Pharmacokinetics of zonisamide after oral single dosing and multiple-dose escalation administration in domestic chickens (Gallus gallus).

BACKGROUND: There are few effective drugs for treatment of seizures in avian species. OBJECTIVES: To investigate the pharmacokinetics and safety of zonisamide in chickens. METHODS: Phase 1: chickens (n = 4) received a single oral dose of zonisamide at 20 mg/kg. Blood samples were collected intermittently for 36 hr after dosing. Phase 2: chickens (n = 8) received zonisamide in a dose escalation protocol (20, 30, 60 and 80 mg/kg orally every 12 hr). The dose was increased weekly, and peak and trough blood samples were collected on Days 1, 3, and 7 each week. Two birds were randomly euthanized at the end of each week. Plasma zonisamide concentrations were analysed using a commercial immunoassay. Drug concentration vs. time data were subjected to non-compartmental pharmacokinetic analysis. RESULTS: For Phase 1, peak plasma zonisamide (Cmax ) was 15 ± 3 µg/ml at 2 ± 1 hr (Tmax ). The disappearance half-life was 6.5 ± 1 hr. Mean plasma concentrations remained within the (human) therapeutic range (10-40 µg/ml) for 6 hr. For Phase 2 of the study, plasma concentrations of zonisamide remained within or close to the recommended mammalian therapeutic range for birds in the 20 and 30 mg/kg dose. Area under the curve (AUC) and Cmax were dose dependent. Two birds developed immune-mediated haemolytic anaemia. CONCLUSIONS: Zonisamide appears to be a viable drug for use in chickens at a dose of 20 mg/kg orally every 12 hr.

Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND): Case report, pharmacological trial, and literature review.

Early-onset severe spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND, MIM#604065) is an ultrarare autosomal dominant syndrome related to de novo CACNA1G gain-of-function pathogenic variants. All patients with SCA42ND show cerebellar atrophy and/or hypoplasia on neuroimaging and share common features such as dysmorphic features, global developmental delay, and axial hypotonia, all manifesting within the first year of life. To date, only 10 patients with SCA42ND have been reported with functionally confirmed gain-of-function variants, bearing either of two recurrent pathogenic variants. We describe a girl with congenital ataxia, without epilepsy, and a de novo p.Ala961Thr pathogenic variant in CACNA1G. We review the published subjects with the aim of better characterizing the dysmorphic features that may be crucial for clinical recognition of SCA42ND. Cerebellar atrophy, together with digital anomalies, particularly broad thumbs and/or halluces, should lead to clinical suspicion of this disease. We describe the first pharmacological attempt to treat a patient with SCA42ND using zonisamide, an antiepileptic drug with T-type channel blocker activity, in an off-label indication using an itemized study protocol. No efficacy was observed at the dose tested. However, without pharmacological treatment, she showed a positive evolution in neurodevelopment during the follow-up.

Zonisamide Therapy for Patients With Paroxysmal Kinesigenic Dyskinesia.

BACKGROUND: We evaluated zonisamide therapy in patients with paroxysmal kinesigenic dyskinesia (PKD). METHODS: We analyzed zonisamide therapy in 17 patients with PKD at Saitama Children's Medical Center between November 1994 and April 2020. We collected information regarding family history, previous history, age at onset, age at zonisamide commencement, dyskinesia characteristics, brain magnetic resonance imaging, interictal electroencephalography, treatment lag, zonisamide efficacy, zonisamide dose, serum zonisamide concentration, and adverse effects. We evaluated PKD frequency at six months after zonisamide therapy commencement. RESULTS: Fourteen patients met the inclusion criteria. The median age at zonisamide therapy commencement was 12.8 (9.4 to 16.3) years. Zonisamide therapy was effective in 13 of 14 (92.9%) patients: complete remission for more than three months after zonisamide therapy (n = 7), decreased dyskinesia frequency by more than 90% (n = 4), dyskinesia frequency by 75% to 90% (n = 2), and no change of dyskinesia frequency (n = 1). The initial and maintenance zonisamide doses were 2.0 (1.4 to 3.8) and 2.0 (1.5 to 5.9) mg/kg/day, respectively. The median duration between zonisamide therapy commencement and dyskinesia decrease or cessation was 4 (1 to 60) days: 10 of 14 (71.4%) patients responded to zonisamide within one week after zonisamide therapy commencement. Regarding adverse effects, two patients experienced somnolence and one developed reduced perspiration. CONCLUSIONS: We suggest that zonisamide monotherapy is effective for patients with PKD as a first-line treatment. We can evaluate the efficacy of zonisamide therapy within one week. Because zonisamide lacks the enzyme-inducing effects of carbamazepine and phenytoin, it may be useful for PKD treatment.

