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Biomedical subjects

T A Glauser

Publications and source records attributed to T A Glauser.

At least 19 recordsLinked to original sources
PubMed2006

Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures. METHODS: This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day. RESULTS: One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event. CONCLUSION: Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures.

Anticonvulsants↗
PubMed2005

Randomized dose-controlled study of topiramate as first-line therapy in epilepsy.

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. MATERIALS AND METHODS: We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. RESULTS: Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. CONCLUSION: Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.

Adolescent↗
PubMed2004

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy [RETIRED]: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Acetates↗
PubMed2004

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy [RETIRED]: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Acetates↗
PubMed2004

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Adolescent↗
PubMed2001

Pharmacokinetic study of levetiracetam in children.

PURPOSE: The pharmacokinetics of the novel antiepileptic drug (AED) levetiracetam and its major metabolite, ucb L057, were studied in children with partial seizures in a multicenter, open-label, single-dose study. METHODS: Twenty-four children (15 boys, nine girls), 6 to 12 years old, received a single dose of levetiracetam (20 mg/kg) as an adjunct to their stable regimen of a single concomitant AED, followed by a 24-h pharmacokinetic evaluation. RESULTS: In children, the half-lives of levetiracetam and its metabolite ucb L057 were 6.0 +/- 1.1 and 8.1 +/-2.7 hours, respectively. The Cmax and area under the curve (AUC) of levetiracetam equated for a 1-mg/kg dose were lower in children (Cmax, norm=1.33 plus minus 0.35 microg/ml; AUCnorm=12.4 +/- 3.5 microg/h/ml) than in adults (Cmax, norm=1.38 +/- 0.05 microg/ml; AUCnorm=11.48 +/- 0.63 microg/h/ml), whereas the renal clearance was higher. The apparent body clearance (1.43 +/- 0.36 ml/min/kg) was approximately 30-40% higher in children than in adults. Levetiracetam was generally well tolerated. CONCLUSIONS: On the basis of these data, a daily maintenance dose equivalent to 130-140% of the usual daily adult maintenance dosage (1,000-3,000 mg/day) in two divided doses, on a weight-normalized level (mg/kg/day) is initially recommended. Clinical efficacy trials in children are ongoing with dosages of 20 to 60 mg/kg/day.

Adult↗
PubMed2001

Oxcarbazepine in the treatment of epilepsy.

Oxcarbazepine is a new antiepileptic drug (AED) that has been registered in more than 50 countries worldwide since 1990 and recently received approval in the United States and the European Union. Oxcarbazepine is a keto analog of carbamazepine and has a more favorable pharmacokinetic profile. It is rapidly absorbed after oral administration and undergoes rapid and almost complete reductive metabolism to form the pharmacologically active 10-monohydroxy derivative. Oxcarbazepine exhibits linear pharmacokinetics, no autoinduction, and minimal interaction with other AEDs. Ten controlled trials demonstrated that oxcarbazepine is safe and efficacious in the treatment of partial seizures across a wide range of ages (children to adults), situations (recent onset to treatment-resistant epilepsy), and uses (monotherapy and adjunctive therapy). The most common treatment-emergent adverse events are related to the central nervous system. Treatment-emergent hyponatremia (defined as serum sodium level < 125 mEq/L) occurred in 3% of patients treated with oxcarbazepine in clinical trials. According to the efficacy and safety profile established in the controlled trials, oxcarbazepine represents an important new treatment option indicated for monotherapy and adjunctive therapy in adults with partial seizures and as adjunctive therapy in children aged 4 years or older with partial seizures. Although structurally similar to carbamazepine, significant differences exist in the pharmacokinetics, drug interaction potential, adverse-effect profile, and dosage and titration between these two agents, and they should be considered distinct therapeutic agents.

Anticonvulsants↗
PubMed2000

Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group.

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). BACKGROUND: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. DESIGN: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30-46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. METHODS: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. RESULTS: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. CONCLUSION: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Adolescent↗
PubMed2000

Topiramate therapy of epilepsy associated with Angelman's syndrome.

Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.

Angelman Syndrome↗
PubMed2000

An improved gas chromatography assay for topiramate monitoring in pediatric patients.

