bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lamotrigine
Authors: Matsuo Fumisuke 
Published: August 2005

Summary:Clinical use of the antiepileptic drug (AED) lamotrigine (LTG) has dramatically increased since its introduction in Europe in 1991 and in the United States in 1994. This article surveys the English‐language literature of LTG published before 1998. This literature is concerned with the molecular mechanisms of LTG's antiepileptic action, evaluation of its clinical antiepileptic efficacy, adverse experiences associated with its clinical use, and current guidelines for its initiation. LTG's efficacy has been extensively confirmed in multiple postmarketing studies, and its applications are broad. The most serious adverse experiences have involved skin rash. Valproic acid affects LTG metabolism, and a specific set of guidelines for the concurrent use of valproic acid and LTG has been developed. Unique issues are also associated with its pediatric use. LTG has a significant place in clinical management of a wide range of epilepsy syndromes, and the scope of its use is expanding. Accumulating clinical data enable the clinician to maximize its efficacy and minimize adverse experiences. Guidelines for its pediatric use must be followed diligently.
Monotherapy Trials with Gabapentin for Partial Epilepsy
Authors: Beydoun Ahmad 
Published: August 2005

Summary:The efficacy and safety of gabapentin as monotherapy for treatment of partial onset seizures were evaluated in three large multicenter, double‐blind, parallel‐group, dose‐controlled trials. In the first trial, 275 outpatients with refractory partial epilepsy maintained on stable doses of one or two antiepileptic drugs (AEDs) were switched to gabapentin (GBP) monotherapy at 600 mg, 1200 mg, or 2400 mg daily. Patients were required to exit the 26‐week double‐blind phase of the study if they experienced worsening of seizure frequency. With respect to time to exit, there was no statistically significant difference among the three groups; only 3% of patients withdrew from the trial because of adverse events. In the second study, 82 hospitalized patients with medically refractory epilepsy were tapered off baseline AEDs and randomly assigned to GBP monotherapy at 300 mg/day or 3600 mg/day. Patients remained in the trial for a maximum of 8 days but had to exit the trial if they experienced one or more exit events. Time to exit was significantly longer in patients in the 3600‐mg group (151 h) compared with those in the 300‐mg group (85 h) (p= 0.0001). None of the patients withdrew from the trial because of side effects. In the third study, 292 patients with newly diagnosed partial seizures were randomized to GBP 300, 900, or 1800 mg/day or to carbamazepine (CBZ) 600 mg/day. Patients remained in the trial for up to 6 months or until they experienced an exit event. Mean time to exit was significantly longer for patients who received GBP 900 mg/day (p= 0.02) or 1800 mg/day (p= 0.04) compared with those who received 300 mg/day. The completion rate for the CBZ group (37%) was similar to that of the GBP 900‐mg (39%) and 1800‐mg (38%) groups. Patients receiving CBZ had a higher withdrawal rate because of adverse events compared with the GBP 900‐mg and 1800‐mg groups. The results of these trials provide good evidence of the efficacy and safety of GBP as monotherapy for the treatment of partial‐onset seizures.
Dosing to Efficacy with Neurontin: The STEPS Trial
Authors: Morrell Martha J. 
Published: August 2005

Summary:The STEPS (Study of Titration to Effect Profile of Safety) trial, a 16‐week, open‐label, postmarketing multicenter study, assessed the efficacy of gabapentin as adjunctive therapy in patients with inadequately controlled partial seizures. Inclusion criteria were less restrictive than for Phase III studies, to include a population more representative of the patient population treated in clinical practice. Gabapentin was titrated up to a maximal dosage of 3600 mg/day to achieve seizure control or to tolerability. The efficacy analysis included compliant patients who had completed ∼16 weeks of therapy (n= 1055); 573 received ≤1800 mg/day and 482 received ≥1800 mg/day. The average decrease in seizure frequency was 61%, the percentage of seizure‐free patients was 46.35%, and the percentage of patients with a ≥50% decrease in seizure frequency was 76.05%. The cumulative percentage of responders and of patients who were seizure free increased with each dosage increase. The results confirm that titration to efficacy is appropriate for adjunctive therapy with gabapentin in patients with partial epilepsy treated in clinical practice.
Use of New Antiepileptic Drugs in the Treatment of Childhood Epilepsy
Authors: Pellock John M. , Appleton Richard 
Published: August 2005

