Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in s...Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury（SCI）. After rat models of thoracic contusive SCI were established by free weight-drop method, TPM（40 mg/kg） was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.展开更多
Drug-induced peripheral neuropathy had been rarely reported as an adverse effect of some antiepileptic drugs(AEDs) at high cumulative doses or even within the therapeutic drug doses or levels.We describe clinical and ...Drug-induced peripheral neuropathy had been rarely reported as an adverse effect of some antiepileptic drugs(AEDs) at high cumulative doses or even within the therapeutic drug doses or levels.We describe clinical and diagnostic features of a patient with peripheral neuropathy as an adverse effect of chronic topiramate(TPM) therapy.A 37-year-old woman was presented for the control of active epilepsy(2010).She was resistant to some AEDs as mono-or combined therapies(carbamazepine,sodium valproate,levetiracetam,oxcarbazepine and lamotrigine).She has the diagnosis of frontal lobe epilepsy with secondary generalization and has a brother,sister and son with active epilepsies.She became seizure free on TPM(2013-2017) but is complaining of persistent distal lower extremities paresthesia in a stocking distribution.Neurological examination revealed presence of diminished Achilles tendon reflexes,stocking hypesthesia and delayed distal latencies,reduced conduction velocities and amplitudes of action potentials of posterior tibial and sural nerves,indicating demyelinating and axonal peripheral neuropathy of the lower extremities.After exclusion of the possible causes of peripheral neuropathy,chronic TPM therapy is suggested as the most probable cause of patient's neuropathy.This is the first case report of topiramate induced peripheral neuropathy in the literature.展开更多
BACKGROUND: It has been demonstrated that traditional antiepileptics, such as phenytoin, carbamazepine (CBZ), phenobarbital, etc., can result in the decrease of thyroid hormone of epileptic patients. However, there is...BACKGROUND: It has been demonstrated that traditional antiepileptics, such as phenytoin, carbamazepine (CBZ), phenobarbital, etc., can result in the decrease of thyroid hormone of epileptic patients. However, there is still no sufficient evidence for the studies about the effect of new-type antiepileptics, such as topiramate (TPM), on thyroid hormones. OBJECTIVE: To observe the effects of TPM and CBZ on the level of thyroid hormones in serum of adults with epilepsy. DESIGN: A comparative observation. SETTING: Department of Neurology, Sichuan Provincial People's Hospital. PARTICIPANTS: Totally 100 outpatients or inpatients newly diagnosed to have epilepsy were selected from the Department of Neurology, Sichuan Provincial People's Hospital from July 2003 to August 2005, including 60 males and 40 females, aged 18-70 years. All the patients were accorded with the standard for the classification of epilepsy set by International League Against Epilepsy (ILAE) in 1981; Had been Informed and agreed with the detection; Had no history of thyroid gland disease; Had not taken any drugs could affect the thyroid function. Meanwhile, 40 adult healthy examinees were selected from our hospital as the control group, including 24 males and 16 females, aged 18-65 years. METHODS: ① The 100 epileptic patients were randomly divided into TPM group (n =50) and CBZ group (n =50), and they were treated with TPM (Xian-Janssen Pharmaceutical, Ltd.; Batch number: 03AS032, Norm: 25 mg/tablet) and CBZ (Shanghai Sunve Pharmaceutical Co., Ltd.; Batch number: 030201, Norm: 100 mg/tablet) respectively. The initial dosage of TPM was 25 mg per day, increased by 25 mg every week, the objective dosage of 100-200 mg per day was maintained when the symptoms were satisfactorily controlled. The dosage of CBZ was 6-8 mg/kg per day. All the patients were administrated for 1 year. ② The serum levels of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) in the epileptic patients were detected by means of chemiluminescence before treatment and at 3, 6 and 12 months after treatment respectively. ③Standards for judging curative effects: Controlled by without seizure, the frequency of seizure reduced by ≥ 75% was taken as significant effect, reduced by 50%-74% as effect, and reduced by < 49% as invalid, whereas increased by more than 20% was taken as aggravation. ④ The intergroup and intragroup differences of the measurement data were compared by the analysis of variance and paired t test respectively. MAIN OUTCOME MEASURES: Serum levels of thyroid hormones before treatment and at different time points after treatment of TPM and CBZ. RESULTS: All the 100 epileptic patients and 40 healthy subjects were involved in the analysis of results. ① Changes of serum levels of thyroid hormones: The serum levels of TT3, TT4, FT3, FT4 and TSH were close between the epileptic patients and normal subjects before treatment (P > 0.05). In the CBZ group, the serum levels of FT4 at 3, 6 and 12 months after treatment [(16.87±3.77), (16.34±3.98) , (16.97±3.95) pmol/L] were significantly decreased as compared with those before treatment [(18.00±3.54) pmol/L, t =2.74, 3.50, 2.26, P < 0.05]; The levels of TT3 at 3, 6 and 12 months [(2.09±0.54), (1.99±0.49), (1.84±0.47) nmol/L] were significantly decreased as compared with those before treatment [(2.22±0.63) nmol/L, t =2.73, 2.78, 5.18, P < 0.05]. The levels of TT3 at 6 and 12 months [(109.65±23.98), (107.72±23.90) nmol/L] were significantly decreased as compared with those before treatment [(118.98±28.48) nmol/L, t =3.11, 3.30, P < 0.05]. TT4 level in serum at 3 months and the levels of FT3 and TSH at each time point after CBZ treatment had no obvious changes as compared with those before treatment (P > 0.05). In the TPM group, the levels of thyroid hormones at each time point had no obvious changes as compared with those before treatment (P > 0.05). ② Curative effects: Of the 100 epileptic patients, it was controlled in 12 cases, significantly effective in 30 cases, effective in 39 cases and invalid in 19 cases, the total effective rate was 81% (81/100). CONCLUSION: CBZ treatment can lead to the decreases of thyroid hormones in adult epileptic patients. Epilepsy itself and TPM treatment cannot change the thyroid hormones in adult epileptic patients, which suggests that TPM treatment is safer for the thyroid function of adult epileptic patients.展开更多