Non-Dopaminergic Treatments for Motor Control in Parkinson's Disease: An Update.

Glutamatergic, noradrenergic, serotonergic, and cholinergic systems play a critical role in the basal ganglia circuitry. Targeting these non-dopaminergic receptors remains a focus of ongoing research to improve Parkinson's disease (PD) motor symptoms, without the potential side effects of dopamine replacement therapy. This review updates advancements in non-dopaminergic treatments for motor control in PD since 2013. To date, no non-dopaminergic selective drug has shown significant long-term efficacy as monotherapy in PD. The largest area of development in non-dopaminergic targets has been for motor complications of dopamine replacement therapy (motor fluctuations and dyskinesia). For treatment of motor fluctuations, safinamide, zonisamide, and istradefylline are currently approved, and novel glutamatergic and serotonergic drugs are in development. Long-acting formulations of amantadine are approved for treating dyskinesia. Several non-dopaminergic drugs have failed to show anti-dyskinetic efficacy, while some are still in development. Non-dopaminergic targets are also being pursued to treat specific motor symptoms of PD. For example, CX-8998 (a calcium channel modulator) is being evaluated for PD tremor and rivastigmine may improve gait dysfunction in PD. Drug repurposing continues to be a key strategy for non-dopaminergic targets in PD, but the field needs to increase discovery and availability of such drugs.

Zonisamide add-on therapy for focal epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop dug-resistant epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2018. OBJECTIVES: To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. SEARCH METHODS: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (September 2019). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field, to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the certainty of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and certainty of the evidence for each outcome in a 'Summary of findings' table. MAIN RESULTS: We did not find any new studies since the last version of this review. We included eight studies (1636 participants) from previous versions of this review. The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-certainty evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-certainty evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8). Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-certainty evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-certainty evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The following adverse effects were more likely to be associated with zonisamide than with placebo: ataxia (RR 3.85, 99% CI 1.36 to 10.93; 4 trials, 734 participants; low-certainty evidence); somnolence (RR 1.52, 99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-certainty evidence); agitation (RR 2.35, 99% CI 1.05 to 5.27; 4 trials, 598 participants; low-certainty evidence); and anorexia (RR 2.74, 99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-certainty evidence). Across the eight studies, we rated risk of bias domains at low or unclear risk of bias, apart from two studies, which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. AUTHORS' CONCLUSIONS: When used as an add-on treatment in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs, moderate-certainty evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy, or to people with other seizure types or epilepsy syndromes.

Evaluation of zonisamide for the treatment of focal epilepsy: a review of pharmacokinetics, clinical efficacy and adverse effects.

Introduction: Zonisamide is a benzisoxazole with 3-methanesulfonamide side chain, chemically unrelated with other anticonvulsants, and approved as mono-therapy of newly diagnosed focal epilepsy with or without secondary generalization in adults or adjunctive therapy in the treatment of partial seizures, with or without secondary generalization, in adults, adolescents, and children aged 6 years and above.Areas covered: Pharmacokinetics, clinical efficacy, and the adverse effects of zonisamide are discussed in the article. The discussion is based on data from published preclinical studies, clinical trials, observational studies, systematic reviews, and approved summary of product characteristics.Expert opinion: Zonisamide is an anticonvulsant with multiple mechanisms of action on neuronal tissue, which achieves seizure freedom in more than 80% of patients with newly-onset focal epilepsy and in 6.2 to 18.1% of patients with focal onset seizures inadequately controlled by first-line anticonvulsants. Within the recommended dose range, it follows linear kinetic of elimination; it is metabolized in the liver by two cytochrome isoforms, so pharmacokinetic interactions are rare and with little clinical significance. Up to 10% of patients taking zonisamide will have problems with weight loss and more than 10% with irritability, confusion or depression, and long-lasting therapy may cause renal calculi in 1.2% of patients.

Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration.

PURPOSE: Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS: In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS: Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS: This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.

Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: A phase 3 randomized clinical trial.

INTRODUCTION: Zonisamide is approved in Japan for treating motor dysfunction in Parkinson's disease, and might also be effective for parkinsonism in patients with dementia with Lewy bodies (DLB). Our study evaluated the safety and efficacy of zonisamide for treating parkinsonism in patients with DLB. METHODS: This multicenter, randomized, double-blind, phase 3 trial was conducted in Japan between April 2015 and November 2017. Following a 4-week run-in period, outpatients diagnosed with probable DLB who had developed parkinsonism were randomized to receive oral zonisamide (25 or 50 mg/day) or placebo for 12 weeks, followed by a 40-week open-label extension. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score at Week 12. RESULTS: Of 351 patients randomized, 346 (mean age, 77.2 years; 188 males) were included in the modified intention-to-treat population. At Week 12, the group difference (least squares mean ± SEM) for changes from baseline (vs placebo) in UPDRS part III total score was -2.7 ± 0.9 (95% confidence interval [CI]: -4.4, -0.9, P = 0.005) in the zonisamide 25-mg group and -2.6 ± 0.9 (95% CI: -4.4, -0.8, P = 0.005) in the zonisamide 50-mg group. Adverse events were reported in 47.1%, 48.7%, and 54.5% of patients in the placebo and zonisamide 25- and 50-mg groups, and led to treatment discontinuation in 5.0%, 4.3%, and 9.8% of patients, respectively. CONCLUSION: Daily administration of 25- or 50-mg zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated in patients with DLB.

Zonisamide for Cluster Headache Prophylaxis: A Case Series.

OBJECTIVE: There is very little literature surrounding the prophylactic use of zonisamide in cluster headaches. The study aims to evaluate the effectiveness of zonisamide for prophylaxis of cluster headache in patients with chronic or episodic cluster headache. BACKGROUND: Both chronic and episodic cluster headaches are debilitating disorders which are often refractory to multiple prophylactic medication regimens. There is a scarcity of research in this area, and current prophylactic options for patients are fairly limited, which is troublesome for affected patients. Zonisamide is an established antiepileptic with a multifactorial mechanism of action which has shown to be useful in other headache disorders such as migraine. METHODS: Twenty cluster headache patients, both episodic (n = 12; ICHD 3.1.1) and chronic (n = 8; ICHD 3.1.2), who had been or currently were treated with zonisamide, were retrospectively evaluated. Effectiveness of the medication was assessed and identified as headache remission or a reduction in severity or frequency of cluster headache of greater than 50%. Responder status, side effects, and dosage were recorded. RESULTS: Fourteen (70%) patients responded to zonisamide treatment, while 6 (30%) did not. Recorded effective plasma zonisamide levels ranged from 10.2 to 31.9 µg/mL. Of the 6 non-responders, 2 stopped the medication due to ineffectiveness, while 4 discontinued the medication secondary to intolerable side effects ranging from gastrointestinal upset to malaise. No more serious adverse events occurred. Eight patients total experienced weight loss/anorexia which many perceived as a positive effect; they lost an average of 10.5% of their body weight in the first 6 months of therapy. CONCLUSIONS: Zonisamide appears to be an effective prophylactic treatment for patients with chronic and episodic cluster headache disorders. Further research in this area is clearly warranted.

Pharmacological Management of Dementia with Lewy Bodies.

