bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topiramate Modulates GABA‐Evoked Currents in Murine Cortical Neurons by a Nonbenzodiazepine Mechanism
Authors: White H. Steve , Brown S. Douglas , Woodhead J. H. , Skeen Gwendolyn A. , Wolf Harold H. 
Published: August 2005

Summary: Purpose: These studies further investigate the ability of topiramate (TPM) to enhance γ‐aminobutyric acid (GABA)‐mediated inhibition through a benzodiazepine‐insensitive pathway. Methods: Topiramate (30 and 100 μM) enhancement of GABA (1 μM)‐evoked currents in primary cultures of mouse cortical neurons was studied by using whole‐cell electrophysiologic techniques. Results obtained with TPM (30 μM) were compared with those obtained with clonazepam (CZP; 1 μM). Results: Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABA‐evoked currents in CZP‐insensitive neurons, and CZP was effective in a subset of TPM‐insensitive neurons. Related studies in vivo demonstrated that intraperitoneal (i.p.) administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases pentylenetetrazol (PTZ) seizure threshold. This effect of CZP, but not TPM, was reversed by the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.). Conclusions: These results indicate that GABAA‐receptor sensitivity to TPM is not dependent on the presence of BZD sensitivity. Enhancement of GABA‐mediated inhibition through a BZD‐insensitive pathway may represent one mechanism through which TPM exerts its anticonvulsant action.
Differential Sensitivity of Recombinant GABAA Receptors Expressed in Xenopus Oocytes to Modulation by Topiramate
Authors: Gordey Marina , DeLorey Timothy M. , Olsen Richard W. 
Published: August 2005

Summary: Purpose: This study evaluated the modulatory effects of topiramate (TPM) on various subtypes of recombinant rat γ‐aminobutyric acid A (GABAA) receptors expressed in Xenopus oocytes. Methods: Specific subunits of GABAA receptors were expressed in Xenopus oocytes. Voltage‐clamp recordings of currents were performed after application of TPM (1–100 μM) to these oocytes in the presence or absence of GABA. Results: In a concentration‐dependent fashion, TPM (1–100 μM) reversibly inhibited GABA‐evoked Cl− currents in oocytes expressing either α1β2γ2S and α2β2γ2S recombinant GABAA receptors and reduced the current‐fading rate in α1β2γ2S‐expressing oocytes. Topiramate was effective at GABA concentrations of 1–10 μM but not at 100 μM. Topiramate (1–100 μM) potentiated GABA‐evoked Cl− currents and increased the fading rate in oocytes expressing the α6β2γ2S GABAA receptor. It had no effect on Cl− currents mediated through the α4β2γ2S receptor or through the mixed population of GABAA receptors expressed from rat brain mRNA. In general, the observed effects of TPM were more pronounced on fading rates than on peak Cl− currents. Conclusions: These results indicate that TPM may affect desensitization of GABAA receptors as assessed by changes in the fading rates of GABA‐evoked Cl− currents, possibly by effects on second‐messenger systems.
Topiramate Blocks Kainate‐Evoked Cobalt Influx into Cultured Neurons
Authors: Skradski Shana , White H. Steve 
Published: August 2005

Summary: Purpose: This study evaluated topiramate (TPM) antagonism of glutamate receptors activated by kainate. Methods: The ability of TPM (3–30 μM) to attenuate kainate (300 μM)‐activated cobalt (Co2+) flux through nonselective cation channels permeable to Co2+, Mn2+, and Ca2+ into cultured cerebellar granule neurons [9–14 days in vitro (div)] was investigated. Results were compared with those obtained with the non‐N‐methyl‐d‐aspartate (non‐NMDA) antagonist 6,7‐dinitroquinoxalone‐2,3‐dione (DNQX) (10 μM). Results: Topiramate produced a concentration‐ and time‐dependent inhibition of Co2+ uptake into cerebellar granule cells cultured 9–11 div. Inhibition was evident at 10 μM, and complete inhibition was observed at 30 μM. Maximal inhibition of Co2+ uptake required pretreatment with TPM for ges;30 minutes before stimulation by kainate. The effect of 30 μM TPM on Co2+ uptake was similar to that of 10 μM DNQX. However, TPM, unlike DNQX, did not affect kainate‐evoked Co2+ uptake into older neurons (i.e., 13–14 div). Conclusions: These results provide additional support for an antagonistic effect of TPM on some types of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionic acid (AMPA) and/or kainate receptors, and specifically suggest that TPM interacts with a Ca2+‐permeable non‐NMDA receptor that is develop‐mentally regulated. This observation may provide insight into the molecular biology underlying the pathophysiology of seizure disorders and antiepileptic drug resistance.
Modulation of High‐Voltage–Activated Calcium Channels in Dentate Granule Cells by Topiramate
Authors: Zhang Xiao‐lei , Velumian Alexander A. , Jones Owen T. , Carlen Peter L. 
Published: August 2005