OBJECTIVE：To evaluate the treatment effects and safety of topiramate in migraine prophylaxis. DATA RETRIEVAL：We searched the Medline database,EMbase,Cochrane Library and China National Knowledge Infrastructure datab...OBJECTIVE：To evaluate the treatment effects and safety of topiramate in migraine prophylaxis. DATA RETRIEVAL：We searched the Medline database,EMbase,Cochrane Library and China National Knowledge Infrastructure database for articles published between January 1995 and May 2011,using the key words＂migraine＂,＂topiramate＂,and＂prophylaxis＂. SELECTION CRITERIA：We selected randomized controlled trials of migraine patients,in which the experimental group was orally administered topiramate,and the control group was given placebo. Odds ratios（ORs）and mean differences（MDs）were calculated using a fixed effects model/random effects model.Quality evaluation and data extraction were performed independently by two researchers utilizing RevMan 5.0 software. MAIN OUTCOME MEASURES：Efficacy was recorded as the responder rate（response defined as at least a 50%reduction in average monthly migraine frequency）and change in mean monthly number of migraine days.Adverse events were recorded as the number of subjects exhibiting at least one adverse event. RESULTS：Eight randomized controlled trials were found to be appropriate,and had available data. The meta-analysis results revealed that topiramate（100 or 200 mg/d）was more effective than placebo in responder rate（OR=2.97,95%confidence interval（CI）：2.17-4.08,P〈0.01;OR=2.35, 95%CI：1.77-3.12,P〈0.01）.Topiramate（100 mg/d）was more effective than placebo in terms of the change in mean monthly migraine days（MD：-1.14,95%CI：-1.69 to-0.59,P〈0.01）.The total incidence rate of adverse events for topiramate was higher than in the placebo group（P〈0.01）,but most adverse events were mild to moderate. CONCLUSION：Overall,topiramate obtained good outcomes and safety in migraine prophylaxis.展开更多
BACKGROUND： Apoptosis plays an important role in brain injury after seizures and the formation of chronic epilepsy. It is important to investigate whether topiramate exhibits either antiepileptic and/or antiapoptotic...BACKGROUND： Apoptosis plays an important role in brain injury after seizures and the formation of chronic epilepsy. It is important to investigate whether topiramate exhibits either antiepileptic and/or antiapoptotic effects on hippocampal neurons. OBJECTIVE： To observe neuronal apoptosis in hippocampus of rat seizure models, and to investigate the antagonizing effect of topiramate on neuronal apoptosis after seizures. DESIGN： An animal experiment of comparative observation. SETTING： First Affiliated Hospital of Guangxi Medical University. MATERIALS： Sixty healthy male Sprague Dawley （SD） rats, 4-6 weeks old and weighing 160-220 g, were provided by the Experimental Animal Center of Guangxi Medical University. Main apparatus and reagents were as follows： Rat brain solid positioner （SR-6N, made in Japan）; kainic acid by Sigma （USA）; pathological image analyzer （DMR＋550） by Leica （Germany）; in situ apoptosis detection kit by Wuhan Boster Biological Technology Co., Ltd; topiramate by Xi＇an-Janssen Pharmaceutical, Ltd. The treatment on animals in the experiment was in accordance with the standards of animal ethics. METHODS： The experiments were performed at the Scientific Experimental Center of Guangxi Medical University from June to December 2006. The rats were randomly divided into a topiramate-treated group （n = 30） and a model group （n = 30）. ① After anesthesia, all rats were administered a kainic acid injection （0.2 μL, 2 g/L） into the right lateral ventricle. Grade Ⅲ and greater Racine standards were considered to be a successful model establishment. Thirty minutes after seizure , rats in the topiramate-treated group were treated with an intraperitoneal （i.p.） injection of topiramate every day （40 mg/kg/d） for 2 weeks. The rats in the model group were treated with an equal volume of saline for 2 weeks. ③ Six rats in the topiramate-treated group were sacrificed at 1 day, and 1, 2, 3, and 4 weeks after treatment, respectively. The model group animals were sacrificed at corresponding time points. The brain tissues of hippocampal dentate gyrus, CA1, CA2, and CA3 region were removed and prepared into sections. Neuronal apoptosis was detected with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling. MAIN OUTCOME MEASURES： Hippocampal neuronal apoptosis in various rat brain areas was detected in the two groups. RESULTS： All 60 rats were included in the final analysis of results. In the topiramate-treated group, the number of apoptotic cells in hippocampal dentate gyrus and CA3 region at 1 day, 1, and 4 weeks after seizures were significantly lower than the model group （P 〈 0.05-0.01）. The number of apoptotic cells in hippocampal CA1 and CA2 regions at 1 day and 4 weeks after seizures in the topiramate-treated group were significantly lower than the model group （P 〈 0.05）. CONCLUSION： Hippocampal apoptosis is closely associated with kainic acid-evoked seizures, and topiramate can alleviate early （1 day and 1 week） and delayed （4 weeks） hippocampal neuronal injury induced by kainic acid.展开更多
Paroxysmal kinesigenic dyskinesia(PKD)is presented as a short paroxysmal attack of focal or generalized involuntary movement.The most common treatments for PKD are carbamazepine and phenytoin.Though the cases of clini...Paroxysmal kinesigenic dyskinesia(PKD)is presented as a short paroxysmal attack of focal or generalized involuntary movement.The most common treatments for PKD are carbamazepine and phenytoin.Though the cases of clinically diagnosed PKD with a good response to topiramate have been already reported,this patient was unique in several ways.Here,we reported the case of a 24-year-old patient with PKD for one year,and described the pathogenesis of PKD.展开更多
