Food web transfer of plastics to an apex riverine predator.

As a rapidly accelerating expression of global change, plastics now occur extensively in freshwater ecosystems, yet there is barely any evidence of their transfer through food webs. Following previous observations that plastics occur widely in their prey, we used a field study of free-living Eurasian dippers (Cinclus cinclus), to test the hypotheses that (1) plastics are transferred from prey to predators in rivers, (2) plastics contained in prey are transferred by adults to altricial offspring during provisioning and (3) plastic concentrations in faecal and regurgitated pellets from dippers increase with urbanization. Plastic occurred in 50% of regurgitates (n = 74) and 45% of faecal samples (n = 92) collected non-invasively from adult and nestling dippers at 15 sites across South Wales (UK). Over 95% of particles were fibres, and concentrations in samples increased with urban land cover. Fourier transform infrared spectroscopy identified multiple polymers, including polyester, polypropylene, polyvinyl chloride and vinyl chloride copolymers. Although characterized by uncertainty, steady-state models using energetic data along with plastic concentration in prey and excreta suggest that around 200 plastic particles are ingested daily by dippers, but also excreted at rates that suggest transitory throughput. As some of the first evidence revealing that plastic is now being transferred through freshwater food webs, and between adult passerines and their offspring, these data emphasize the need to appraise the potential ecotoxicological consequences of increasing plastic pollution.

Patient and physician perceptions of disease management in Parkinson's disease: results from a US-based multicenter survey.

Background: Clinical care for patients with Parkinson's disease (PD) is complex, and disconnect may exist between patient and physician perceptions of treatment, disease awareness, and impact on quality of life (QoL). Relatively few studies have analyzed patient and physician perspectives of disease management concurrently, and even fewer have compared responses between corresponding patients and their physicians. This study aimed to characterize these aspects and identify opportunities to improve alignment. Methods: This cross-sectional study used an online survey and chart review. Participating physicians completed a profiling survey, followed by patient record forms (PRFs) for their next five patients with PD. Patients completed paper questionnaires. PRFs were matched with patient questionnaires, and patient and physician responses compared. Results: Of 107 participating physicians, 70 completed 350 PRFs. Patients completed 71 questionnaires; 66 were matched to PRFs. From a physician perspective, there was alignment between the motor symptoms that were most bothersome for patients and those that were most discussed (physicians felt tremor was most bothersome for most patients [71%]; 77% of physicians included tremor among top three most discussed), but disconnect between the most bothersome and most discussed nonmotor symptoms (physicians felt fatigue was most bothersome for most patients [35%]; cognitive impairment was the most discussed nonmotor symptom, with 52% of physicians including it in top three most discussed). Patients and physicians reported moderate satisfaction with current PD medication. Patients considered form of delivery more important than did physicians. Physicians showed a strong level of awareness of PD's impact on patient QoL, although validated QoL instruments were not widely used. Physicians were more confident than patients about patients' awareness of support resources for patients with PD. Conclusion: Nonmotor symptoms, form of medication delivery, and awareness of support services are areas where PD physician and patient alignment could be increased to improve outcomes.

Evaluation of brivaracetam efficacy as monotherapy in adult patients with focal seizures.

Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. The goal of the present analysis was to determine if the dose-response of brivaracetam as monotherapy would fall within the range associated with brivaracetam efficacy as adjunctive therapy. An existing brivaracetam population pharmacokinetic model consisting of first-order absorption, single compartment distribution, and first-order elimination components was extended by estimating the clearance changes due to co-administration of 12 widely prescribed AEDs. Data for the population pharmacokinetic analysis originated from three Phase III add-on trials and two terminated Phase III monotherapy trials. An existing population model of daily seizure rate versus brivaracetam daily average concentration was applied to the data from the three add-on trials. Simulations allowed the assessment of the combined impact of covariate effects on both the pharmacokinetics and the pharmacodynamics of brivaracetam, and indicated that in the absence of other AEDs, only marginal changes in the overall dose-response relationship would be expected. This suggests that brivaracetam can be used as monotherapy without dose modifications.

Tolerability, safety, and efficacy of adjunctive brivaracetam for focal seizures in older patients: A pooled analysis from three phase III studies.

