RESUMO
OBJECTIVES: To describe and validate an isotope dilution-liquid chromatograph-tandem mass spectrometry (ID-LC-MS/MS) based reference measurement procedure (RMP) for zonisamide to accurately measure serum and plasma concentrations. METHODS: Quantitative nuclear magnetic resonance (qNMR) spectroscopy was employed to determine the absolute content of the reference material used in order to establish traceability to SI units. Separation of zonisamide from known or unknown interferences was performed on a C8 column. For sample preparation a protocol based on protein precipitation in combination with a high dilution step was established. Assay validation and determination of measurement uncertainty were performed based on guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the expression of uncertainty in measurement. RESULTS: The RMP was proven to be highly selective and specific with no evidence of a matrix effect, allowing for quantification of zonisamide within the range of 1.50-60.0⯵g/mL. Intermediate precision was <1.4â¯% and repeatability CV ranged from 0.7 to 1.2â¯% over all concentration levels. The relative mean bias ranged from 0.0 to 0.8â¯% for native serum levels and from 0.2 to 2.0â¯% for Li-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment ranged from 1.1 to 1.4â¯% and 0.8-1.0â¯%, respectively. CONCLUSIONS: We present a novel LC-MS/MS-based candidate RMP for zonisamide in human serum and plasma which provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples.
Assuntos
Isoxazóis , Espectrometria de Massas em Tandem , Zonisamida , Humanos , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Zonisamida/sangue , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Isoxazóis/sangue , Padrões de Referência , Técnicas de Diluição do Indicador , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.
Assuntos
Anticonvulsivantes , Bloqueadores dos Canais de Cálcio , Cardiomegalia , Quinase 3 da Glicogênio Sintase , Complexo de Endopeptidases do Proteassoma , Zonisamida , Animais , Camundongos , Ratos , Proteínas Quinases Ativadas por AMP/metabolismo , Cardiomegalia/tratamento farmacológico , Quinase 3 da Glicogênio Sintase/farmacologia , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Zonisamida/farmacologia , Zonisamida/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêuticoRESUMO
BACKGROUND: Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. METHODS: PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment. RESULTS: Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. CONCLUSION: ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04182399, in 24/11/2019.
Assuntos
Doença de Parkinson , Humanos , Zonisamida/uso terapêutico , Doença de Parkinson/complicações , Qualidade de Vida , Estudos Cross-Over , Tremor/complicaçõesRESUMO
The objective of this article is to describe a case of suspected zonisamide-induced immune-mediated polyarthritis (IMPA) and anterior uveitis in a dog. A 7-year-old male neutered Siberian Husky with a history of refractory idiopathic epilepsy was presented for cluster seizures. Following the addition of zonisamide to the antiepileptic regime, the dog developed new IMPA and anterior uveitis. Within a few weeks of discontinuation of the zonisamide, the dog's IMPA and anterior uveitis resolved. These immune-mediated conditions were thus presumed to be an idiosyncratic reaction to zonisamide. To our knowledge, this is the first report of IMPA and anterior uveitis in dogs associated with zonisamide administration at its recommended dose.
Assuntos
Artrite , Doenças do Cão , Epilepsia Resistente a Medicamentos , Compostos Organofosforados , Uveíte Anterior , Masculino , Cães , Animais , Zonisamida/efeitos adversos , Epilepsia Resistente a Medicamentos/veterinária , Isoxazóis/efeitos adversos , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Artrite/veterinária , Uveíte Anterior/induzido quimicamente , Uveíte Anterior/veterinária , Doenças do Cão/induzido quimicamente , Doenças do Cão/tratamento farmacológicoRESUMO
This study investigated the effects of zonisamide treatment on cerebellar tissues in an experimental alcohol addiction (AA) model and its potential mechanisms of action, particularly regarding apoptotic protease activating factor-1 (APAF-1) and tumor necrosis factor-alpha (TNF-α) expression. Thirty rats were divided into three groups: sham, ethanol (EtOH), and EtOH + zonisamide. AA was induced by administering 6 cc of EtOH orally every 8 h for 4 days. Zonisamide (100 mg/kg) was given to rats once daily before EtOH administration. Motor defects were evaluated using an open field maze. Serum TNF-α levels were measured from blood samples. Cerebellar sections were processed for histological examination and immunostained for APAF-1 and TNF-α. Protein interaction networks were constructed using Cytoscape, and functional annotations were performed with ShinyGO (version 0.80) software. The traveled area in the EtOH group was significantly reduced compared to the sham group (p = 0.0005). Rats in the EtOH + zonisamide group covered a larger area, with zonisamide treatment significantly improving locomotor ability compared to the EtOH group (p = 0.0463). Serum TNF-α levels were significantly elevated in the EtOH group compared to the sham group (p < 0.0001) and were significantly decreased in the EtOH + zonisamide group compared to the EtOH group (p = 0.0309). Regular cerebellar histological layers were observed in the sham group, while EtOH induction caused loss of cerebellar tissue integrity, neuronal degeneration, vascular dilatation and congestion, reduced myelin density, and neuropils in the EtOH group. Zonisamide treatment improved these pathologies, enhancing myelination and neuropil formation. Negative APAF-1 and TNF-α expressions were observed across cerebellar layers in the sham group. Due to EtOH toxicity, APAF-1 and TNF-α expression were upregulated in the EtOH group compared to the sham group (p < 0.001 for both). Zonisamide treatment downregulated these protein expressions in the EtOH + zonisamide group compared to the EtOH group (p < 0.001 and p = 0.0087, respectively). APAF-1 was primarily associated with AA through antifolate resistance, endopeptidases, and the interleukin-1 pathway, while TNF-α was predominantly enriched in infections and choline-binding, indicating zonisamide's impact on immune and inflammatory pathways. In conclusion, zonisamide treatment significantly mitigated ethanol-induced cerebellar damage and inflammation in an AA model. Zonisamide improved locomotor function and reduced serum TNF-α levels, as well as APAF-1 and TNF-α expression in cerebellar tissues. These findings suggest that zonisamide exerts its protective effects by modulating immune and inflammatory pathways, thereby preserving cerebellar integrity and function.
