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Tracy A Glauser - One of the best experts on this subject based on the ideXlab platform.
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pretreatment behavior and subsequent medication effects in childhood absence epilepsy
Neurology, 2017Co-Authors: Ruth C Shinnar, Avital Cnaan, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Deborah G Hirtz, Chunyan Liu, Erica F Weiss, Tracy A GlauserAbstract:Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of Ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking Ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking Ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than Ethosuximide or lamotrigine, further reinforcing Ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than Ethosuximide or lamotrigine.
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pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy
Annals of Neurology, 2017Co-Authors: Tracy A Glauser, Katherine D Holland, Valerie P Obrien, Mehdi Keddache, Lisa J MartinAbstract:Objective To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE). Methods Four hundred forty-six CAE children in a randomized double-blind trial of Ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to Ethosuximide. Results Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In Ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not–seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25–5.56; p = 0.026, OR = 2.38, 95% CL = 1.11–5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16–4.17) was more common in not–seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28–0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of Ethosuximide. Ethosuximide's effect on rate of decay of CaV3.2 was significantly less for P640L channel compared to wild-type channel. Interpretation Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's Ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444–453
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second monotherapy in childhood absence epilepsy
Neurology, 2017Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C Adamson, Ravindra Arya, Tracy A GlauserAbstract:Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing Ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, Ethosuximide9s (63%, 57%) and valproic acid9s (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine9s (45%, 36%, p = 0.051 and p = 0.062). At both time points, Ethosuximide and valproic acid had superior seizure control compared to lamotrigine ( p Conclusions: As second monotherapy, Ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with Ethosuximide or valproic acid is superior to lamotrigine.
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pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy
Neurology, 2013Co-Authors: David Masur, Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Ruth C Shinnar, Erica F Weiss, Jichuan Wang, Tracy A GlauserAbstract:Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among Ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving Ethosuximide (32%) or lamotrigine (24%) ( p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment ( p Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with Ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than Ethosuximide or lamotrigine in children with newly diagnosed CAE.
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Ethosuximide valproic acid and lamotrigine in childhood absence epilepsy initial monotherapy outcomes at 12 months
Epilepsia, 2013Co-Authors: Tracy A Glauser, Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C AdamsonAbstract:SUMMARY Purpose: Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy. Methods: A double-blind, randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of Ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were Ethosuximide 60 mg/kg/day or 2,000 mg/day, valproic acid 60 mg/kg/day or 3,000 mg/day, and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16‐20 weeks and included a video‐electroencephalography (EEG) assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video-EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit. Key Findings: A total of 453 children were enrolled and randomized; 7 were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the month 12 visit, the freedom-from-failure rates for Ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio [OR]with valproic acid vs. Ethosuximide 0.94; 95% confidence interval [CI] 0.58‐1.52; p = 0.82) and were higher than the rate for lamotrigine (21%; OR with Ethosuximide vs. lamotrigine 3.08; 95% CI 1.81‐5.33; OR with valproic acid vs. lamotrigine 2.88; 95% CI 1.68‐5.02; p < 0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) was significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events was in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16‐ 20 weeks in the valproic acid group compared with the Ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
Stanislaw J Czuczwar - One of the best experts on this subject based on the ideXlab platform.
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Ethosuximide and valproate display high efficacy against lindane induced seizures in mice
Toxicology Letters, 2004Co-Authors: Rafal M Kaminski, Anna M Tochman, Andrzej Dekundy, Waldemar A Turski, Stanislaw J CzuczwarAbstract:Abstract Both lindane (γ-hexachlorocyclohexane), an organochlorine ectoparasiticide and pentylenetetrazol, used as a model of experimental epilepsy, produce convulsive seizures resulting from the blockade of the γ-aminobutyric acid (GABA A ) receptor. In the present study we established the protective effects of Ethosuximide and valproate against seizures induced by lindane and compared them with the well-known protective effects of these drugs against pentylenetetrazol-induced seizures in mice. Both Ethosuximide and valproate afforded complete and dose-dependent protection against seizures induced by lindane. However, the potencies of these drugs were lower than those obtained against pentylenetetrazol seizures. Nevertheless, the protective efficacy of Ethosuximide and valproate against experimentally induced lindane seizures may suggest possible efficacy of these drugs against seizures in lindane-poisoned patients.