INTRODUCTION: This analysis was conducted to assess the tolerability, safety, and efficacy of brivaracetam (BRV) for adjunctive treatment of focal (partial-onset) seizures in patients aged ≥65 years. METHODS: Safety/tolerability and efficacy data for patients aged ≥65 years were pooled from three randomized, double-blind, placebo-controlled, fixed-dose Phase III studies (NCT00490035, NCT00464269, and NCT01261325). Data were pooled by treatment group: placebo or the proposed therapeutic dose range of 50-200 mg/day: BRV 50, 100, 200mg/day. RESULTS: Thirty-two patients aged ≥65 years were randomized to placebo or BRV 50-200 mg/day. Of these, 30 patients (93.8%) completed their respective study. In the safety population (n=32), 87.5% placebo- vs 73.3% BRV-treated patients reported treatment-emergent adverse events (TEAEs) during the treatment period; most commonly, headache (25.0% vs 12.5%), paresthesia (0% vs 12.5%), and somnolence (50.0% vs 12.5%) for placebo- vs BRV-treated patients, respectively. During the treatment period, drug-related TEAEs were reported by 62.5% of placebo- vs 53.3% of BRV-treated patients, and serious TEAEs (SAEs) were reported by 0% of placebo- and 4.2% of BRV-treated patients; there were no drug-related SAEs and no deaths. Three SAEs (placebo 1/8; BRV 2/24) and two deaths (placebo 1/8; BRV 1/24) occurred in the post-treatment period. In the efficacy population (n=31), median percent reduction from baseline in focal seizure frequency/28days was 14.0% for placebo vs 25.5%, 49.6%, and 74.9% for BRV 50, 100, and 200 mg/day, respectively. The ≥50% responder rate was 14.3% for placebo vs 25.0%, 50.0%, and 66.7% for BRV 50, 100, and 200 mg/day, respectively. CONCLUSIONS: Safety/tolerability and efficacy findings in this small subgroup of older patients treated with adjunctive BRV are consistent with those observed in the much larger overall pooled population. BRV may be a suitable adjunctive treatment for older patients with uncontrolled focal seizures. Further larger studies in this population are warranted.

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam.

We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients ≥16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a ≤1-week screening period, an immediate switch from LEV to BRV 200mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV.

Why should I?--Acceptance of Health Information Technology Among health professionals.

Applying the Technology Acceptance Model, the end user intentions to use technology applications is studied. The study finds the end users negative perception of the usefulness of the application as a major factor in its suboptimal utilisation.

Clinical features associated with placebo response in refractory focal epilepsy.

For clinical trial design and for clinical practice, it is of importance to assess factors associated with placebo response in patients with refractory epilepsy. We determined factors associated with placebo response in 359 adult patients with refractory focal epilepsy participating in three randomized placebo-controlled trials of the new antiepileptic drug lacosamide. At the end of the randomized 12-week maintenance period, 81 (23%) of the 359 patients randomized to placebo achieved at least a 50% seizure reduction (responders) compared to baseline. In contrast, 278 (77%) patients did not achieve a 50% seizure reduction (non-responders) compared to baseline. In multivariate analysis, five factors, which were present prior to the exposure to placebo, were found to be associated with placebo response. Higher age at study entry improved the chances of placebo response for each year [p=0.023, odds ratio (OR) 1.034 (95% confidence interval (95% CI): 1.005-1.063)]. In contrast, a lower chance of placebo response was seen with age at diagnosis of epilepsy of 6-20 years compared to ≤5 years [p=0.041, OR 0.475 (95% CI: 0.232-0.971)]. A history of 7 or more prior lifetime AEDs lowered the chance of achieving placebo response compared to 1-3 prior lifetime AEDs [p<0.001, OR 0.224 (95% CI: 0.101-0.493)] as did a baseline seizure frequency >10 seizures per 28 days compared to ≤5 seizures per 28 days [p=0.026, OR 0.431 (95% CI: 0.205-0.904)]. Prior epilepsy surgery lowered the likelihood of placebo response [p=0.02, OR 0.22 (95% CI: 0.062-0.785)]. We suggest that age at exposure to placebo, age at diagnosis of epilepsy, the number of prior lifetime AEDs, baseline seizure frequency and a history of epilepsy surgery appear to be associated with placebo response in adults with refractory focal epilepsy.

Treatment of idiopathic generalized epilepsy - a review of the evidence.