The use of generic formulation of therapeutic agents may allow a significant reduction of costs for patients and the National Health Services. This is particularly true for drugs used in prolonged therapies such as to...The use of generic formulation of therapeutic agents may allow a significant reduction of costs for patients and the National Health Services. This is particularly true for drugs used in prolonged therapies such as topiramate which is effective in the treatment of epilepsy, migraine, alcohol abuse and psychiatric conditions. The purposes of this study were: 1) evaluate Topiramate (50 mg) release in vitro from a generic (Sincronil) and the reference formulation (Topamax);2) compare the above mentioned generic and reference formulations in bioavailability studies in healthy volunteers. Dissolution tests in vitro showed that more than 95% of the active principle was released within 15 minutes both from the reference and the generic formulation. No difference in release kinetics was found between the two topiramate preparations. In vivo pharmacokinetic data were obtained by administering 1 tablet containing 50 mg of topiramate of each of the two formulations to 28 healthy volunteers under fasting conditions, using a randomized, single-dose, open-label, 2-way crossover design. The treatment phases were separated by a washout period of 21 days. The maximum concentration reached in plasma (Cmax) for the reference and the generic formulation, were 946 ± 308 and 849 ± 247 (ng/mL) and the area under the curve (AUC0-t) were 35,900 ± 7800 and 34,300 ± 8100 (ng·h/mL) respectively. The data indicate that the rate and extent of absorption of the reference or generic 50 mg topiramate formulation are not significantly different and suggest that the therapeutic effects of the two preparations do not significantly differ.展开更多
BACKGROUND： Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is o...BACKGROUND： Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is one of the important transmitters for alcohol tolerance in central nervous system. OBJECTIVE： To observe the changes of excitatory amino acids in hippocampal dentate gyrus in rats with long-term alcohol drinking after withdrawal under consciousness, and investigate the therapeutic effect of topiramate on alcohol withdrawal. DESIGN ： A randomized control animal experiment SETTING ： Department of Neurology, Affiliated Hospital of Yanbian University MATERIALS： Thirty male Wistar rats of 4 months old, weighing 300-350 g, were purchased from the Experimental Animal Department, Medical College of Yanbian University. Topiramate was produced by Swish Cilag Company, and the batch number was 02CS063. METHODS： The experiments were carried out in the Department of Physiology, Medical College of Yanbian University from August 2005 to February 2006. ① The rats were divided randomly into three groups： control group （n=10）, alcohol group （n=10） and topiramate-treated group （n=10）. Rats in the alcohol group and topiramate-treated group were given intragastric perfusion of 500 g/L alcohol （10 mL/kg）, once a day for 4 weeks successively, and then those in the topiramate-treated group were treated with 80 mg/kg topiramate at 24 hours after the last perfusion of alcohol, once a day for 3 days successively. Rats in the control group were intragastricly given isovolume saline. ② The withdrawal symptoms were assessed at 6, 30, 48 and 72 hours after the last perfusion of alcohol by using the withdrawal rating scale set by Erden et al, which had four observational indexes of stereotyped behaviors, agitation, tail stiffness and abnormal posture, each index was scored by 5 points, the higher the score, the more obvious the symptoms. ③ The contents of aspartic acid and glutamic acid in hippocampal dentate gyrus were detected with microdialysis technique and high-performance liquid chromatograpy （HPLC） respectively at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the three groups. MAIN OUTCOME MEASURES ： ① Scoring results of alcohol withdrawal symptoms; ② Changes of the contents of aspartic acid and glutamic acid in hippocampal dentate gyrus at the alcohol withdrawal symptoms, and the effects of topiramate. RESULTS： Seven rats were excluded due to inaccurate localization and natural death, and 23 rats were involved in the analysis of results. ①In the alcohol group, the scores of alcohol withdrawal symptoms at 30 and 48 hours after the last perfusion of alcohol were obviously higher than those in the control group （10.50±0.96, 14.17±1.25; 3.50±0.92, 3.16±0,31; P 〈 0.01）. In the topiramate-treated group, the scores at 30 hours after the last perfusion of alcohol （6.06±0.82, 3.50±0.92, P 〈 0.05）, and the withdrawal scores at 48 and 72 hours were close to those in the control group （4.57±0.58, 3.30±0.71; 3.16±0.31, 3.66±0.67; P 〉 0.05）.② Changes of the contents of glutamic acid in hippocampal dentate gyrus： In the alcohol group, the content of glutamic acid at 48 hours after the last perfusion of alcohol was significantly increased as compared with that at 6 hours [（143.32±11.42）%, （99.12±0.69）%; P 〈 0.05], and that at 72 hours was close to that at 6 hours [（78.50±16.40）%, （99.12±0.69）%; P 〉 0.05]. The contents of glutamic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [（100.30±0.37）%, （118.91±10.40）%, （99.55±12.81）%, （99.08±11.42）%; P 〉 0.05], The content of glutamic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group （P 〈 0.05）, and those at 30 and 72 hours were close （P 〉 0.05）. ③ Changes of the contents of aspartic acid in hippocampal dentate gyrus： In the alcohol group, the contents of aspartic acid at 30 and 48 hours after the last perfusion of alcohol were significantly increased as compared with that at 6 hours [（126.60±8.67）%, （129.17±10.40）%, （99.25±0.87）%; P 〈 0.05], and that at 72 hours was close to that at 6 hours [（89.87±9.93）%, （99.25±0.87）%; P 〉 0.05]. The contents of aspartic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [（100.27±0.32）%, （120.81 ±12.63）%, （98.91±7.83）%, （85.92±8.07）%; P 〉 0.05]. The content of aspartic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group （P 〈 0.05）, and those at 30 and 72 hours were close （P 〉 0.05）. CONCLUSION： ① The occurrences of alcohol withdrawal symptoms are correlated with the increased contents of excitatory amino acids in hippocampal dentate gyrus in rats. ② Topiramate can alleviate the alcohol withdrawal symptoms, which may be correlated with the decreased contents of excitatory amino acids in hippocampal dentate gyrus in rats.展开更多