Summary: Purpose: In this study, we assessed the effects of topiramate (TPM) on high‐voltage‐activated calcium channel (HVACC) currents in vitro. Methods: HVACC currents were recorded from rat dentate gyrus granule cells by using whole‐cell patch‐clamp techniques. The biophysical properties of HVACCs were used to separate voltage‐activated Ca2+ currents into different subtypes. Three concentrations of TPM were tested: 1, 10, and 50 μM. Results: TPM inhibited L‐type currents and was more effective at 10 μM than at 50 μM, suggesting that there may be an optimal concentration at which TPM decreases L‐type currents. Non‐L‐type currents were transiently increased by TPM at a high concentration (50 μM). Conclusions: Because the location of L‐type calcium channels on soma and proximal dendrites gives these channels a crucial role in controlling dendritic excitability and in providing calcium for intracellular effectors, the decrease in the L‐type HVA Ca2+ currents may be an important anticonvulsant mechanism of TPM.
Topiramate as Add‐On Therapy: Pooled Analysis of Randomized Controlled Trials in Adults
Authors: Reife Ross , Pledger Gordon , Wu Shu‐Chen 
Published: August 2005

Summary: Purpose: Six double‐blind, placebo‐controlled trials were conducted with topiramate (TPM) initiated as adjunctive therapy in adults with treatment‐resistant partial‐onset seizures with or without secondary generalization. Methods: Because protocols and study populations were similar, data from the studies were pooled and analyzed for 527 patients treated with TPM and 216 treated with placebo. Results: Seizures were reduced 50% in 43% of TPM‐treated patients and in 12% of placebo‐treated patients (p < 0·001); 5% of TPM‐treated patients, but no placebo‐treated patients, were seizure free during 11–19 weeks of double‐blind treatment (p < 0·001). The therapeutic effect was consistent regardless of seizure type, age, gender, baseline seizure rate, or concomitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage and weekly dosage increments of 100–200 mg/day added to maximally tolerated dosages of AEDs, the most common treatment‐emergent adverse events (TEAEs) were dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia, ataxia, memory difficulty and speech problems. These central nervous system effects were generally mild to moderate in severity, usually occurred early in treatment, often during titration, and resolved with continued treatment. Other notable TEAEs were weight loss and, in a small percentage of patients, renal calculi.
Effectiveness, Tolerability, and Safety of Topiramate in Children with Partial‐Onset Seizures
Authors: Ritter Frank , Glauser Tracy A. , Elterman Roy D. , Wyllie Elaine ,   the Topiramate YP Study Group
Published: August 2005

Summary: 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 ges;50% in 57% of children; 14% of children were seizure‐free ges;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.
Long‐Term Response to Topiramate in Patients with West Syndrome
Authors: Glauser Tracy A. , Clark Peggy O. , McGee Kathy 
Published: August 2005

Summary: 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 ges;50% reduction in spasms, and three (38%) were able to achieve TPM mono‐therapy. 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.
Increment of Synapsin I Protein in the Hippocampus of Kindled Rats
Authors: Suemaru Shuji , Sato Keiko , Sato Toshiki , Kodama Masazumi , Kitamura Yoshihiro , Koyama Fumihiko , Sato Soichiro , Ninomiya Yotaro , Morimoto Kiyoshi , Yamada Norihito , Kuroda Shigetoshi 
Published: August 2005

