Protective effect and mechanism of zonisamide on oxygen-glucose deprivation cell model of traumatic brain injury / 中华急诊医学杂志

Objective:To explore the protective effect of zonisamide (ZNS) on oxygen-glucose deprivation (OGD) cell model of traumatic brain injury (TBI), and its underlying mechanism.Methods:Human neuroblastoma cells (SH-SY5Y) were cultured in vitro and divided into the control group, OGD group, and drug administration group (OGD+ZNS group) according to the random number table method. The OGD method was used to establish a TBI cell model. After modeling, the cell activity, the release of lactate dehydrogenase (LDH), and β-galactosidase staining were detected to evaluate cell function and senescence. Additionally, mitochondrial morphology and potential membrane changes were observed using Mito Tracker Red and JC-1 mitochondrial membrane potential staining. ATP concentration was measured, and protein was extracted from SH-SY5Y cells and then subjected to Western blot analysis to detect endoplasmic reticulum stress-related markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), protein disulfide isomerase (PDI), and β-actin.Results:The OGD group had a significantly lower cell survival rate compared to the control group ( P<0.01), while the OGD+ZNS group had a significant higher cell survival rate than the OGD group ( P<0.01). The LDH release rate was significantly higher in the OGD group than in the control group ( P<0.01), while the OGD+ZNS group had a significant lower LDH release rate compared to the OGD group ( P<0.01). Moreover, the cell staining results indicated that compared to the control and OGD+ZNS groups, the cells in the OGD group exhibited significant damage and senescence with darker staining while the mitochondrial staining results demonstrated a significant reduction in mitochondrial linear junctions and decreased mitochondrial activity in the OGD group compared to the control and OGD+ZNS groups. Compared to the control and OGD+ZNS groups, the OGD group exhibited a significant reduction in mitochondrial staining red fluorescence, a significant increase in green fluorescence, and a significant decrease in mitochondrial membrane potential. The OGD group demonstrated a significant decrease in ATP concentration compared to the control group ( P<0.01), whereas the OGD+ZNS group exhibited a significant higher ATP concentration compared to the OGD group ( P<0.01). Western blot analysis revealed significant upregulation of GRP78, CHOP, and PDI in the OGD group compared to the control group (all P<0.05), while in the OGD+ZNS group, the expression levels of these proteins were significantly downregulated compared to the OGD group (all P<0.05). Conclusions:Zonisamide can protect OGD TBI cell model by preserving mitochondrial activity and inhibiting endoplasmic reticulum stress.

Neuroprotective effects of zonisamide on cerebral ischemia injury via inhibition of neuronal apoptosis

It is known that neuronal apoptosis contributes to pathology of cerebral ischemia injury. Zonisamide (ZNS) has shown anti-apoptosis effects in recent studies. The present study investigated whether the anti-apoptotic effect can account for the neuroprotective action of ZNS on cerebral ischemia. Neuronal cells were maintained under oxygen-glucose deprivation conditions to simulate cerebral ischemia and treated with ZNS simultaneously. The apoptosis of the cells and expression of apoptosis-related proteins were investigated by flow cytometry and western blot analysis, respectively. A cerebral ischemia mouse model was created via middle cerebral artery occlusion, and the mice were treated with ZNS. Neurological deficit scores and infarct volumes of the cerebral ischemia mice were measured. The apoptosis status of the neuronal cells was evaluated by TUNEL staining. In vitro, the ZNS treatment inhibited both the apoptosis of the neuronal cells and apoptosis-related protein expression (caspase-3, caspase-8, and calpain-1) induced by the oxygen-glucose deprivation. The anti-apoptosis effect of ZNS could occur through the blocking of reactive oxygen species. Moreover, ZNS treatment significantly ameliorated neurological deficits and reduced infarct volumes in the cerebral ischemia mice model. In this study, ZNS exerted neuroprotective effects by inhibition of apoptosis in neuronal cells in cerebral ischemia. Therefore, ZNS might be a promising therapy for cerebral ischemia.