Background Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate mo...Background Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate monotherapy (TPM control IS). Methods The clinical manifestations, treatment processes and outcomes were analyzed in 11 pyridoxine responsive IS and 17 TPM-control IS. Results Of the 11 patients with pyridoxine responsive IS, nine were cryptogenic/idiopathic. Age of seizure onset was 5.36 ± 1.48 months. Spasms were controlled within a week in most of the patients. At the last follow-up, EEG returned to normal in 8. Psychomotor development was normal in 6, mild delay in 3, severe delay in 2. Of the 17 patients with TPM-control IS, 10 were cryptogenic/idiopathic. The age of seizure onset was 5.58 ± 2.09 months. All patients were controlled within a month. At the last follow-up, EEG was normal in 10. Psychomotor development was normal in 8, mild delay in 5, severe delay in 4. Genetic analysis did not show any meaningful results. Conclusions The clinical characteristics and disease courses of pyridoxine responsive IS and TPM-control IS were similar, which possibly clued for a same pathogenic mechanism. Pyridoxine should be tried first in all IS patients, even in sympto-matic cases. If patients were not responsive to pyridoxine, TPM could be tried.展开更多
Adrenocorticotropic hormone is recommended worldwide as an initial therapy for infantile spasms. However, infantile spasms in about 50% of children cannot be fully controlled by adrenocorticotropic hormone monotherapy...Adrenocorticotropic hormone is recommended worldwide as an initial therapy for infantile spasms. However, infantile spasms in about 50% of children cannot be fully controlled by adrenocorticotropic hormone monotherapy, seizures recur in 33% of patients who initially respond to adrenocorticotropic hormone monotherapy, and side effects are relatively common during adrenocorticotropic hormone treatment. Topiramate, vitamin B6, and immunoglobulin are effective in some children with infantile spasms. In the present study, we hypothesized that combined therapy with adrenocorticotropic hormone, topiramate, vitamin B6, and immunoglobulin would effectively treat infantile spasms and have mild adverse effects. Thus, 51 children newly diagnosed with West syndrome including infantile spasms were enrolled and underwent polytherapy with the four drugs. Electroencephalographic hypsarrhythmia was significantly improved in a majority of patients, and these patients were seizure-free, had mild side effects, and low recurrence rates. The overall rates of effective treatment and loss of seizures were significantly higher in cryptogenic children compared with symptomatic children. The mean time to loss of seizures in cryptogenic children was significantly shorter than in symptomatic patients. These findings indicate that initial polytherapy with adrenocorticotropic hormone, topiramate, vitamin Be, and immunoglobulin effectively improves the prognosis of infantile spasms, and its effects were superior in cryptogenic children to symptomatic children.展开更多
A simple, rapid, specific and precise liquid chromatography—tandem mass spectrophotometric (LC-MS/MS) method was developed and validated for the quantification of chiral separated R-bicalutamide from S-bicalutamide, ...A simple, rapid, specific and precise liquid chromatography—tandem mass spectrophotometric (LC-MS/MS) method was developed and validated for the quantification of chiral separated R-bicalutamide from S-bicalutamide, in human plasma. Topiramate (TPM) was used as internal standard, added to plasma sample prior to extraction using t-butyl methyl ether (TBME). Chromatographic separation was achieved on CHIRALPAK AD-RH column (150 mm×4.6 mm, 5 μm) with acteonitrile: 0.1% formic acid Buffer (50:50 v/v) as an isocratic mobile phase with a flow rate of 1.0 mL·min-1. Quantitation was performed by transition of 429.0 → 255.0 (m/z) for R-bicalutamide and 338.1 → 77.8 (m/z) for topiramate. The lower limit of quantitation was 20 ng·mL-1with a 100 μL plasma sample. The concentrations of eight working standards showed linearity between 20 to 3200 ng·mL-1(r2≥ 0.9990). Chromatographic separation was achieved within 6 min, compared to the 15 min of previous methods. The average extraction recoveries of 3 quality control concentrations were 98.56% for R-bicalutamide and 92.42% for topiramate. The coefficient of variation was ≤15% for intra- and inter-batch assays. Therefore a rapid, specific and sensitive LC-MS/MS method for the quantification of R-bicalutamide in human plasma was developed and validated can be used in the bioequivalence study of this drug.展开更多
Background:West syndrome is a devastating disorder characterized by a triad of epileptic spasms,abnormal electroencephalography(EEG),and developmental arrest or psychomotor delay.In addition to early diagnosis,knowing...Background:West syndrome is a devastating disorder characterized by a triad of epileptic spasms,abnormal electroencephalography(EEG),and developmental arrest or psychomotor delay.In addition to early diagnosis,knowing the etiology of the condition is also important for its treatment.Among various etiologies,the genetic factors,especially mutations of ion channel genes,are very common and strongly linked to West syndrome.Case presentation:A boy who had epileptic spasms from the age of 4 months was diagnosed with West syndrome based on the clinical manifestation and EEG results in Shenzhen Children's Hospital in June 2019.Trios whole-exome sequencing(WES)test and protein structural model prediction were performed.We also reviewed the clinical and genetic features of this syndrome and the mechanisms of action of topiramate(TPM)by literature search in databases of Online Mendelian Inheritance in Man,Clinical Genome Resource,PubMed,Chinese National Knowledge Infrastructure and Wanfang database using keywords"KCNA2""West syndrome"and"Topiramate"by December 2020.The relationship between the effect of TPM and the pathogenesis of the KCNA2 variant was also assessed.The WES test revealed c.244C>T/p.Arg82Cys varaint of KCNA2(NM_004974.3)in this patient,and Sanger sequencing identified this was a de novo mutation.As far as we know,this is the first report of the C.244C>T/p.Arg82Cys variant in KCNA2,which was likely a pathogenic mutation.The seizures were successfully controlled for 10 months by TPM after failure of sodium valproate,large doses of vitamin B6,and adrenocorticotropic hormone.We speculate that the therapeutic effect of TPM in this patient is partially due to the inhibition of carbonic anhydrase.Conclusions:Mutations in the KCNA2 gene should be considered for patients with West syndrome.The TPM treatment is probably effective for KCNA2-associated disorders.展开更多
基金partly supported by Turkish Neurosurgical Society
文摘Topiramate（TPM） is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury（SCI）. After rat models of thoracic contusive SCI were established by free weight-drop method, TPM（40 mg/kg） was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.