Introduction: Synapsin is a vesiele‐associated protein considered to be involved in synaptogenesis and neurotransmitter release. Previously, we havc reported that synapsin I mRNA is significantly increased in the bilalcral dentate gyrus after amygdala‐kindled scizures. In this study, we investigated amygdala kindling‐induced changes i n synapsin I protein using immunohistochemistry. Quantitativc densitomctry (Mathern ct al., Ncurosciene, 1997) was performed to evaluatc changes i n synapsin I protein i n the hippocampus.Method: Fifteen inale Sprague‐Dawley rats weighing 300–350 g wcre uscd. A tripolar elcctrode was implanted stcreotaxically in the hasolateral amygdala under pcntobarbital anesthesia. After a recovery period, the rats were subjected to daily kindling stimuli (a 2‐second train of 50 HL, I‐ins rectangular waves at a currcnt intensity of 75–250 PA). Animals with implanted electrodes without atimulation were used as controls (n = 7). They werc then pcrfused 8 hours aftcr the 24–32nd (average 293th) stage 4 or 5 (Racine's classification) generalized seiztirc under anesthesia. The brains were removed and placed in 4% paraloriiialdehyde for 2 days and then transferred to 15% sucrose dissolved in 0.1 M phosphate buffer (PB) for I week. They werc then quickly frozen with dry ice powder, and coronal scctions 20 +in thick wcrc cut with a cryostat. Immunohistochemistry was performcd with polyclonal synapsin I antibody (Calhiochem). The optical density of hippocampus staining was mcasured by a computer‐bascd image analyhtem as an average of the gray value, compensated by the original control sample between white (0) and black (255). Sections were imaged using a chat‐ged‐couplcd devicc camera attached to a microscope and captured and digitized using a Macintosh computer. Illuminance waa unformly maintained and checkcd after cvery I0 measurements using the original control samplc. The image was analysed using imaging software (NIH Image). Measurements were taken at the right and left hippocampus in >2 coronal sections for each animal. Results and Discussion: The kindled slice exhibited bilatcrd increases i n synapsin I protein of approximately 20%–30% in the bilateral str. lucidurn of CA3, and by approximately 20%–40% in the bilateral dentate gyrus. In the hippocampus, neuronal plastic changes including sprouting have becn shown to develop as generalized kindled scizures are repeated. Therefore, the increased synapsin I protein in these brain regions may reilect the enhanced synaptic activity and the prcsynaptic plastic changes in the specific neural network of the hippocampus of kindled rats.
Regional Relationships Between Focal Abnormalities on SPECTs and High Power Zones on EEG Topographies of Background H Activities in Adult Patients with Partial Epilepsies
Authors: Jibiki Itsuki , Nakamura Mitsuhiko 
Published: August 2005

Purpose: In previous studics regarding adult patients with partial epilepsies, we statistically found that the relativc power of 8 band with power spectral analysis of their hackground EEGs showed significant inverse correlation with absolute rCBF values with 123Tc‐HMPAO SPECT or the binding potential of benzodiaapinc receptors with 1211 ‐ iomazcnil SPECT, i n each cerebral region including epileptic foci or even in the whole cerebral regions. As ii series of study aiming at iuvcstigating the utility of SPECT scans for the clinic of epilepsy, we examined with visual inspection whether thcrc were regional relationships between EEG topographies of H hand i n the background EEGs and focal ahnormalitics on 123Tc‐HMPAO SPECT or 2I‐iomazenil SPECT i n adult patients with partial epilepsies. Methods: Subjects were 27 adult epilcptic patients, composed of I4 mcn and I women, age range of 20–57 years old. Or the 27 patients, 6, 14, 2, and I patients had frontal, temporal, parietal, and occipital lobe epilepsies, respectively. The remaining 4 patients had u n tial epilepsies. Furthermore, 16 o l the 27 patients had intractable epilcpsics with seizure interval of days or weeks. All the subjects received 123Tc‐HMPAO SPECT and 99mI‐iomazenil SPECT scans and EEG examinations in the interictal periods, once an each within two weeks. MRI examinations were performed on 24 patients. EEG topographies of 0 band in background EEG activities were produced in the torm of 2‐dimensional brain mapping based on a quantitative analysis of the discontinuous monopolar recording of 24 sessions per EEG, each of which consisted of a continuous record of 5 second duration without artifacts or seizurc discharges. Results: Epileptic foci on EEG were definitely dctcrmiiicd in 24 of the 27 patients, and 18 of the 24 patients (75.0%) showed a regional agrccment between the epileptic EEG foci and the highest or higher power zones in the topographies of H band in background EEG. Thirteen of the 27 patients showed focal abnormalities consisting of hypoperfusion images in 123Tc‐HMPAO SPECT scans. Eight of the 13 patients (6 I .5%) had a regional agreement between the hypoperfusion areas and the highest or higher 0 power m i e s in EEG topographies, whereas 9 of the 13 patients (69.2%) showed a regional agreement between the hypoperfusion areas and epilcptic EEG foci. 99m1‐ iomazenil SPECT scans revealed focal hypoaccumulation images i n 17 of thc 27 patients. Twelve of thc 17 patients (70.6%) showed a regional agreement between the hypoaccumulation areas and the highest or higher H power xones i n EEG topographies, although 10 of the 17 patients (58.8%1) had a regional agreement between the hypoaccumulation areas and epileptic EEG foci. In addition, MRI showed focal organic lesions in 9 of the 24 patients, and 4 of the 9 patients (44.4%J) showed a regional agreement between the lesions and the highest or higher 0 power zones in EEG topographies.
Delayed Reaction Time in Patients with Temporal Lobe Epilepsy.
Authors: Zheng Jiying , Okajima Hiroaki , Aikawa Hiroshi , Yamauchi Toshio 
Published: August 2005