Dementia with Lewy bodies (DLB) is a complex disease that involves a variety of cognitive, behavioral and neurological symptoms, including progressive memory loss, visual hallucinations, parkinsonism, cognitive fluctuations and rapid eye movement sleep behavior disorder (RBD). These symptoms may appear in varying combinations and levels of severity in each patient who is seen in the clinic, making diagnosis and treatment a challenge. DLB is the third most common of all the neurodegenerative diseases behind both Alzheimer's disease and Parkinson's disease (PD). The median age of onset for DLB (76.3 years) is younger than that seen in PD dementia (81.4 years). New pathological studies have shown that most DLB patients have variable amounts of Alzheimer's changes in their brains, explaining the wide variability in this disease's clinical presentation and clinical course. This review discusses the three cholinesterase inhibitors that have been shown to be effective in managing the cognitive and behavioral symptoms of DLB: rivastigmine, galantamine and donepezil. Memantine is able to improve clinical global impression of change in those with mild to moderate DLB. Levodopa can treat the parkinsonism of some DLB patients, but the dose is often limited due to the fact that it can cause agitation or worsening of visual hallucinations. A recent phase 2 clinical trial showed the benefit of zonisamide when it is added as an adjunct to levodopa for treating DLB parkinsonism. While atypical antipsychotic drugs may not always be helpful as monotherapy in managing the agitation associated with DLB, low doses of valproic acid can be effective when added as an adjunct to drugs like quetiapine. Pimavanserin may prove to be a useful treatment for psychosis in DLB patients, but like other antipsychotic drugs that are used in dementia patients, there is a small increased risk of mortality. RBD, which is a common core clinical feature of DLB, can be managed with either melatonin or clonazepam. Two agents targeting alpha-synuclein (NPT200-11 and ambroxol) currently hold promise as disease-modifying therapies for DLB, but they are yet to be tested in clinical trials. An agent (E2027) that offers hope of neuroprotection by increasing central cyclic guanosine monophosphate (cGMP) levels is currently being examined in clinical trials in DLB patients.

Safety, tolerability, and effectiveness of oral zonisamide therapy in comparison with intramuscular adrenocorticotropic hormone therapy in infants with West syndrome.

West syndrome is a distinct, infantile onset, epileptic encephalopathy, associated with poor neurodevelopmental outcome. The present study was designed as a randomized, open-label, pilot study to evaluate the safety, feasibility, and effectiveness of oral zonisamide therapy in comparison with adrenocorticotropic hormone therapy in infants with West syndrome. Thirty infants with West syndrome were randomized to receive treatment with either synthetic, intramuscular adrenocorticotropic hormone (30-60 IU) or oral zonisamide (4-25 mg/kg/day). The study participants had a long treatment lag and preponderance of male sex (90%). The primary effectiveness outcome measure was the cessation of epileptic spasms at 2 weeks of initiation of therapy and persistent till 6 weeks as per West Delphi consensus statement recommendations. Comparison of efficacies of zonisamide versus adrenocorticotropic hormone was as following: the cessation of epileptic spasms (27% vs. 40%, p = 0.70), resolution of hypsarrhythmia at 14 days (20% vs. 33%, p = 0.68) and resolution of hypsarrhythmia at 6 weeks (36% vs. 71%, p = 0.14). Overall, the study observed a poor efficacy of both adrenocorticotropic hormone and zonisamide therapy, which is probably due to long treatment lag and a high proportion of structural aetiology. However, oral zonisamide appeared to be safe and tolerable in the study.

Biosynthesis of gold nanoparticles, characterization and their loading with zonisamide as a novel drug delivery system for the treatment of acute spinal cord injury.

In the present work, a facile biosynthetic approach for the synthesis of AuNPs using bark extract of Juglans regia (J. regia) is reported. Ultra-violet visible (UV-vis) absorption spectroscopic studies exhibited and narrow SPR absorption band at 540 nm, represented the isotropy in particle size. The transmission electron microscopy (TEM) and X-ray diffraction (XRD) analysis, confirmed the fabrication of spherical and crystalline nanoparticles of average size of about 14 nm. Also, typical characteristic selected area electron diffraction (SAED) pattern showed the crystalline nature of AuNPs. The prepared AuNPs were loaded with zonisamide which can be used for future spinal cord injury repair applications. The fourier transform infrared spectroscopy (FTIR) analysis represented the zonisamide loading onto AuNPs. The biological preparation of AuNPs using the bark extract of J. regia is prominent approach because of its eco friendly nature without using any toxic chemicals. The controlled-release of zonisamide-AuNPs was about 43.0 ±â€¯2.2 nm with high stability and solubility under room temperature conditions. Further, the cytotoxicity results showed the comparatively higher toxicity of zonisamide-AuNPs towards CTX TNA2 cells than free zonisamide. Hence, zonisamide-AuNPs may act as very good clinical drug for future therapeutic treatment of spinal cord injury.