文摘Drug-induced peripheral neuropathy had been rarely reported as an adverse effect of some antiepileptic drugs(AEDs) at high cumulative doses or even within the therapeutic drug doses or levels.We describe clinical and diagnostic features of a patient with peripheral neuropathy as an adverse effect of chronic topiramate(TPM) therapy.A 37-year-old woman was presented for the control of active epilepsy(2010).She was resistant to some AEDs as mono-or combined therapies(carbamazepine,sodium valproate,levetiracetam,oxcarbazepine and lamotrigine).She has the diagnosis of frontal lobe epilepsy with secondary generalization and has a brother,sister and son with active epilepsies.She became seizure free on TPM(2013-2017) but is complaining of persistent distal lower extremities paresthesia in a stocking distribution.Neurological examination revealed presence of diminished Achilles tendon reflexes,stocking hypesthesia and delayed distal latencies,reduced conduction velocities and amplitudes of action potentials of posterior tibial and sural nerves,indicating demyelinating and axonal peripheral neuropathy of the lower extremities.After exclusion of the possible causes of peripheral neuropathy,chronic TPM therapy is suggested as the most probable cause of patient's neuropathy.This is the first case report of topiramate induced peripheral neuropathy in the literature.
文摘BACKGROUND: It has been demonstrated that traditional antiepileptics, such as phenytoin, carbamazepine (CBZ), phenobarbital, etc., can result in the decrease of thyroid hormone of epileptic patients. However, there is still no sufficient evidence for the studies about the effect of new-type antiepileptics, such as topiramate (TPM), on thyroid hormones. OBJECTIVE: To observe the effects of TPM and CBZ on the level of thyroid hormones in serum of adults with epilepsy. DESIGN: A comparative observation. SETTING: Department of Neurology, Sichuan Provincial People's Hospital. PARTICIPANTS: Totally 100 outpatients or inpatients newly diagnosed to have epilepsy were selected from the Department of Neurology, Sichuan Provincial People's Hospital from July 2003 to August 2005, including 60 males and 40 females, aged 18-70 years. All the patients were accorded with the standard for the classification of epilepsy set by International League Against Epilepsy (ILAE) in 1981; Had been Informed and agreed with the detection; Had no history of thyroid gland disease; Had not taken any drugs could affect the thyroid function. Meanwhile, 40 adult healthy examinees were selected from our hospital as the control group, including 24 males and 16 females, aged 18-65 years. METHODS: ① The 100 epileptic patients were randomly divided into TPM group (n =50) and CBZ group (n =50), and they were treated with TPM (Xian-Janssen Pharmaceutical, Ltd.; Batch number: 03AS032, Norm: 25 mg/tablet) and CBZ (Shanghai Sunve Pharmaceutical Co., Ltd.; Batch number: 030201, Norm: 100 mg/tablet) respectively. The initial dosage of TPM was 25 mg per day, increased by 25 mg every week, the objective dosage of 100-200 mg per day was maintained when the symptoms were satisfactorily controlled. The dosage of CBZ was 6-8 mg/kg per day. All the patients were administrated for 1 year. ② The serum levels of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) in the epileptic patients were detected by means of chemiluminescence before treatment and at 3, 6 and 12 months after treatment respectively. ③Standards for judging curative effects: Controlled by without seizure, the frequency of seizure reduced by ≥ 75% was taken as significant effect, reduced by 50%-74% as effect, and reduced by < 49% as invalid, whereas increased by more than 20% was taken as aggravation. ④ The intergroup and intragroup differences of the measurement data were compared by the analysis of variance and paired t test respectively. MAIN OUTCOME MEASURES: Serum levels of thyroid hormones before treatment and at different time points after treatment of TPM and CBZ. RESULTS: All the 100 epileptic patients and 40 healthy subjects were involved in the analysis of results. ① Changes of serum levels of thyroid hormones: The serum levels of TT3, TT4, FT3, FT4 and TSH were close between the epileptic patients and normal subjects before treatment (P > 0.05). In the CBZ group, the serum levels of FT4 at 3, 6 and 12 months after treatment [(16.87±3.77), (16.34±3.98) , (16.97±3.95) pmol/L] were significantly decreased as compared with those before treatment [(18.00±3.54) pmol/L, t =2.74, 3.50, 2.26, P < 0.05]; The levels of TT3 at 3, 6 and 12 months [(2.09±0.54), (1.99±0.49), (1.84±0.47) nmol/L] were significantly decreased as compared with those before treatment [(2.22±0.63) nmol/L, t =2.73, 2.78, 5.18, P < 0.05]. The levels of TT3 at 6 and 12 months [(109.65±23.98), (107.72±23.90) nmol/L] were significantly decreased as compared with those before treatment [(118.98±28.48) nmol/L, t =3.11, 3.30, P < 0.05]. TT4 level in serum at 3 months and the levels of FT3 and TSH at each time point after CBZ treatment had no obvious changes as compared with those before treatment (P > 0.05). In the TPM group, the levels of thyroid hormones at each time point had no obvious changes as compared with those before treatment (P > 0.05). ② Curative effects: Of the 100 epileptic patients, it was controlled in 12 cases, significantly effective in 30 cases, effective in 39 cases and invalid in 19 cases, the total effective rate was 81% (81/100). CONCLUSION: CBZ treatment can lead to the decreases of thyroid hormones in adult epileptic patients. Epilepsy itself and TPM treatment cannot change the thyroid hormones in adult epileptic patients, which suggests that TPM treatment is safer for the thyroid function of adult epileptic patients.