Summary:The management of epilepsy in children requires careful evaluation, classification, and pharmacologic treatment. With classic antiepileptic drugs (AEDs), at least 25% of children remain refractory to appropriate therapy. The past decade has allowed the introduction of a number of newer AEDs for treatment of both adults and children with epilepsy. These include felbamate, gabapentin, lamotrigine, topiramate, tiagabine, and vigabatrin. Emerging information regarding the efficacy of these AEDs in treating childhood epilepsy syndromes suggests advantages for many patients. Limited data are available that define the optimal use of new AEDs in pediatric patients. Further research must be completed to validate the positive effects described in existing clinical trials of the new AEDs in the treatment of childhood epilepsy.
Gabapentin in the Management of Convulsive Disorders
Authors: McLean Michael J. 
Published: August 2005

Summary:Gabapentin, in clinical use since 1993, is indicated as an adjunctive antiepileptic drug (AED) for treatment of complex partial seizures, with or without secondary generalization, in patients over 12 years of age. Although several cellular actions have been described in the literature, the molecular mechanism(s) of action responsible for the anticonvulsant effect of gabapentin has not been conclusively determined. It is likely that gabapentin has multiple concentration‐dependent actions that combine in a unique manner to produce antiepileptic efficacy. The pharmacokinetic properties of this water‐soluble, amino‐acid AED are generally favorable. Absorption appears to be dependent on transport by the L‐system amino acid transporter. Elimination of unmetabolized drug occurs by the renal route. Although its therapeutic range is not well characterized, gabapentin has a broad therapeutic index. This implies that a wide range of doses can be used, based on individual patient needs, without significant limitation due to dose‐dependent side effects. Gabapentin has few drug‐drug interactions, none of which is clinically limiting. Several studies have demonstrated the long‐term efficacy of gabapentin with no systematic evidence of tachyphylaxis. In addition, there is increasing evidence to support the use of gabapentin as monotherapy. Gabapentin is safe and is generally well tolerated. To date, nearly 3 million patients have been treated in studies and in open use without causal relationship to a specific life‐threatening organ toxicity. Seizure control superior to that observed in well‐controlled trials has been reported at higher doses used in clinical practice and in studies. Therefore, gabapentin dosing must be optimized on an individual basis to achieve an adequate trial of the drug and obtain the best seizure control.
Postherpetic Neuralgia: Role of Gabapentin and Other Treatment Modalities
Authors: Beydoun Ahmad 
Published: August 2005

Summary:Postherpetic neuralgia (PHN) is a chronic and painful condition that may occur after a herpes zoster infection. The frequency of PHN after untreated zoster varies widely. Age is the most important risk factor for development of PHN. The condition occurs in an estimated 50% of patients older than 50 years. The pain of PHN can be severe and debilitating and is frequently associated with allodynia. Although in most patients pain remits within the first year, it may persist for a lifetime. Tricyclic antidepressants (TCAs), topical agents, opioids, and gabapentin, a structural γ‐amino butyric acid (GABA) analogue, are the only agents that have demonstrated efficacy in randomized clinical trials for treatment of both the shooting and the burning form of pain associated with PHN. TCAs are among the most commonly used classes of agents for treating PHN and are effective in a significant proportion of patients. However, various adverse events can limit treatment. These side effects tend to be more acute in the elderly, the population most likely to suffer from PHN. Topical agents have led to mild to moderate improvement in patients with PHN but are usually ineffective as monotherapy for this condition. Until recently, carbamazepine was the only antiepileptic drug evaluated for the treatment of PHN. Over the past few years, however, gabapentin has received increasing attention as a useful treatment for neuropathic pain. Gabapentin lacks significant drug‐drug interactions and has a favorable safety profile, which makes it particularly useful for treatment of PHN.
Gabapentin Monotherapy for the Symptomatic Treatment of Painful Neuropathy: A Multicenter, Double‐blind, Placebo‐controlled Trial in Patients With Diabetes Mellitus1
Authors: Backonja Misha‐Miroslav 
Published: August 2005