Immunity function changes of zonisamide treatment on epilepsy children / 中国综合临床

Objective To estimate the immune function changes of zonisamide treatment as a new antiepileptic drug monotherapy on epileptic children.Methods Forty children with epilepsy (25 girls and 15 boys,aged from 1 to 6 years old) were enrolled in the Children' s Hospital of Hebei Province as our subjects and they were followed 3 and 6 months after treatment.The venous blood sample was collected respectively from the children on empty stomach.Applying automatic biochemical analyzer to detect serum immunoglobulin.IgG,IgA,IgM through immune turbidimetry methods.While CD3,CD4,CD8 were detected through the application of flow cytometry.Results Compared with the healthy control group,IgA,IgG,CD8 levels increased and the level of CD3,CD4 decreased in epileptic children and there were significant differences (F=160.94,262.66,539.09,634.36,164.27;P＜0.05).The level of IgM between epilepsy group and control group did not showed difference (P＞0.05).After 3 months and 6 months treatment of zonisamide,the level of IgA,IgG,CD8 were decreased,while CD3,CD4 levels increased than those in epilepsy group before treatment (P＜ 0.05).Conclusion Zonisamide may play a role of the antiepileptic mechanism by improving children' s immune function.

Effects of zonisamide on NO content and NOS activity in serum and brain tissue of epileptic rats / 天津医药

Objective To investigate the effect of zonisamide as a new antiepileptic drug on nitric oxide (NO) content and nitric oxide synthase (NOS) activity in serum and brain tissue of epileptic rats. Methods Eight healthy rats were used as normal control group, and twenty-four epileptic rats induced by pentrazol were randomly divided into epilepsy model group, zonisamide group and phenobarbital group. Levels of NO and malondialdehyde (MDA) content, NOS and superoxide dismutase (SOD) activity in serum and brain tissue were detected in four groups. Results Forty-two rats were injected pentrazol, and 35 (83%) rats were established the rat model successfully. Epileptic waves were visible in EEG of epileptic rats. The concentrations of NO, MDA and the activity of NOS in serum and brain were significantly increased, the activity of SOD was significantly decreased, in epileptic rats than those of control rats. The concentrations of NO and MDA were significantly increased; the activity of SOD was significantly decreased, in brain in phenobarbital group compared with those of control group. There were significantly lower levels of NO, MDA and NOS, and significantly higher level of SOD in serum and brain tissue in zonisamide group and phenobarbital group than those of epileptic model group (P＜0.05). Conclusion Zonisamide plays an antiepileptic role by reducing the concentration of NO in brain of epileptic rats.

A Case of Zonisamide-Induced Stevens-Johnson Syndrome / 대한내과학회지

Stevens-Johnson syndrome (SJS) is a rare but severe disorder typically caused by medications and characterized by mucocutaneous eruptions. Zonisamide is an antiepileptic drug that is structurally different from other drugs of the same class. It is considered safe for patient use, and few cases describing severe cutaneous adverse reactions from zonisamide have been reported. We herein report a case of zonisamide-induced SJS in a 36-year-old woman. The patient presented with a widespread erythematous maculopapular rash after taking zonisamide. The symptoms of SJS improved after zonisamide was discontinued and systemic steroids and intravenous immunoglobulins were administered. This is the first case of zonisamide-induced SJS in Korea. Although this drug is generally considered safe, we suggest that clinicians be aware of potential adverse reactions, including SJS.

Zonisamide in the Treatment of Obesity: A Meta-Analysis.