RESUMO
Zonisamide is used in dogs for the treatment of epileptic seizures. It is predominantly metabolised by CYP450 hepatic enzymes. When used concurrently with phenobarbital (PB), zonisamide clearance is increased and its elimination half-life decreases. However, the effect that zonisamide may have on serum PB concentrations in dogs has not been previously described. Eight dogs diagnosed with idiopathic epilepsy and two dogs with structural epilepsy commenced zonisamide at 8.0 mg/kg/12 h [7.4-10 mg/kg/12 h] following an increase in the frequency of epileptic seizures. Nine dogs were receiving PB every 12 h (4.2 mg/kg/12 h [3.8-6 mg/kg/12 h]), and one dog was receiving PB every 8 h (6 mg/kg/8 h). Following the addition of zonisamide and despite no increase in PB dosage, an increase in phenobarbital serum PB concentration was observed in 9 out of 10 dogs in subsequent measurements. In five dogs, phenobarbital serum concentrations were raised to concentrations higher than the reported hepatotoxic concentrations (trough>35 mg/L). This required a reduction in daily doses of PB. This case series suggests that zonisamide affects the metabolism of PB and causes an increase in PB serum concentrations over time.
RESUMO
PURPOSE: To investigate the risk of teratogenesis occurring in relation to intrauterine exposure to infrequently used antiseizure medications in Australia. METHODS: Analysis of data contained in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs. RESULTS: There was statistically significant evidence that zonisamide, but not any other of nine infrequently used antiseizure medications in Australia, was associated with a risk of teratogenesis related to the maternal dose of the drug taken in at least the earlier half of pregnancy. CONCLUSIONS: The teratogenesis associated with zonisamide, like that associated with topiramate and possibly acetazolamide, may be an expression of a class effect shared among sulphonamide-derived carbonic anhydrase inhibitors that possess anti-seizure activity.
Assuntos
Anticonvulsivantes , Zonisamida , Humanos , Zonisamida/efeitos adversos , Anticonvulsivantes/efeitos adversos , Feminino , Gravidez , Austrália , Isoxazóis/efeitos adversos , Anormalidades Induzidas por Medicamentos/etiologia , Sistema de Registros , Epilepsia/tratamento farmacológico , AdultoRESUMO
BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.
Assuntos
Epilepsias Mioclônicas , Hipertermia Induzida , Masculino , Humanos , Adulto Jovem , Adulto , Zonisamida/uso terapêutico , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Convulsões/tratamento farmacológico , Convulsões/etiologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Ácido Valproico/uso terapêutico , Hipertermia/tratamento farmacológico , Anticonvulsivantes/uso terapêuticoRESUMO
The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1-2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide+) that did and one (zonisamide-) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([11C]DPA713 PET), dopamine transporter availability ([11C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [11C]DPA713 (BPND) and [11C]CFT (SUVR) were compared with normal data and between the zonisamide+ and zonisamide- PD groups. The cerebral [11C]DPA713 BPND increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide+ group with the zonisamide- group showed lower levels in the cerebral [11C]DPA713 BPND in the zonisamide+ group. While the striatal [11C]CFT SUVR decreased longitudinally, the [11C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide+ group. A significant annual increase in attention score were found in the zonisamide+ group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Zonisamida , Doenças Neuroinflamatórias , Tomografia por Emissão de Pósitrons , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismoRESUMO
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.