Summary:Pain is the most disturbing symptom of diabetic neuropathy. Traditionally this type of pain was treated with tricyclic antidepressants which frequently have many side effects. In the study reported here, gabapentin was administered in escalating doses up to 3600 mg per day to eligible patients with moderate to severe diabetic neuropathy pain in a double blind placebo controlled fashion. Gabapentin provided superior and significant pain relief over placebo. In addition, patients taking gabapentin had improvement of sleep scores and a number of items on mood and quality of life questionnaires. Gabapentin was tolerated well with mild and tolerable side effects.
NMDA‐Receptors 1 and 2A/B Coassembly Increased in Human Epileptic Focal Cortical Dysplasia
Authors: Mikuni Nobuhiro , Babb Thomas L. , Ying Zhong , Najm Imad , Nishiyama Kazutoshi , Wylie Christi , Yacubova Karina , Okamoto Takashi , Bingaman William 
Published: August 2005

Summary: Purpose: This study was designed to quantify the relation between expressions of NMDA receptor (NMDAR) subunits (1 and 2A/B) and the epileptogenicity in human focal cortical dysplasia. Methods: Immunoblotting and immunoprecipitation were used to quantify these receptor subunits in tissue resected from EEG‐verified epileptic and distal nonepileptic frontal cortical areas in each of three patients as determined by chronic subdural electrode recordings. In each patient, adjacent sections were immunostained to verify that the numbers of dysplastic neurons were greater in epileptic than in nonepileptic cortex. Results: In all patients, NMDAR2A/B expressions and their coassemblies with NMDAR1 were increased in epileptic dysplastic cortex compared with the relatively normal appearing nonepileptic cortex. For all three patients, there were no significant differences in NMDAR1 protein expressions between the two EEG groups. Conclusions: These results suggest that increased NMDAR1‐NMDAR2A/B coassembly contributes to hyperexcitability in dysplastic cortical neurons and focal seizure onsets.
Prognostic Factors in Anterior Temporal Lobe Resections for Mesial Temporal Lobe Epilepsy: Multivariate Analysis
Authors: Jeong Sang‐Wuk , Lee Sang Kun , Kim Kwang‐Ki , Kim Ho , Kim Joo‐Yong , Chung Chun‐Ki 
Published: August 2005

Summary: Purpose: Even though there have been several studies on the prognostic factors of temporal lobe epilepsy (TLE) after lobectomy, no studies have been performed for homogeneous mesial TLE. Furthermore, most studies on the predictors of outcome of epileptic surgery were based on univariate analyses and did not consider modern epileptic surgery investigation modalities such as brain magnetic resonance imaging (MRI) and positron emission tomography (PET). We attempted to identify the prognostic factors in anterior temporal lobectomy (ATL) for mesial TLE with multivariate analysis. Methods: Ninety‐three patients with mesial TLE (54 men and 39 women, mean age at surgery, 28.3 ± 8.2 years) were included in the study. The primary outcome variable was the status of patients in the second postoperative year, classified as either seizure free (except aura), or not seizure free. Clinical, electroencephalographic, MRI, PET, Wada test, and pathological data were considered. Results: Seventy‐eight (84.0%) patients had remission of seizures. With univariate analysis, age at surgery (p < 0.001), epilepsy duration before surgery (p = 0.04), and ipsilateral hippocampal sclerosis on MRI (p = 0.02) were found to be significant. By using multivariate analysis, age at surgery (p = 0.001) and ipsilateral hippocampal sclerosis on MRI (p = 0.03) were found to be the most significant prognostic factors. Conclusions: Age at surgery and hippocampal sclerosis are independent prognostic factors for ATL in mesial TLE. These findings suggest that mesial TLE may be a progressive disorder, and surgical outcome is better when early ATL is performed.
Long‐Term Treatment of Children with Epilepsy with Valproate or Carbamazepine May Cause Subclinical Hypothyroidism
Authors: Eirís‐Puñal J. , Río‐Garma M. Del , Del Río‐Garma M. C. , Lojo‐Rocamonde S. , Novo‐Rodríguez I. , Castro‐Gago M. 
Published: August 2005