Incidence of obesity continues to rise worldwide with each year especially in developed countries. On the other hand success achieved with pharmacotherapy of obesity is disappointing, with some of the unmet needs in management strategies for obesity. Zonisamide an anti-epileptic drug has been found to have significant weight reduction properties with favorable safety profile. Present meta-analysis has been done with the aim of analyzing the efficacy of zonisamide in obesity. Electronic data bases were searched for all types of studies related to use of zonisamide in obesity and binge eating disorder. Change in body weight following treatment with zonisamide was the primary outcome measure analyzed. Both fixed and random effect models were used for statistical analysis of the data. With total 111 patients analyzed from 3 eligible studies; a significant reduction in weight from baseline by 5.88 kg (MD: -5.88; 95% CI:-7.51 to -4.25) at 16 weeks could be expected by treatment with zonisamide. As the data on safety profile of zonisamide especially long term was either incomplete or not available, analysis of safety profile was not carried out. Future studies analyzing the efficacy and long term safety of zonisamide on large population and for long term are preferred.

Determination of furosemide and zonisamide as a drug substance and in dosage form by ion pair - reversed phase liquid chromatographic technique.

An isocratic, selective, and accurate Ion pair - reversed phase liquid chromatographic method of analysis of Furosemide and Zonisamide both as a bulk drug and formulations was developed and validated. An ODS chromatographic column (250mmx4.6mm, 5μm) was used for the separation. The mobile phase consisted of a mixture of methanol and Tetrabutyl ammonium hydrogen sulphate (TBHS) 0.035 molar aqueous solution, pH adjusted to 6.0 using 1 N sodium hydroxide solution. The composition of TBHS with methanol used for Furosemide was 40:60(v/v) and that for Zonisamide was 50:50(v/v) delivered at a flow rate of 1.0ml/min and detection at wave length 240 nm. The developed method was validated in terms of selectivity, Linearity, limit of quantitation, precision, accuracy and solution stability. The proposed LC method achieved satisfactory resolution between Furosemide and 4-Chloro-5-sulphamoyl salicylic acid (CSSA), Zonisamide and CSSA an intermediate product possibly present in Furosemide and Zonisamide. The method can be employed as stability indicating method for both the drugs furosemide and zonisamide and its dosage form.

Zonisamide Changes Unilateral Cortical Excitability in Focal Epilepsy Patients

BACKGROUND AND PURPOSE: To evaluate changes in cortical excitability induced by zonisamide (ZNS) in focal epilepsy patients. METHODS: Twenty-four drug-nasmall yi, Ukrainianve focal epilepsy patients (15 males; overall mean age 29.8 years) were enrolled. The transcranial magnetic stimulation parameters obtained using two Magstim 200 stimulators were the resting motor threshold, amplitude of the motor-evoked potential (MEP), cortical silent period, short intracortical inhibition, and intracortical facilitation. These five transcranial magnetic stimulation parameters were measured before and after ZNS, and the findings were compared. RESULTS: All 24 patients were treated with ZNS monotherapy (200-300 mg/day) for 8-12 weeks. After ZNS, MEP amplitudes decreased (-36.9%) significantly in epileptic hemispheres (paired t-test with Bonferroni's correction for multiple comparisons, p0.05). ZNS did not affect cortical excitability in nonepileptic hemispheres. CONCLUSIONS: These findings suggest that ZNS decreases cortical excitability only in the epileptic hemispheres of focal epilepsy patients. MEP amplitudes may be useful for evaluating ZNS-induced changes in cortical excitability.

Zonisamide Changes Unilateral Cortical Excitability in Focal Epilepsy Patients

BACKGROUND AND PURPOSE: To evaluate changes in cortical excitability induced by zonisamide (ZNS) in focal epilepsy patients. METHODS: Twenty-four drug-nasmall yi, Ukrainianve focal epilepsy patients (15 males; overall mean age 29.8 years) were enrolled. The transcranial magnetic stimulation parameters obtained using two Magstim 200 stimulators were the resting motor threshold, amplitude of the motor-evoked potential (MEP), cortical silent period, short intracortical inhibition, and intracortical facilitation. These five transcranial magnetic stimulation parameters were measured before and after ZNS, and the findings were compared. RESULTS: All 24 patients were treated with ZNS monotherapy (200-300 mg/day) for 8-12 weeks. After ZNS, MEP amplitudes decreased (-36.9%) significantly in epileptic hemispheres (paired t-test with Bonferroni's correction for multiple comparisons, p0.05). ZNS did not affect cortical excitability in nonepileptic hemispheres. CONCLUSIONS: These findings suggest that ZNS decreases cortical excitability only in the epileptic hemispheres of focal epilepsy patients. MEP amplitudes may be useful for evaluating ZNS-induced changes in cortical excitability.