Purpose: Many reports have indicated that patients with temporal lobe epilepsy display a variety of cognitive impairments. The delay of reaction time is one of these impairments. However, it has been suggested that most of the tests used to measure cognitive function, such as reaction time, are influenced by motor speed. To clarify this ques‐ tion, we measured reaction times and carried out a Finger Tapping Test (FTT) in patients and controls, and differences in reaction time between these groups were analyzed after the motor speed component was removed. To avoid the influence of difference in stimulation and test difficulty, we measured 3 different reaction times. In addition, we investigated relationships between performance on these tasks and clinical characteristics to clarify factors related to these impairments. Methods: The subjects were 21 patients with temporal lobe epilepsy (mean age 31.8 years: mean duration of illness 14.5 years) and 11 normal controls (mean age 31.2years). All patients had received AEDs. All subjects were examined by auditory simple reaction time, visual simple reaction time, visual choice reaction time, and FTT. Student's t test was applied to each variable across the 2 groups. Analysis of covariance was then applied, by which the variance in reaction times between the 2 groups that could be attributed to the most simple measure of motor speed (FTT) was factored out. Spearman's correlation analysis was applied to investigate relationships between performance on these tasks and clinical characteristics Resulrs: Performance on all 3 reaction times, including auditory simple reaction time (p<0.05), visual simple reaction time (p<O.O1), and visual choice reaction time (p<0.05), were longer in patients than controls. FTT yielded a significant (p<O.O1) inter‐group difference. When the variance in reaction times attributable to a simple measure of motor speed were factored out, differences in performance on visual simple reaction time (F=5.51, p<0.05) and in performance on visual choice reaction time (F=3.88, p<O.I) persisted. There was a significant positive correlation between performance on the FTT and seizure frequency (rs=O.48, p<0.05), as well as dosage of AEDs (rs= 0.65, p<O.Ol). Conclusions: Our results suggest that the delayed reaction time in patients with temporal lobe epilepsy was not only due to reduction of motor speed but also due to impairment of other cognitive processes. It is generally accepted that many patients have some kind of cognitive impairments and many factors such as seizure, epileptic discharge, AEDs, and others may influence cognitive function. In present study it is indicated that delayed reaction time is due to several cognitive processes. Impairments of motor speed may have a relation to seizure frequency and dosage of AEDs. Several prior reports have indicated that some AEDs affect motor function. Our findings may reflect such a relationship.
A Case with Absence Seizures After Neuroimaging Changes of Rasmussen Syndrome
Authors: Yamanaka Erik , Noma Yurie , Ono Taeko , Yamada Keisuke , Takahashi Ryutarou , Miyake Susumu , Endo Shoichi 
Published: August 2005