INTRODUCTION: Epilepsy is stratified into idiopathic partial, symptomatic partial, idiopathic generalized (IGE) and symptomatic generalized epilepsies. AREAS COVERED: The epidemiology and clinical characteristics of IGE are reviewed in this paper. Clinically, IGE is characterized by the occurrence of any of the following three seizure types: absence seizures, myoclonic seizures and primarily generalized tonic-clonic seizures. To assess the presence of evidence-based data on the treatment of IGE, the literature was extensively reviewed for studies evaluating the treatment of IGE with various antiepileptic drugs. These studies were stratified into four classes based on recently described criteria. Class I studies were considered as providing evidence of the efficacy of the drug in patients with IGE. Finally, suggestions to evaluate the efficacy of a study drug in patients with IGE are presented. EXPERT OPINION: Based on the reviewed data, there is strong evidence-based data to support the use of valproate and ethosuximide for the treatment of childhood absence seizures; for the use of topiramate as monotherapy or adjunctive therapy for patients with primarily generalized tonic-clonic seizures; for the use of adjunctive therapy with lamotrigine for the treatment of primarily generalized tonic-clonic seizures; and for the use of levetiracetam as adjunctive therapy for the treatment of myoclonic or primarily generalized tonic-clonic seizures. To evaluate a new drug as a potential treatment for patients with IGE requires a rational methodology, discussed in this review.

Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures.

Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug-drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.

Efficacy, safety, and tolerability of oxcarbazepine monotherapy.

OBJECTIVE: This prospective, open-label, multicenter study evaluated the efficacy and tolerability of oxcarbazepine as monotherapy in patients with partial seizures who switched from their current antiepileptic drug (AED) monotherapy because of lack of efficacy or poor tolerability. METHOD: Patients (>or=12 years old) experiencing 2-40 seizures per month while receiving an AED were included. During a 16-week treatment phase, oxcarbazepine was initiated (8-10mg/kg for children; 600 mg/day for adults) and titrated up over 4 weeks while the existing AED was tapered off. Improvement in seizure frequency (defined as >or=50% reduction compared with baseline) was evaluated for all patients, as well as the subgroups of patients switched due to poor tolerability or lack of efficacy. RESULTS: Overall, 52% of patients experienced a 50% reduction in seizure frequency, 35% had a >or=75% reduction, and 18% were seizure-free. The most frequent (>10%) adverse events were dizziness, nausea, headache, somnolence, and fatigue. Overall, 17% of patients prematurely withdrew because of an adverse event; 62% of these withdrawals occurred during the conversion period. CONCLUSION: Oxcarbazepine as monotherapy may be a favorable treatment option for patients with partial seizures or poor tolerability of their existing monotherapy regimen.

Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy.

OBJECTIVE: Quality of life (QOL) was assessed in patients who switched to oxcarbazepine monotherapy because of the lack of efficacy or poor tolerability of their current antiepileptic drug (AED). METHOD: This open-label, single-arm study consisted of patients aged 12 >or= years with partial onset seizures. Oxcarbazepine (8-10mg/kg/day for children, 600 mg/day for adults) was titrated up over 4 weeks while the existing AED was tapered off. QOL was evaluated at baseline and end of study (Week 16) using the validated-in-epilepsy QOLIE-31 questionnaire. RESULTS: For all patients who completed the QOLIE-31 at baseline and completion, a statistically significant improvement was noted for both the composite and multi-item subscale QOL scores (P<0.05 vs baseline). Statistically significant mean percentage improvements of >or=10% from baseline (range=10.8-50.1%) were also noted. Significant improvements were seen in health-related QOL for patients who experienced seizure freedom or >or=50% reductions in seizure frequency with oxcarbazepine monotherapy. CONCLUSIONS: Patients with partial seizures who switched to oxcarbazepine monotherapy showed statistically significant, clinically relevant improvements in QOL.

A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents.

OBJECTIVE: This multicenter trial examined the efficacy and safety of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. METHOD: A total of 116 outpatients 7 to 18 years of age with bipolar I disorder, manic or mixed, were recruited at 20 centers in the United States and randomly assigned to receive 7 weeks of double-blinded, flexibly dosed treatment with oxcarbazepine (maximum dose 900-2400 mg/day) or placebo. The primary efficacy measure was the mean change from baseline to endpoint in the Young Mania Rating Scale (YMRS), using the last-observation-carried-forward method. RESULTS: Oxcarbazepine (mean dose=1515 mg/day) did not significantly improve YMRS scores at endpoint compared with placebo [adjusted mean change: oxcarbazepine, -10.90 (N=55); placebo, -9.79 (N=55)]. Dizziness, nausea, somnolence, diplopia, fatigue, and rash were each reported in at least 5% of the patients in the oxcarbazepine group with an incidence at least twice that of the placebo group. The majority of adverse events were mild to moderate and occurred during the titration period. Eleven patients (19%) in the oxcarbazepine group discontinued the study because of adverse events, compared with two (4%) in the placebo group. CONCLUSIONS: Oxcarbazepine is not significantly superior to placebo in the treatment of bipolar disorder in youths. While the overall adverse event profile was similar to that reported for patients with epilepsy, the incidence of psychiatric adverse events for both the oxcarbazepine and placebo groups was higher than that reported for the epilepsy population.