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influence of vigabatrin a novel antiepileptic drug on the anticonvulsant activity of conventional antiepileptics in pentetrazole induced seizures in mice
Polish Journal of Pharmacology, 2003Co-Authors: Mariusz J Swiader, Jarogniew J łuszczki, Marian Wielosz, Stanislaw J CzuczwarAbstract:: Vigabatrin is a novel antiepileptic drug, which increases GABA levels by irreversible inhibition of GABA-aminotransferase. The aim of this study was to evaluate the effects of vigabatrin on the anticonvulsant activity of valproate, Ethosuximide and clonazepam against pentetrazole-induced seizures in mice. In addition, the effects of antiepileptic drugs alone or in combination with vigabatrin were studied on motor performance and long-term memory. Chemical seizures were induced by subcutaneous injection of pentetrazole at its CD(97) and defined as a clonus of the whole body with an accompanying loss of righting reflex, lasting for over 3 s. Vigabatrin inhibited the clonic pentetrazole-induced seizures and ED(30) of the drug was 879 mg/kg. Vigabatrin (at the subthreshold dose of 250 mg/kg) potentiated the protective activity of Ethosuximide, reducing its ED(30) from 142 to 95 mg/kg against clonic seizures induced by pentetrazole, but simultaneously elevated its plasma level. The protective activity of valproate and clonazepam remained almost unchanged. However, vigabatrin (250 mg/kg) decreased TD(30) (50% toxic dose - corresponding to the impairment of motor coordination in 50% of the animals) of Ethosuximide and clonazepam from 549 and 3.84 to 460 and 1.1 mg/kg, respectively, in the chimney test. Vigabatrin (250 mg/kg) did not influence TD(30) value of valproate in this test. Vigabatrin (at the dose of 250 mg/kg) did not impair long-term memory in combination with antiepileptics. Potentiation of the Ethosuximide's protective activity was apparently due to a pharmacokinetic interaction. Consequently, no pharmacodynamic interactions between vigabatrin and the studied conventional antiepileptic drugs were evident.
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7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of Ethosuximide and clonazepam against pentylenetetrazol induced convulsions
Journal of Neural Transmission, 2000Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J. Łuszczki, Stanislaw J CzuczwarAbstract:The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of Ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on Ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither Ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with Ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of Ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.
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7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of Ethosuximide and clonazepam against pentylenetetrazol induced convulsions
Journal of Neural Transmission, 2000Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J łuszczki, Stanislaw J CzuczwarAbstract:The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of Ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on Ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither Ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with Ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of Ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.
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ng nitro l arginine impairs the anticonvulsive action of Ethosuximide against pentylenetetrazol
European Journal of Pharmacology, 1999Co-Authors: Stanislaw J Czuczwar, Piotr Tutka, Pawel Klonowski, Zdzisław KleinrokAbstract:Abstract NG-nitro- l -arginine (NNA; an inhibitor of nitric oxide synthase) in a dose of 40 mg/kg impaired the protective activity of Ethosuximide against the clonic phase of pentylenetetrazol-induced seizures in mice. The ED50 value of Ethosuximide was significantly increased from 108 to 158 mg/kg. NNA (40 mg/kg) was ineffective against the protective effects of diazepam, phenobarbital and valproate against pentylenetetrazol-induced seizures. NNA (40 mg/kg) did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. l -Arginine (500 mg/kg) prevented the NNA-induced reduction of the anticonvulsive activity of Ethosuximide. It can be concluded that nitric oxide participates in the expression of the anticonvulsive action of Ethosuximide, but not that of diazepam, phenobarbital and valproate, against pentylenetetrazol-induced seizures.
Nicolas Kerckhove - One of the best experts on this subject based on the ideXlab platform.
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Ethosuximide improves chronic pain induced anxiety and depression like behaviors
European Neuropsychopharmacology, 2019Co-Authors: Nicolas Kerckhove, Alain Eschalier, Ludivine Boudieu, Guillaume Ourties, Justine Bourdier, Laurence Daulhac, Christophe MalletAbstract:Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of Ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of Ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of Ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make Ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.