Zonisamide add-on therapy for focal epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2013. OBJECTIVES: To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs. SEARCH METHODS: For this update, on 4 September 2017, we searched the Cochrane Epilepsy Group Specialised Register, Cochrane Register of Studies Online, MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform ICTRP. We searched SCOPUS on 13 February 2013, but this is no longer necessary, because RCTs and quasi-RCTs in Embase are now included in CENTRAL. In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and quality of the evidence for each outcome in a 'Summary of findings' table. MAIN RESULTS: We included eight studies (1636 participants). The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency compared to placebo for 300 mg to 500 mg/day of zonisamide was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-quality evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-quality evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8) for this outcome. Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-quality evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-quality evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The CIs of the following adverse effects indicated that they were significantly associated with zonisamide: ataxia RR 3.85 (99% CI 1.36 to 10.93; 4 trials, 734 participants; low-quality evidence); somnolence RR 1.52 (99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-quality evidence); agitation RR 2.35 (99% CI 1.05 to 5.27; 4 trials, 598 participants; low-quality evidence); and anorexia RR 2.74 (99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-quality evidence).Across the eight studies, we rated risk of bias domains at low or unclear risk of bias apart from two studies which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide. AUTHORS' CONCLUSIONS: When used as an add-on treatment in people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs, moderate-quality evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide.

BACKGROUND: Extended-release levetiracetam (LEV-XR) has gained acceptance as an antiepileptic drug in dogs. No studies have evaluated its disposition in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: To evaluate the pharmacokinetics of LEV-XR in epileptic dogs when administered alone or with phenobarbital or zonisamide. ANIMALS: Eighteen client-owned dogs on steady-state maintenance treatment with LEV-XR (Group L, n = 6), LEV-XR and phenobarbital (Group LP, n = 6), or LEV-XR and zonisamide (Group LZ, n = 6). METHODS: Pharmacokinetic study. Blood samples were collected at 0, 2, 4, 8, and 12 hours after LEV-XR was administered with food. Plasma LEV concentrations were determined by high-pressure liquid chromatography. A population pharmacokinetic approach and nonlinear mixed effects modeling were used to analyze the data. RESULTS: Treatment group accounted for most of the interindividual variation. The LP group had lower CMAX (13.38 µg/mL) compared to the L group (33.01 µg/mL) and LZ group (34.13 µg/mL), lower AUC (134.86 versus 352.95 and 452.76 hours·µg/mL, respectively), and higher CL/F (0.17 versus 0.08 and 0.07 L/kg/hr, respectively). The half-life that defined the terminal slope of the plasma concentration versus time curve (~5 hours) was similar to values previously reported for healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Considerable variation exists in the pharmacokinetics of LEV-XR in dogs with epilepsy being treated with a common dose regimen. Concurrent administration of phenobarbital contributed significantly to the variation. Other factors evaluated, including co-administration of zonisamide, were not shown to contribute to the variability. Drug monitoring may be beneficial to determine the most appropriate dose of LEV-XR in individual dogs.

Zonisamide Administration Improves Fatty Acid ß-Oxidation in Parkinson's Disease.

Although many experimental studies have shown the favorable effects of zonisamide on mitochondria using models of Parkinson's disease (PD), the influence of zonisamide on metabolism in PD patients remains unclear. To assess metabolic status under zonisamide treatment in PD, we performed a pilot study using a comprehensive metabolome analysis. Plasma samples were collected for at least one year from 30 patients with PD: 10 without zonisamide medication and 20 with zonisamide medication. We performed comprehensive metabolome analyses of plasma with capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. We also measured disease severity using Hoehn and Yahr (H&Y) staging and the Unified Parkinson's Disease Rating Scale (UPDRS) motor section, and analyzed blood chemistry. In PD with zonisamide treatment, 15 long-chain acylcarnitines (LCACs) tended to be increased, of which four (AC(12:0), AC(12:1)-1, AC(16:1), and AC(16:2)) showed statistical significance. Of these, two LCACs (AC(16:1) and AC(16:2)) were also identified by partial least squares analysis. There was no association of any LCAC with age, disease severity, levodopa daily dose, or levodopa equivalent dose. Because an upregulation of LCACs implies improvement of mitochondrial ß-oxidation, zonisamide might be beneficial for mitochondrial ß-oxidation, which is suppressed in PD.