A cost comparison of alternative regimens for treatment-refractory partial seizure disorder: an econometric analysis.

BACKGROUND: Partial seizure disorder is typically treated by monotherapy with antiepileptic drugs (AEDs). However, when the condition is refractory to the initial treatment regimen, patients may be switched to monotherapy with another AED or to combination therapy with the initial AED plus a second AED. OBJECTIVES: The purpose of this study was to examine the economic costs associated with treatment-refractory partial seizure disorder and to compare the costs of 2 alternative approaches: a switch to oxcarbazepine (OXC) monotherapy or the addition to the regimen of another AED (AED add-on). METHODS: Adult patients with a diagnosis of partial seizure disorder who received initial AED monotherapy between January 1, 2000, and March 31, 2003, were identified from the PharMetrics Patient-Centric Database, a health plan administrative claims database. The medical and pharmacy history of these patients was analyzed from 6 months before a change to either OXC monotherapy or AED add-on therapy through 12 months after the change in treatment. Total health care resource utilization and the associated costs were compared within each cohort before and after the change, as well as between cohorts, with statistical differences tested using Wilcoxon rank sum tests. Multivariate econometric analyses were performed to examine the impact of age, sex, geographic location, Charlson Comorbidity Index, and the presence of specific comorbidities. RESULTS: Demographic and clinical characteristics 102 were similar between the OXC monotherapy cohort (n = 259) and the AED add-on cohort (n = 795). Annual direct treatment costs increased in both groups in the period after the failure of initial monotherapy, increasing from 10,462 US dollars to 11,360 US dollars in the OXC cohort and from 10,137 US dollars to 12,201 US dollars in the AED add on cohort (P < 0.01). Increased pharmacy costs were the primary driver behind cost increases in both cohorts. Patients in the AED add-on cohort were significantly more likely to have an emergency department visit during the period after the failure of initial monotherapy compared with the OXC monotherapy cohort (odds ratio = 1.52; P < 0.05). CONCLUSION: Despite limitations, the results of retrospective analysis of claims data suggest that the care of patients with treatment-refractory partial seizure disorder is costly and may vary significantly based on the pattern of care.

Long-term safety and tolerability of oxcarbazepine in children: a review of clinical experience.

Relatively few well-designed studies have demonstrated the long-term safety and tolerability of newer antiepileptic drugs (AEDs) in a large group of children. Extensive clinical data from the worldwide Clinical Development Program (CDP) and a compassionate use program on the safety and tolerability of oxcarbazepine in children are presented. Oxcarbazepine is a newer AED that is indicated for use as monotherapy and adjunctive therapy in children (United States 4 years of age, Europe 6 years of age) with partial epilepsy. The most common adverse events (10%) in the CDP were headache (32.5%), somnolence (31.5%), vomiting (27.6%), and dizziness (23.1%), whereas in the compassionate use program (clinical practice situation), the most common adverse events (1%) reported were rash (2.7%), fatigue (1.6%), nausea (1.2%), and somnolence (1.2%). These data indicate that oxcarbazepine has a good long-term safety and tolerability profile, whether given as monotherapy or adjunctive therapy, in children with partial seizures.

Oxcarbazepine pharmacokinetics and tolerability in children with inadequately controlled epilepsy.

This two-part, open-label study evaluated the pharmacokinetics, safety, and tolerability of oxcarbazepine as combination therapy in 112 children 2 to 12 years old with inadequately controlled epilepsy. Part I was a pharmacokinetic study in children stratified by age (2-5 years and 6-12 years) and randomized to receive a single oxcarbazepine dose of 5 mg/kg or 15 mg/kg. Mean specific AUC and t(1/2) values of the active metabolite (MHD) were approximately 30% lower in younger children compared with older children, regardless of dose. Part II was a 4-month safety, tolerability, and pharmacokinetic study in which children received oxcarbazepine doses of 11 to 68 mg/kg/day. The mean specific oxcarbazepine daily dose was 38% higher in younger children compared with older children. Similarly, mean trough plasma MHD concentrations were 34% lower in younger children. Six (5%) children discontinued due to adverse events. Oxcarbazepine was safe and well tolerated. Younger children require higher oxcarbazepine doses because of rapid clearance.

Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy.

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy. METHODS: This study is the open-label extension phase that followed a multicenter, randomized, double-blind, dose-response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open-label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double-blind phase of the core study by an intent-to-treat and completer analysis. Safety and tolerability were evaluated by using an intent-to-treat analysis. RESULTS: Of the 87 patients enrolled in the double-blind study, 76 patients participated in the open-label extension phase. Fifty-five (72%) patients completed 48 weeks of open-label treatment on a median OXC dose of 2,400 mg/day. Based on an intent-to-treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient. CONCLUSIONS: The efficacy of OXC is sustained with good safety and tolerability profiles during long-term treatment of patients with medically refractory partial epilepsy.