Summary: Purpose: The aim of the study was to evaluate serum thyroid hormone balance in children receiving long‐term therapy with carbamazepine (CBZ), valproate (VPA), and phenobarbital (PB). Methods: We determined serum levels of triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), thyroxine‐binding globulin (TBG), and thyroid‐stimulating hormone (TSH) in 148 healthy children and 141 children with epilepsy who had been receiving CBZ (61 patients), VPA (51 patients), or PB (29 patients) for 12–161 months. In view of TSH values, three categories of subclinical hypothyroidism were considered: I, TSH greater than the control‐group mean + 2 SD (4.37 mIU/L in our study) and <6 mIU/L; II, TSH between 6 and 12 mIU/L; and III, TSH >12 mIU/L. Results: In all treated groups, mean T4 and FT4 levels were lower than in the control group, whereas the CBZ‐ and VPA‐treated children additionally showed reduced mean T3 and TBG levels and increased mean TSH levels. In the group receiving CBZ, 8.2% had TSH values higher than the normal‐range maximum, by comparison with only 3.6% of healthy children. The increase in TSH levels was particularly marked in VPA‐treated children, accounting for 26% of patients with subclinical hypothyroidism. Conclusions: Our results, in contrast to previous reports, suggest that CBZ and particularly VPA may induce subclinical hypothyroidism. This suggests a need for careful monitoring of TSH levels in children receiving CBZ or VPA.
Topiramate in Medically Intractable Partial Epilepsies: Double‐Blind Placebo‐Controlled Randomized Parallel Group Trial
Authors:   Korean Topiramate Study Group
Published: August 2005

Summary: Purpose: To evaluate the efficacy and safety of topiramate (TPM) as add‐on therapy in medically intractable partial epilepsies. Methods: We used a multicenter double‐blind placebo‐controlled randomized parallel‐group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of stabilization phase. The primary efficacy variable was the median seizure frequency reduction rate (MSFRR), and the other efficacy variables included responder rate, seizure‐free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs (AEDs) and should have two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600 mg/day. The study drugs were started at the initial dose of 50 mg/day and gradually increased to the target dose over a 10‐week period. Results: A total of 177 patients was randomized into the TPM group (n = 91) and the placebo (PLC) group (n = 86). Baseline median seizure frequencies were 5.6 episodes/4 weeks in the TPM and the PLC groups. Among those who were randomized, 174 patients (TPM, 89 patients; PLC, 85 patients) were available for the efficacy measurement by intention‐to‐treat analysis. The MSFRR was 51.3% for TPM and 9.1% for PLC, which was highly in favor of TPM (p = 0.0001). The responder rate was 50.6% for TPM and 12.9% for PLC (p = 0.001). Seven (7.9%) of 89 patients taking TPM became seizure free compared with one (1.2%) of 85 patients taking PLC (p = 0.004). The global evaluation greatly favored TPM (p = 0.001). The incidence of adverse events (AEs) was higher in the TPM (81.3%) than in the PLC (48.9%) group, with central nervous system (CNS)‐related AEs being the most frequent. Among individual AEs, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AEs in the TPM group. AEs precipitated early drop‐out in seven (7.6%) patients taking TPM and three (3.5%) patients taking PLC. No serious systemic AEs were observed. Conclusions: TPM was highly effective and safe as add‐on therapy in medically intractable partial epilepsies. Slower titration of TPM might be responsible for the lesser drop‐out rate than previous trials, but the incidence of AEs was still high. The AE profile of TPM in Koreans was different from that in whites.
Seizure‐Refractory Period After a Single Stimulation and Inhibition of Seizures After Repetitive Stimulation in the Gerbil: Effects on Blood Cortisol Levels
Authors: Revilla Victoria , Robles María Sagrario , Bermejo Juan Carlos , Paniagua Miguel Angel , Fernádez‐López Arsenio 
Published: August 2005