A Case of Epilepsy Exhibiting a Severe, Dose-Dependent, Memory Deficit after Zonisamide Administration / 대한간질학회지

Zonisamide (ZNS) has been proven as a safe, effective, and well-tolerated antiepileptic drug. We report an epilepsy patient who had a severe, dose-dependent, memory deficit after ZNS administration. A 65-year-old man visited our epilepsy clinic due to the occurrence of nocturnal convulsions. Despite the absence of seizures, he developed a severe impairment of verbal and visual memory functions after the increment of ZNS dosage from 200 mg/day to 300 mg/day. We substituted 1,000 mg/day valproic acid for ZNS. His cognitive performances were returned to original levels.

Long-Term Efficacy and Safety of Zonisamide Monotherapy in Epilepsy Patients

BACKGROUND AND PURPOSE: Zonisamide (ZNS) is a useful antiepileptic drug with a broad therapeutic spectrum. However, there is limited information on the long-term use of ZNS as a monotherapy. This study investigated the long-term effects of ZNS as a monotherapy for the treatment of epilepsy. METHODS: We retrospectively analyzed the records of epilepsy patients treated with ZNS monotherapy at our clinic. We identified outcomes for patients treated with ZNS monotherapy for a minimum of 6 months. Efficacy was quantified as the percentage change in seizure frequency, and safety was assessed by the frequency and types of adverse events. RESULTS: Sixty patients who received ZNS for a minimum of 6 months were included. The mean duration of treatment was 19.8 months (range, 6-37 months), and the mean ZNS dosage was 255 mg/day (range, 100-500 mg/day). Twenty-seven patients (45%) were seizure-free, and an additional 20 patients (33%) had above 50% seizure frequency reduction at the last follow-up visit. Partial seizures with or without secondary generalization and generalized seizures were well controlled by ZNS, whereas complex partial seizures were not. Forty-eight patients (80%) reported mild-to-moderate adverse events, including memory loss (35%), attention deficit (27%), and weight loss (20%). CONCLUSIONS: Long-term ZNS monotherapy is effective at treating a broad spectrum of seizure disorders, except complex partial seizures. However, a specific adverse event, such as cognitive impairment, is common and long-lasting.

A Case of Renal stones during treatment with Zonisamide

Following its approval in Japan, zonisamide (Excegran ) has been accepted as a new antiepileptic drug having broad spectrum activity. However, it does not have marketing approval in the US. Clinical trials were suspended in the US because of the high incidence of renal stone development (3.7%). We experienced a case of renal calculus which was identified during the course of zonisamide treatment. We believe this is the first case report of renal stone development suspecting the causal relation to the zonisamide treatment in Korea.

The effect of zonisamide in children with refractory epilepsies

Zonisamide was administered to 20 patients with refractory epileptic seizures. The mean duration of the administration was 6 months, and the mean dosage was 7.2 mg/kg/day. The efficacy of zonisamide was rated remarkable in 15% of the cases, improvement in 40%, and no change in 45%. The response rates of zonisamide were 62.5% for myoclonic seizures, 50% for tonic-clonic seizures, 80% for atonic seizures and 33.3% for atypical absence seizures. There was no correlation between the clinical response and dose or serum concentration of the drug. The adverse effects were observed in 35% of the cases which were drowsiness, dizziness, ataxia, nausea, and vomiting. In all cases, however, the administration of zonisamide could be continued.