Pharmacokinetic drug interactions in children taking oxcarbazepine.

OBJECTIVE: Our objective was to evaluate the drug-drug interactions of oxcarbazepine with coadministered antiepileptic drugs in children. METHODS: In a clinical trial, pediatric patients receiving an oxcarbazepine dose titrated to 30 to 46 mg. kg(-1). d(-1) given twice daily had 1 to 4 blood samples collected per patient for population pharmacokinetic analysis of oxcarbazepine's major bioactive 10-monohydroxy metabolite. With the use of NONMEM, 7 concomitant antiepileptic drugs and 12 additional covariates were examined for their effects on the pharmacokinetics of 10-monohydroxy metabolite. In addition, for each concomitant antiepileptic drug, the ratio of its mean concentration with coadministration of oxcarbazepine to that without coadministration at baseline was calculated to evaluate the effect of oxcarbazepine on the coadministered antiepileptic drugs. RESULTS: The population pharmacokinetic data for 10-monohydroxy metabolite consisted of a total of 376 observations from 109 patients, aged 3 to 17 years. Body surface area and 3 antiepileptic drugs (carbamazepine, phenobarbital, and phenytoin) were significant predictors of the apparent clearance of 10-monohydroxy metabolite, whereas height was a significant predictor of apparent volume. Weight-normalized clearance of 10-monohydroxy metabolite was higher in young children than in older children and adults. Carbamazepine, phenobarbital, or phenytoin administered with oxcarbazepine increased the apparent clearance of 10-monohydroxy metabolite by 31% to 35%, whereas carbamazepine levels decreased by 15% and phenobarbital levels increased by 14%. CONCLUSIONS: Oxcarbazepine has a low propensity to inhibit or induce oxidative enzymes. Young children could be given higher milligrams-per-kilogram oxcarbazepine doses than older children and adults to achieve the same mean steady-state concentration of 10-monohydroxy metabolite. The adjustment is based simply on body size.

Safety and tolerability of oxcarbazepine in elderly patients with epilepsy.

Despite the high incidence of seizures and epilepsy in the elderly, the tolerability and safety of anticonvulsants are rarely evaluated in this patient population. We compared the safety and tolerability of oxcarbazepine in a cohort of 52 patients aged 65 years and older and a group of 1574 adult patients ranging in age between 18 and 64 years. There was no significant difference between the two groups with respect to premature discontinuation due to adverse events. The four most common adverse events experienced by patients in the elderly group, irrespective of their causal relationship to oxcarbazepine, were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Three patients developed an asymptomatic hyponatremia, with at least one serum sodium level below 125mEq/L. Elderly patients on concomitant natriuretic drugs were significantly more likely to develop serum sodium levels below 135mEq/L. The results indicate that oxcarbazepine is safe to use in elderly patients and that its tolerability in this age group is similar to that of younger adult patients.

Effects of oxcarbazepine on sodium concentration and water handling.

Oxcarbazepine, a keto-analogue of carbamazepine, was recently approved in the United States for the treatment of seizures of partial onset. Some patients treated with oxcarbazepine showed the development of hyponatremia, which in most instances was asymptomatic. Understanding the mechanisms by which oxcarbazepine can lead to a reduction of serum sodium levels could have therapeutic implications for the few patients in whom symptomatic hyponatremia develops. In this study, we evaluated sodium and water handling in patients with epilepsy and in healthy subjects titrated over 3 weeks to a maximum daily oxcarbazepine dose of 2,400mg. All subjects were evaluated in a hospital setting after an overnight fast and after an acute water-load test performed before oxcarbazepine exposure and after maintenance on the medication for 3 weeks. Before oxcarbazepine exposure, the percentage of water load excreted was normal as both groups excreted more than 80% of the administered water load. After the intake of oxcarbazepine, the water load resulted in a reduction of the serum sodium and free water clearance without a concomitant increase in the arginine vasopressin serum levels. Most subjects in both groups failed to excrete 80% or more of the water load, suggesting that the effect of oxcarbazepine is physiological. We found that, after the water load, serum sodium and free water clearance were diminished in both groups without a concomitant increase in the arginine vasopressin serum levels. These findings indicate that oxcarbazepine-induced hyponatremia is not attributable to the syndrome of inappropriate secretion of antidiuretic hormone. Possible mechanisms include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating antidiuretic hormone.