Summary: Purpose: To determine the epileptic response of gerbils to external shock stimulus, assessing blood cortisol levels as a parameter to determine stress conditions. Methods: Five sets of two‐month‐old Mongolian gerbils were stimulated to elicit seizures by the clapping of a sheaf of papers. Stimulation was done once a week over a 10‐week period to obtain a stable situation and a similar response in all the animals. Four of the sets were killed to collect blood samples: those not manipulated; those stimulated twice a day for 5 days; those stimulated once to obtain samples immediately after seizure recovery; and those stimulated once to obtain samples 30 min after seizure recovery. Blood samples from the fifth set of animals were taken in vivo from the retro‐orbital plexus. Results: Eliciting seizures with this stimulus, twice a day in a repetitive way, prevented further induced seizures from the second day of stimulation on. Changes in the gerbils’behavior—from exploratory to escape mode—were also observed. The blood cortisol levels found in the sets of animals killed without induced seizures were similar to the others, regardless of whether the animals had been subjected to repetitive stimulation. Additionally, significant decreases in blood cortisol levels were detected in the animals killed immediately and 30 min after recovering from an induced epileptic episode. Conclusions: The normal refractory period in gerbils can be estimated at 1 h. The lack of correlation between cortisol levels and the inhibition of seizure‐elicitation through repetitive stimulation supports the environmental and exploratory hypothesis of seizure generation rather than a stress hypothesis.
Muscarinic Receptors Mediate Carbachol‐Induced Inhibition of Maximal Electroshock Seizures in the Nucleus Reticularis Pontis Oralis
Authors: Peterson Steven L. , Armstrong Juli J. 
Published: August 2005

Summary: Purpose: Previous reports from this laboratory indicated a role for N‐methyl‐D‐aspartic acid (NMDA) and γ‐aminobutyric acid (GABA) receptors among the neuronal mechanisms of the nucleus reticularis pontis oralis (RPO) that regulate the tonic hindlimb extension (THE) component of maximal electroshock seizures (MESs) in rats. This study was intended to determine the role of cholinergic mechanisms in the RPO regulation of THE. Methods: Rats were surgically prepared with microinjection guide cannulas for the focal administration of drug solutions directly into the RPO. MES was induced with corneal electrodes. Results: RPO microinjection of carbachol significantly inhibited the incidence of THE. RPO microinjection of atropine by itself had no effect on the seizure response but significantly antagonized the anticonvulsant effect induced by RPO microinjection of carbachol. The selective nicotinic agonist dimeth‐ylpiperizinium (DMPP) by itself had no effect on THE. RPO microinjection of 10 ng pertussis toxin by itself had no effect on THE but significantly antagonized the anticonvulsant effect induced by RPO microinjection of carbachol. Conclusions: RPO microinjection of carbachol inhibited the THE component of MESs in rats. The carbachol effect appeared to be mediated by muscarinic receptors as the anticonvulsant activity was antagonized by atropine, and the selective nicotinic agonist DMPP induced no anticonvulsant activity. Because pertussis toxin acts to inhibit muscarinic receptor‐linked G proteins, the pertussis toxin antagonism of carbachol also supports a muscarinic mechanism of action.
Dose–Response Study of Vigabatrin as Add‐On Therapy in Patients with Uncontrolled Complex Partial Seizures
Authors: Dean Christine , Mosier Michael , Penry Kiffin 
Published: August 2005

Summary: Purpose: This placebo‐controlled, randomized, double‐blind, multicenter study examined the efficacy and safety of three daily doses of vigabatrin (VGB; 1, 3, or 6 g) as add‐on therapy in 174 patients with previously uncontrolled complex partial seizures with or without secondary generalization. Methods: A 12‐week pretreatment assessment period was followed by drug therapy with a 6‐week titration period and a 12‐week maintenance phase. Results: VGB doses of 3 and 6 g/day reduced median monthly frequency of seizures by 4.3 and 4.5 seizures, respectively, compared with 0.2 seizures for placebo (p = 0.0001). The percentages of patients classified as therapeutic successes (≤50% reduction in seizure frequency) were 7% for placebo and 24, 51, and 54% for patients taking daily VGB doses of 1, 3, and 6 g, respectively; the comparison with placebo was significant for all treatment groups. The linear trend for dose response was highly significant (p ≥ 0.0001) for both median monthly seizure frequency and therapeutic success. Vigabatrin was well tolerated, causing no clinically significant changes in laboratory parameters, brain magnetic resonance imaging, evoked potentials, cognitive function, or psychosocial tests. Fatigue, drowsiness, and dizziness were the most common treatment‐related adverse events in all treatment groups. Dropouts due to adverse events were higher in the 6‐g/day group. Conclusions: VGB was significantly more effective than placebo as add‐on therapy in reducing seizure frequency. VGB at 3 and 6 g/day produced the best efficacy: however, adverse events may limit the use of the 6‐g/day dose in some patients.