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assessment of the effectiveness and safety of Ethosuximide in the treatment of abdominal pain related to irritable bowel syndrome ibset protocol of a randomised parallel controlled double blind and multicentre trial
BMJ Open, 2017Co-Authors: Nicolas Kerckhove, Bruno Pereira, Julien Scanzi, Denis Ardid, Michel DapoignyAbstract:Introduction Irritable bowel syndrome (IBS) is characterised by the association of abdominal chronic pain with bowel habit disorders in the absence of identifiable organic disease. This is the first reason for consultation in gastroenterology, with an estimated prevalence of 10%–15% in industrialised countries. Although this is a benign gastrointestinal disease, its chronicity profoundly impacts the patient’s quality of life and causes considerable health spending. Actual medical treatments are poorly efficient on IBS-related abdominal pain, making it a major public health concern. The mechanisms causing IBS symptoms are unknown. Recent studies have shown the involvement of T-type channel in abdominal pain. We aim to evaluate the therapeutic potential of Ethosuximide, a T-type channel blocker, on the abdominal pain of patients presenting an IBS. Methods and analysis The IBSET trial is a randomised, controlled, parallel, double-blind and multicentre study. It is the first clinical trial evaluating the efficacy and safety of Ethosuximide on abdominal pain related to IBS. Adults with IBS that report significant abdominal pain (≥4/10) at least for 3 months will be included. 290 patients will be randomly assigned to receive either Ethosuximide or placebo over 12 weeks after 1 week of run-in period. The primary endpoint is the rate of responders (pain reduction ≥30% and Subject Global Assessment of Relief score ≥4). The intensity of abdominal pain will be assessed by an 11-point Numerical Rating Scale before and after 12 weeks of treatment and the score of the Subject Global Assessment of Relief scale at the end of treatment. The secondary endpoints are the safety of Ethosuximide, the intensity and features of IBS and quality of life. Ethics and dissemination The study was approved by an independent medical ethics committee (CPP Sud-Est VI, Clermont-Ferrand, France). The results will be published in a peer-review journal and presented at international congresses. Trial registration number NCT02973542; Pre-results.
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assessment of the effectiveness and safety of Ethosuximide in the treatment of non diabetic peripheral neuropathic pain edonot protocol of a randomised parallel controlled double blinded and multicentre clinical trial
BMJ Open, 2016Co-Authors: Nicolas Kerckhove, Christophe Mallet, Bruno Pereira, Chouki Chenaf, Christian Duale, Claude Dubray, Alain EschalierAbstract:Introduction Currently available analgesics are ineffective in 30–50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, Ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, Ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use. Despite numerous preclinical data demonstrating an antinociceptive effect of Ethosuximide in various animal models of neuropathic pain, no clinical studies have been published to date on the analgesic efficacy of Ethosuximide in patients with neuropathic pain. Methods and analysis The Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain (EDONOT) trial is a randomised, parallel, controlled, double-blinded, multicentre clinical study. It is the first clinical trial to evaluate the efficacy and safety of Ethosuximide in the treatment of non-diabetic peripheral neuropathic pain. Adult patients exhibiting peripheral neuropathic pain (Numeric Rating Scale (NRS) ≥4 and Douleur Neuropathique 4 (DN4)≥4) for at least 3 months and under stable analgesic treatment for at least 1 month will be included. Patients (n=220) will be randomly assigned to receive either Ethosuximide or control treatment for 6 weeks following a 1 week run-in period. The primary end point is the intensity of neuropathic pain, assessed by NRS (0–10) before and after 6 weeks of treatment. The secondary end points are safety (adverse events are collected during the study: daily by the patient on the logbook and during planned phone calls by investigators), the intensity and features of neuropathic pain (assessed by Brief Pain Inventory (BPI) and Neuropathic Pain Symptom Inventory (NPSI) questionnaires) and health-related quality of life (assessed by Medical Outcome Study Short Form 12 (MOS SF-12) and Leeds questionnaires). Ethics and communication The study was approved by an independent ethics committee (CPP Sud-Est VI, France, IRB00008526) and registered by the French competent authority (Agence nationale de securite du medicament (ANSM)). Trial registration number NCT02100046, Recruiting.
Zdzisław Kleinrok - One of the best experts on this subject based on the ideXlab platform.