文摘OBJECTIVE：To evaluate the treatment effects and safety of topiramate in migraine prophylaxis. DATA RETRIEVAL：We searched the Medline database,EMbase,Cochrane Library and China National Knowledge Infrastructure database for articles published between January 1995 and May 2011,using the key words＂migraine＂,＂topiramate＂,and＂prophylaxis＂. SELECTION CRITERIA：We selected randomized controlled trials of migraine patients,in which the experimental group was orally administered topiramate,and the control group was given placebo. Odds ratios（ORs）and mean differences（MDs）were calculated using a fixed effects model/random effects model.Quality evaluation and data extraction were performed independently by two researchers utilizing RevMan 5.0 software. MAIN OUTCOME MEASURES：Efficacy was recorded as the responder rate（response defined as at least a 50%reduction in average monthly migraine frequency）and change in mean monthly number of migraine days.Adverse events were recorded as the number of subjects exhibiting at least one adverse event. RESULTS：Eight randomized controlled trials were found to be appropriate,and had available data. The meta-analysis results revealed that topiramate（100 or 200 mg/d）was more effective than placebo in responder rate（OR=2.97,95%confidence interval（CI）：2.17-4.08,P〈0.01;OR=2.35, 95%CI：1.77-3.12,P〈0.01）.Topiramate（100 mg/d）was more effective than placebo in terms of the change in mean monthly migraine days（MD：-1.14,95%CI：-1.69 to-0.59,P〈0.01）.The total incidence rate of adverse events for topiramate was higher than in the placebo group（P〈0.01）,but most adverse events were mild to moderate. CONCLUSION：Overall,topiramate obtained good outcomes and safety in migraine prophylaxis.
基金Foundation for the Returned Overseas Chinese Scholars, Guangxi Science and Technology Committee, No. 0342012
文摘BACKGROUND： Apoptosis plays an important role in brain injury after seizures and the formation of chronic epilepsy. It is important to investigate whether topiramate exhibits either antiepileptic and/or antiapoptotic effects on hippocampal neurons. OBJECTIVE： To observe neuronal apoptosis in hippocampus of rat seizure models, and to investigate the antagonizing effect of topiramate on neuronal apoptosis after seizures. DESIGN： An animal experiment of comparative observation. SETTING： First Affiliated Hospital of Guangxi Medical University. MATERIALS： Sixty healthy male Sprague Dawley （SD） rats, 4-6 weeks old and weighing 160-220 g, were provided by the Experimental Animal Center of Guangxi Medical University. Main apparatus and reagents were as follows： Rat brain solid positioner （SR-6N, made in Japan）; kainic acid by Sigma （USA）; pathological image analyzer （DMR＋550） by Leica （Germany）; in situ apoptosis detection kit by Wuhan Boster Biological Technology Co., Ltd; topiramate by Xi＇an-Janssen Pharmaceutical, Ltd. The treatment on animals in the experiment was in accordance with the standards of animal ethics. METHODS： The experiments were performed at the Scientific Experimental Center of Guangxi Medical University from June to December 2006. The rats were randomly divided into a topiramate-treated group （n = 30） and a model group （n = 30）. ① After anesthesia, all rats were administered a kainic acid injection （0.2 μL, 2 g/L） into the right lateral ventricle. Grade Ⅲ and greater Racine standards were considered to be a successful model establishment. Thirty minutes after seizure , rats in the topiramate-treated group were treated with an intraperitoneal （i.p.） injection of topiramate every day （40 mg/kg/d） for 2 weeks. The rats in the model group were treated with an equal volume of saline for 2 weeks. ③ Six rats in the topiramate-treated group were sacrificed at 1 day, and 1, 2, 3, and 4 weeks after treatment, respectively. The model group animals were sacrificed at corresponding time points. The brain tissues of hippocampal dentate gyrus, CA1, CA2, and CA3 region were removed and prepared into sections. Neuronal apoptosis was detected with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling. MAIN OUTCOME MEASURES： Hippocampal neuronal apoptosis in various rat brain areas was detected in the two groups. RESULTS： All 60 rats were included in the final analysis of results. In the topiramate-treated group, the number of apoptotic cells in hippocampal dentate gyrus and CA3 region at 1 day, 1, and 4 weeks after seizures were significantly lower than the model group （P 〈 0.05-0.01）. The number of apoptotic cells in hippocampal CA1 and CA2 regions at 1 day and 4 weeks after seizures in the topiramate-treated group were significantly lower than the model group （P 〈 0.05）. CONCLUSION： Hippocampal apoptosis is closely associated with kainic acid-evoked seizures, and topiramate can alleviate early （1 day and 1 week） and delayed （4 weeks） hippocampal neuronal injury induced by kainic acid.
基金the National Natural Science Foundation of China(81400957)
文摘Paroxysmal kinesigenic dyskinesia(PKD)is presented as a short paroxysmal attack of focal or generalized involuntary movement.The most common treatments for PKD are carbamazepine and phenytoin.Though the cases of clinically diagnosed PKD with a good response to topiramate have been already reported,this patient was unique in several ways.Here,we reported the case of a 24-year-old patient with PKD for one year,and described the pathogenesis of PKD.