An improved micromethod involving capillary gas chromatographic assay with liquid-liquid extraction and nitrogen phosphorus detection (GC/NPD) was developed and validated for the determination of topiramate (TPM) in human body fluids. The galactopyranose analog of TPM was used as the internal standard. Capillary gas chromatographic conditions yielded typical retention times of 6.8 min for TPM and 7.2 min for the internal standard. Calibrations were linear between 1.0 and 32 microg/mL. Between-day precision (n = 17) for three serum controls (3.0, 10, and 24.5 microg/mL) resulted in coefficients of variation of 6.9%, 7.3%, and 4.9%, respectively. The limit of detection was 0.42 microg/mL. There was an excellent linear correlation between the fluorescence-polarization immunoassay (FPIA) and GC/NPD determinations of 56 patient specimens (r2 = 0.981). Chromatograms showed no interfering peaks with the respective blank human samples or from many commonly prescribed drugs. Because of improved specificity and decreased sample volume requirements, this micromethod should be particularly useful for monitoring TPM therapy in pediatric patients, for patients with impaired renal function, and for research studies.

Anticonvulsants↗
PubMed2000

Effectiveness, tolerability, and safety of topiramate in children with partial-onset seizures. Topiramate YP Study Group.

PURPOSE: Children with partial-onset seizures, with or without secondary generalization, participating in a double-blind, placebo-controlled trial of topiramate (TPM) as adjunctive therapy were eligible to participate in an open-label, long-term extension study. METHODS: A total of 83 children (mean age, 9 years) continued long-term open-label TPM therapy in which the dosages of TPM and concomitant antiepileptic drugs (AEDs) were adjusted according to clinical response (mean TPM dosage, 9 mg/kg/day). RESULTS: Seizure frequency over the last 3 months of therapy was reduced > or =50% in 57% of children; 14% of children were seizure-free > or =6 months at the last visit. During treatment periods up to 2 1/2 years (mean, 15 months), 6% of children discontinued because of treatment-emergent adverse events; 13% discontinued because of inadequate seizure control. CONCLUSIONS: From these findings, TPM is well tolerated and provides long-term seizure control in children with partial-onset seizures.

Adolescent↗
PubMed2000

Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients completing a randomized controlled trial. Topiramate YL Study Group.

PURPOSE: The response to topiramate (TPM) as long-term adjunctive therapy was evaluated in patients with Lennox-Gastaut syndrome (LGS) in a long-term, open-label extension to a double-blind, placebo-controlled trial. METHODS: In 97 patients with LGS (mean age, 11 years), dosages of TPM and concomitant antiepileptic drugs (AEDs) were adjusted to optimal clinical response (mean TPM dosage, 10 mg/kg/day). RESULTS: For those patients who had completed 6 months of TPM therapy, drop attacks were reduced > or =50% in 55% of patients; 15% of patients had no drop attacks for > or =6 months at the last visit. After treatment up to 3+ years, 71% of patients who started open-label TPM were continuing therapy at the last visit. CONCLUSIONS: During long-term therapy, TPM is effective and well tolerated in controlling the treatment-resistant drop attacks and seizures associated with LGS.

Adolescent↗
PubMed2000

Long-term response to topiramate in patients with West syndrome.

PURPOSE: The long-term effectiveness of topiramate (TPM) was evaluated in children with West syndrome previously refractory to antiepileptic drug (AED) therapy. METHODS: Children with infantile spasms who completed a pilot study were eligible to enter a long-term extension phase in which the dosages of TPM and other AEDs could be adjusted to optimal response (maximum, 50 mg/kg/day TPM). The mean duration of long-term therapy was 18 months in the 11 children who were followed; the mean TPM dosage was 29 mg/kg/day. RESULTS: Eight (73%) children were continuing TPM therapy at the time data were analyzed; four (50%) children were spasm free, seven (88%) had experienced a > or =50% reduction in spasms, and three (38%) were able to achieve TPM monotherapy. CONCLUSIONS: TPM was well tolerated in that no patients discontinued because of adverse events. The response achieved with TPM during the pilot study was maintained in most children.

Age of Onset↗
PubMed2000

Idiosyncratic reactions: new methods of identifying high-risk patients.

