 28 gestational weeks. Exposure to chemical substances at the current workplace was assessed by a job-exposure matrix constructed by Pannett in 1985 and weighted for the number of working hours per week. Women not working at the time of the interview, women with multiple births, and women with stillbirths were excluded from analysis. Data were analyzed using dichotomous and polytomous logistic regression to control for age, smoking status, alcohol consumption, body mass index, and number of former births., Results: The results of the dichotomous logistic regression analysis suggest that leather work might be associated with the birth of infants small-for-gestational-age through exposure to chlorophenols (P = 0.02) and aromatic amines (P = 0.05). In the polytomous logistic regression analysis, only the association between exposure to mercury and growth retardation reached statistical significance (P = 0.02); however, the power of the study is limited. Further adjustment for income, shift work, and heavy physical work had no substantial effect on the results., Conclusions: These findings suggest that maternal exposure to specific chemicals at work may be a risk factor for the birth of SGA infants.