文摘The use of generic formulation of therapeutic agents may allow a significant reduction of costs for patients and the National Health Services. This is particularly true for drugs used in prolonged therapies such as topiramate which is effective in the treatment of epilepsy, migraine, alcohol abuse and psychiatric conditions. The purposes of this study were: 1) evaluate Topiramate (50 mg) release in vitro from a generic (Sincronil) and the reference formulation (Topamax);2) compare the above mentioned generic and reference formulations in bioavailability studies in healthy volunteers. Dissolution tests in vitro showed that more than 95% of the active principle was released within 15 minutes both from the reference and the generic formulation. No difference in release kinetics was found between the two topiramate preparations. In vivo pharmacokinetic data were obtained by administering 1 tablet containing 50 mg of topiramate of each of the two formulations to 28 healthy volunteers under fasting conditions, using a randomized, single-dose, open-label, 2-way crossover design. The treatment phases were separated by a washout period of 21 days. The maximum concentration reached in plasma (Cmax) for the reference and the generic formulation, were 946 ± 308 and 849 ± 247 (ng/mL) and the area under the curve (AUC0-t) were 35,900 ± 7800 and 34,300 ± 8100 (ng·h/mL) respectively. The data indicate that the rate and extent of absorption of the reference or generic 50 mg topiramate formulation are not significantly different and suggest that the therapeutic effects of the two preparations do not significantly differ.
文摘BACKGROUND： Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is one of the important transmitters for alcohol tolerance in central nervous system. OBJECTIVE： To observe the changes of excitatory amino acids in hippocampal dentate gyrus in rats with long-term alcohol drinking after withdrawal under consciousness, and investigate the therapeutic effect of topiramate on alcohol withdrawal. DESIGN ： A randomized control animal experiment SETTING ： Department of Neurology, Affiliated Hospital of Yanbian University MATERIALS： Thirty male Wistar rats of 4 months old, weighing 300-350 g, were purchased from the Experimental Animal Department, Medical College of Yanbian University. Topiramate was produced by Swish Cilag Company, and the batch number was 02CS063. METHODS： The experiments were carried out in the Department of Physiology, Medical College of Yanbian University from August 2005 to February 2006. ① The rats were divided randomly into three groups： control group （n=10）, alcohol group （n=10） and topiramate-treated group （n=10）. Rats in the alcohol group and topiramate-treated group were given intragastric perfusion of 500 g/L alcohol （10 mL/kg）, once a day for 4 weeks successively, and then those in the topiramate-treated group were treated with 80 mg/kg topiramate at 24 hours after the last perfusion of alcohol, once a day for 3 days successively. Rats in the control group were intragastricly given isovolume saline. ② The withdrawal symptoms were assessed at 6, 30, 48 and 72 hours after the last perfusion of alcohol by using the withdrawal rating scale set by Erden et al, which had four observational indexes of stereotyped behaviors, agitation, tail stiffness and abnormal posture, each index was scored by 5 points, the higher the score, the more obvious the symptoms. ③ The contents of aspartic acid and glutamic acid in hippocampal dentate gyrus were detected with microdialysis technique and high-performance liquid chromatograpy （HPLC） respectively at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the three groups. MAIN OUTCOME MEASURES ： ① Scoring results of alcohol withdrawal symptoms; ② Changes of the contents of aspartic acid and glutamic acid in hippocampal dentate gyrus at the alcohol withdrawal symptoms, and the effects of topiramate. RESULTS： Seven rats were excluded due to inaccurate localization and natural death, and 23 rats were involved in the analysis of results. ①In the alcohol group, the scores of alcohol withdrawal symptoms at 30 and 48 hours after the last perfusion of alcohol were obviously higher than those in the control group （10.50±0.96, 14.17±1.25; 3.50±0.92, 3.16±0,31; P 〈 0.01）. In the topiramate-treated group, the scores at 30 hours after the last perfusion of alcohol （6.06±0.82, 3.50±0.92, P 〈 0.05）, and the withdrawal scores at 48 and 72 hours were close to those in the control group （4.57±0.58, 3.30±0.71; 3.16±0.31, 3.66±0.67; P 〉 0.05）.② Changes of the contents of glutamic acid in hippocampal dentate gyrus： In the alcohol group, the content of glutamic acid at 48 hours after the last perfusion of alcohol was significantly increased as compared with that at 6 hours [（143.32±11.42）%, （99.12±0.69）%; P 〈 0.05], and that at 72 hours was close to that at 6 hours [（78.50±16.40）%, （99.12±0.69）%; P 〉 0.05]. The contents of glutamic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [（100.30±0.37）%, （118.91±10.40）%, （99.55±12.81）%, （99.08±11.42）%; P 〉 0.05], The content of glutamic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group （P 〈 0.05）, and those at 30 and 72 hours were close （P 〉 0.05）. ③ Changes of the contents of aspartic acid in hippocampal dentate gyrus： In the alcohol group, the contents of aspartic acid at 30 and 48 hours after the last perfusion of alcohol were significantly increased as compared with that at 6 hours [（126.60±8.67）%, （129.17±10.40）%, （99.25±0.87）%; P 〈 0.05], and that at 72 hours was close to that at 6 hours [（89.87±9.93）%, （99.25±0.87）%; P 〉 0.05]. The contents of aspartic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [（100.27±0.32）%, （120.81 ±12.63）%, （98.91±7.83）%, （85.92±8.07）%; P 〉 0.05]. The content of aspartic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group （P 〈 0.05）, and those at 30 and 72 hours were close （P 〉 0.05）. CONCLUSION： ① The occurrences of alcohol withdrawal symptoms are correlated with the increased contents of excitatory amino acids in hippocampal dentate gyrus in rats. ② Topiramate can alleviate the alcohol withdrawal symptoms, which may be correlated with the decreased contents of excitatory amino acids in hippocampal dentate gyrus in rats.