This article describes the mechanisms of idiosyncratic drug reactions (IDRs) and provides an analysis of potential methods for identifying patients at high risk for antiepileptic idiosyncratic drug reactions. IDRs may be caused by toxic metabolites, either directly or indirectly (by way of an immunologic response or a free radical-mediated process). Four methods to potentially identify patients at high risk for AED IDRs are discussed: development of an "at-risk" clinical profile for a particular AED: identification of biomarkers that measure the formation of a toxic metabolite by a previously unrecognized bioactivation pathway for a particular AED; identification of biomarkers indicating deficient detoxification abilities [e.g., deficient free radical scavenging enzyme activities or low calculated oxidative protection (COP) ratios 1 and 2]; and identification of at-risk genetic markers. Clinical profiles for patients receiving valproic acid (VPA), felbamate (FBM), and lamotrigine (LTG) and who are at risk for development of AED IDRs are presented. Patients with VPA IDRs have deficient erythrocyte glutathione peroxidase activity, low plasma selenium concentrations, low COP1 ratios, and low COP2 ratios compared with age-matched controls. Patients with FBM-associated aplastic anemia have deficient erythrocyte glutathione peroxidase, superoxide dismutase (SOD), and glutathione reductase activities compared with age-matched controls. Use of at-risk clinical profiles (for VPA, FBM, and LTG) and measurement of erythrocyte glutathione peroxidase activity, erythrocyte SOD activity, and calculation of COP1 and COP2 ratios (for VPA and FBM) are inexpensive, simple methods of identifying high-risk patients for IDRs. Research is needed to further characterize the mechanism of IDRs, to investigate the clinical utility of free radical-scavenging enzyme activity measurement and calculation of COP ratios for other AED IDRs, and to develop additional methods of identifying patients at high risk for AED IDRs.

Anticonvulsants↗
PubMed2000

Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy.

This article reexamines the role of blood-level monitoring (therapeutic drug monitoring, TDM) of antiepileptic drugs (AEDs) in the current treatment of epilepsy and identifies situations in which TDM can be useful. Basic pharmacokinetic and pharmacodynamic principles are reviewed, with specific emphasis on kinetics of absorption/distribution/metabolism, elimination half-life, time to steady state, and plasma drug concentrations. The relationship between AED intensity of effect (pharmacodynamics) and plasma concentration (pharmacokinetics) is expressed mathematically, examined in the context of the major old and new AEDs, and integrated with a historical look at the role of TDM. Situations in which TDM can be useful in the modern treatment of epilepsy are presented and discussed. For both older and newer AEDs, TDM is useful in six clinical situations: establishing "baseline" effective concentrations, evaluating potential causes for lack of efficacy, evaluating potential causes for toxicity, evaluating potential causes for loss of efficacy, judging "room to move" or when to change AEDs, and minimizing predictable problems. TDM remains a valuable tool in the modern treatment of epilepsy. It can be selectively and appropriately utilized to help maximize seizure control and minimize side effects if levels are obtained in response to a patient-specific pharmacokinetic or pharmacodynamic issue or problem.

Anticonvulsants↗
PubMed2000

Topiramate in the catastrophic epilepsies of childhood.

Several epileptic syndromes that occur during childhood are characterized by severe treatment-resistant seizures, progressive loss of higher intellectual functions, and characteristic electroencephalographic abnormalities. These catastrophic epileptic syndromes include epileptic encephalopathy with diffuse slow spike waves (Lennox-Gastaut syndrome), West syndrome, progressive myoclonic epilepsies, and electrical status epilepticus during sleep. This article summarizes each syndrome and reviews the most recent information concerning the effectiveness of topiramate with respect to each condition. Suggestions are offered to help clinicians maximize topiramate's efficacy and tolerability in patients suffering with these syndromes. Overall, topiramate is a valuable antiepileptic medication in the treatment of catastrophic pediatric epileptic syndromes.

Anticonvulsants↗
PubMed2000

Expanding first-line therapy options for children with partial seizures.

Carbamazepine and phenytoin are considered first-line therapies for children with partial seizures on the basis of the adult Veterans Administration studies, open-label controlled and uncontrolled pediatric studies, and clinical experience. Although many new antiepileptic drugs (AEDs) have demonstrated efficacy in controlled trials in adults with partial seizures, additional issues must be examined before these new AEDs are considered as first-line therapy for children with partial seizures. This article proposes three criteria for assessing the suitability of a new AED as first-line therapy for pediatric partial seizures: (a) demonstrated efficacy against pediatric partial seizures in two or more randomized, double-blind controlled trials involving patients less than 12 years old (with at least one of the trials utilizing a monotherapy design); (b) a favorable safety profile in monotherapy trials and no severe idiosyncratic reactions; and (c) ease of use in children across a wide range of ages. On the basis of these criteria, two new AEDs, oxcarbazepine (OXC) and topiramate (TPM), are suitable for consideration. OXC has demonstrated efficacy in monotherapy and adjunctive therapy in pediatric partial seizures, along with good tolerability and the ability to be titrated rapidly. TPM has also demonstrated efficacy and tolerability in pediatric partial seizures but should be titrated slowly. In addition, gabapentin (GBP) can be considered as first-line therapy for pediatric partial seizures if the preliminary analysis of a monotherapy trial is confirmed. There are not yet enough data on efficacy to support consideration of lamotrigine, tiagabine, felbamate, levetiracetam, or zonisamide as first-line therapy for pediatric partial seizures.

Anticonvulsants↗