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7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of Ethosuximide and clonazepam against pentylenetetrazol induced convulsions
Journal of Neural Transmission, 2000Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J. Łuszczki, Stanislaw J CzuczwarAbstract:The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of Ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on Ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither Ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with Ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of Ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.
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7 nitroindazole a nitric oxide synthase inhibitor enhances the anticonvulsive action of Ethosuximide and clonazepam against pentylenetetrazol induced convulsions
Journal of Neural Transmission, 2000Co-Authors: Kinga K. Borowicz, Zdzisław Kleinrok, Jarogniew J łuszczki, Stanislaw J CzuczwarAbstract:The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50 mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of Ethosuximide and clonazepam, significantly reducing their ED50s against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on Ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither Ethosuximide nor clonazepam, administered at their ED50s (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with Ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of Ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.
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ng nitro l arginine impairs the anticonvulsive action of Ethosuximide against pentylenetetrazol
European Journal of Pharmacology, 1999Co-Authors: Stanislaw J Czuczwar, Piotr Tutka, Pawel Klonowski, Zdzisław KleinrokAbstract:Abstract NG-nitro- l -arginine (NNA; an inhibitor of nitric oxide synthase) in a dose of 40 mg/kg impaired the protective activity of Ethosuximide against the clonic phase of pentylenetetrazol-induced seizures in mice. The ED50 value of Ethosuximide was significantly increased from 108 to 158 mg/kg. NNA (40 mg/kg) was ineffective against the protective effects of diazepam, phenobarbital and valproate against pentylenetetrazol-induced seizures. NNA (40 mg/kg) did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. l -Arginine (500 mg/kg) prevented the NNA-induced reduction of the anticonvulsive activity of Ethosuximide. It can be concluded that nitric oxide participates in the expression of the anticonvulsive action of Ethosuximide, but not that of diazepam, phenobarbital and valproate, against pentylenetetrazol-induced seizures.
Peter C Adamson - One of the best experts on this subject based on the ideXlab platform.
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second monotherapy in childhood absence epilepsy
Neurology, 2017Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C Adamson, Ravindra Arya, Tracy A GlauserAbstract:Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure. Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing Ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits. Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, Ethosuximide9s (63%, 57%) and valproic acid9s (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine9s (45%, 36%, p = 0.051 and p = 0.062). At both time points, Ethosuximide and valproic acid had superior seizure control compared to lamotrigine ( p Conclusions: As second monotherapy, Ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with Ethosuximide or valproic acid is superior to lamotrigine.
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Ethosuximide valproic acid and lamotrigine in childhood absence epilepsy initial monotherapy outcomes at 12 months
Epilepsia, 2013Co-Authors: Tracy A Glauser, Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Peter C AdamsonAbstract:SUMMARY Purpose: Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy. Methods: A double-blind, randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of Ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were Ethosuximide 60 mg/kg/day or 2,000 mg/day, valproic acid 60 mg/kg/day or 3,000 mg/day, and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16‐20 weeks and included a video‐electroencephalography (EEG) assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video-EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit. Key Findings: A total of 453 children were enrolled and randomized; 7 were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the month 12 visit, the freedom-from-failure rates for Ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio [OR]with valproic acid vs. Ethosuximide 0.94; 95% confidence interval [CI] 0.58‐1.52; p = 0.82) and were higher than the rate for lamotrigine (21%; OR with Ethosuximide vs. lamotrigine 3.08; 95% CI 1.81‐5.33; OR with valproic acid vs. lamotrigine 2.88; 95% CI 1.68‐5.02; p < 0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) was significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events was in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16‐ 20 weeks in the valproic acid group compared with the Ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
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Ethosuximide valproic acid and lamotrigine in childhood absence epilepsy
The New England Journal of Medicine, 2010Co-Authors: Avital Cnaan, Deborah Hirtz, Peggy Clark, Shlomo Shinnar, Dennis J. Dlugos, David Masur, Tracy A Glauser, Edmund V Capparelli, Peter C AdamsonAbstract:Background Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with Ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. Methods In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of Ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. Results The 453 children who were randomly assigned to treatment with Ethosuximide (156), lamotrigine (149), or valproic acid (148) wer...