文摘Background Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate monotherapy (TPM control IS). Methods The clinical manifestations, treatment processes and outcomes were analyzed in 11 pyridoxine responsive IS and 17 TPM-control IS. Results Of the 11 patients with pyridoxine responsive IS, nine were cryptogenic/idiopathic. Age of seizure onset was 5.36 ± 1.48 months. Spasms were controlled within a week in most of the patients. At the last follow-up, EEG returned to normal in 8. Psychomotor development was normal in 6, mild delay in 3, severe delay in 2. Of the 17 patients with TPM-control IS, 10 were cryptogenic/idiopathic. The age of seizure onset was 5.58 ± 2.09 months. All patients were controlled within a month. At the last follow-up, EEG was normal in 10. Psychomotor development was normal in 8, mild delay in 5, severe delay in 4. Genetic analysis did not show any meaningful results. Conclusions The clinical characteristics and disease courses of pyridoxine responsive IS and TPM-control IS were similar, which possibly clued for a same pathogenic mechanism. Pyridoxine should be tried first in all IS patients, even in sympto-matic cases. If patients were not responsive to pyridoxine, TPM could be tried.
文摘Adrenocorticotropic hormone is recommended worldwide as an initial therapy for infantile spasms. However, infantile spasms in about 50% of children cannot be fully controlled by adrenocorticotropic hormone monotherapy, seizures recur in 33% of patients who initially respond to adrenocorticotropic hormone monotherapy, and side effects are relatively common during adrenocorticotropic hormone treatment. Topiramate, vitamin B6, and immunoglobulin are effective in some children with infantile spasms. In the present study, we hypothesized that combined therapy with adrenocorticotropic hormone, topiramate, vitamin B6, and immunoglobulin would effectively treat infantile spasms and have mild adverse effects. Thus, 51 children newly diagnosed with West syndrome including infantile spasms were enrolled and underwent polytherapy with the four drugs. Electroencephalographic hypsarrhythmia was significantly improved in a majority of patients, and these patients were seizure-free, had mild side effects, and low recurrence rates. The overall rates of effective treatment and loss of seizures were significantly higher in cryptogenic children compared with symptomatic children. The mean time to loss of seizures in cryptogenic children was significantly shorter than in symptomatic patients. These findings indicate that initial polytherapy with adrenocorticotropic hormone, topiramate, vitamin Be, and immunoglobulin effectively improves the prognosis of infantile spasms, and its effects were superior in cryptogenic children to symptomatic children.
文摘A simple, rapid, specific and precise liquid chromatography—tandem mass spectrophotometric (LC-MS/MS) method was developed and validated for the quantification of chiral separated R-bicalutamide from S-bicalutamide, in human plasma. Topiramate (TPM) was used as internal standard, added to plasma sample prior to extraction using t-butyl methyl ether (TBME). Chromatographic separation was achieved on CHIRALPAK AD-RH column (150 mm×4.6 mm, 5 μm) with acteonitrile: 0.1% formic acid Buffer (50:50 v/v) as an isocratic mobile phase with a flow rate of 1.0 mL·min-1. Quantitation was performed by transition of 429.0 → 255.0 (m/z) for R-bicalutamide and 338.1 → 77.8 (m/z) for topiramate. The lower limit of quantitation was 20 ng·mL-1with a 100 μL plasma sample. The concentrations of eight working standards showed linearity between 20 to 3200 ng·mL-1(r2≥ 0.9990). Chromatographic separation was achieved within 6 min, compared to the 15 min of previous methods. The average extraction recoveries of 3 quality control concentrations were 98.56% for R-bicalutamide and 92.42% for topiramate. The coefficient of variation was ≤15% for intra- and inter-batch assays. Therefore a rapid, specific and sensitive LC-MS/MS method for the quantification of R-bicalutamide in human plasma was developed and validated can be used in the bioequivalence study of this drug.
基金This study was sponsored by the Sanming Project of Medicine in Shenzhen(SZSM 201812005)Shenzhen Key Medical Discipline Construction Fund(SZXK033)+1 种基金Epilepsy Research Fund of China Association Against Epilepsy(CU-C-2021-02)Support Project for Clinical Research of Young and Middle-aged Doctors in South of the Ten Ridges Neurology(Z20210308).
文摘Background:West syndrome is a devastating disorder characterized by a triad of epileptic spasms,abnormal electroencephalography(EEG),and developmental arrest or psychomotor delay.In addition to early diagnosis,knowing the etiology of the condition is also important for its treatment.Among various etiologies,the genetic factors,especially mutations of ion channel genes,are very common and strongly linked to West syndrome.Case presentation:A boy who had epileptic spasms from the age of 4 months was diagnosed with West syndrome based on the clinical manifestation and EEG results in Shenzhen Children's Hospital in June 2019.Trios whole-exome sequencing(WES)test and protein structural model prediction were performed.We also reviewed the clinical and genetic features of this syndrome and the mechanisms of action of topiramate(TPM)by literature search in databases of Online Mendelian Inheritance in Man,Clinical Genome Resource,PubMed,Chinese National Knowledge Infrastructure and Wanfang database using keywords"KCNA2""West syndrome"and"Topiramate"by December 2020.The relationship between the effect of TPM and the pathogenesis of the KCNA2 variant was also assessed.The WES test revealed c.244C>T/p.Arg82Cys varaint of KCNA2(NM_004974.3)in this patient,and Sanger sequencing identified this was a de novo mutation.As far as we know,this is the first report of the C.244C>T/p.Arg82Cys variant in KCNA2,which was likely a pathogenic mutation.The seizures were successfully controlled for 10 months by TPM after failure of sodium valproate,large doses of vitamin B6,and adrenocorticotropic hormone.We speculate that the therapeutic effect of TPM in this patient is partially due to the inhibition of carbonic anhydrase.Conclusions:Mutations in the KCNA2 gene should be considered for patients with West syndrome.The TPM treatment is probably effective for KCNA2-associated disorders.