Case Report The patient was a 5 year and 5 month‐old boy. A brother had a history of febrile convulsions. The patient was born after 38 weeks of pregnancy, birth weight 3,260 g. The neonatal period was uneventful. His development was normal until 1 year and 3 months of age, after which he suffered generalized tonic seizures 2–3 times per year. Episodes of unconsciousness as often as ten times per day began at 5 years of age. Brain MRI, performed at 2 years of age, was normal. EEG revealed spikes from the right mid‐temporel and right central regions and diffuse irregular spike and waves at 4 years of age. Cryptogenic localization‐related epilepsy was diagnosed and treated with phenobarbital, carhamazepine, valproic acid, and acetazolamide without control of his convulsions. After 5 years of age, he began losing consciousness approximately 10 times per day. At 5 years and 5 months of age, he had fever, cough, rhinorrhea, and 2 generalized tonic‐clonic convulsions for about 2 minutes and subsequently generalized tonicclonic convulsive status epilepticus for 30 minutes. He was admitted to Kagawa Prefectural Central Hospital. At admission, his consciousness score was 200 points (JCS) and he had intermittent clonic convulsions of the right hand and face. He also exhibited right hemiplegia. Partial seizures continued for about 2 weeks, Blood examination revealed CRP of 1.4 mg/dl, with negative antibody titers for herpes simplex and EB virus. CSF findings were normal. At 6 days of admission, T2‐weighted brain MRI studies revealed high density i n the gray matter in the left hemisphere. After 2 months of hospitalization, MRI revealed remarkable left hemispheric atrophy. Two SPECT studies done at an interval of 2 months disclosed hyperperfusion of the left hemisphere. These findings were considered compatible with Rasmussen syndrome. At admission, the EEG revealed left high‐voltage slow wave activity and frequent spikes in the left anterior temporal region. After 4 months of hospitalization, tonic‐clonic convulsions occurred once per month. After 8 months of hospitalization, episodes of unconsciousness occurred 10 times per day. The ictal EEG revealed diffuse right hemisphere dominant 3isecond spike and wave bursts, which were induced by hyperventilation. Ethosuximide completely controlled these episodes and also improved EEG findings. Conclusion: The clinical findings suggested that this patient had RdS‐ mussen syndrome during the course of a cryptogenic localizationrelated epilepsy and subsequently experienced absence seizures. Despite his organic brain damage, his ictal 3/second spike and wave bursts exhibited no preceding focal spikes or slow waves, and ethosuximide markedly improved these absence seizures and EEG abnormalities. The mechanism of these absence seizures was thus not secondary bilateral synchrony and appeared to be the same as that of the primary generalized seizures.
Examining the Impact of Interorganizational Systems on Process Efficiency and Sourcing Leverage in Buyer–Supplier Dyads
Authors: Saeed Khawaja A. , Malhotra Manoj K. , Grover Varun 
Published: August 2005

ABSTRACTManufacturing firms are increasingly seeking cost and other competitive advantages by tightly coupling and managing their relationship with suppliers. Among other mechanisms, interorganizational systems (IOS) that facilitate boundary‐spanning activities of a firm enable them to effectively manage different types of buyer–supplier relationships. This study integrates literature from the operations and information systems fields to create a joint perspective in understanding the linkages between the nature of the IOS, buyer–supplier relationships, and manufacturing performance at the dyadic level. External integration, breadth, and initiation are used to capture IOS functionality, and their effect on process efficiency and sourcing leverage is examined. The study also explores the differences in how manufacturing firms use IOS when operating under varying levels of competitive intensity and product standardization. In order to test the research models and related hypothesis, empirical data on buyer–supplier dyads is collected from manufacturing firms. The results show that only higher levels of external integration that go beyond simple procurement systems, as well as who initiates the IOS, allow manufacturing firms to enhance process efficiency. In contrast, IOS breadth and IOS initiation enable manufacturing firms to enhance sourcing leverage over their suppliers. In addition, firms making standardized products in highly competitive environments tend to achieve higher process efficiencies and have higher levels of external integration. The study shows how specific IOS decisions allow manufacturing firms to better manage their dependence on the supplier for resources and thereby select system functionalities that are consistent with their own operating environments and the desired supply chain design.