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PubMed2002

Three new drugs for epilepsy: levetiracetam, oxcarbazepine, and zonisamide.

During the last decade, nine new antiepileptic drugs were approved for use by the US Food and Drug Administration. The characteristics of three of these new antiepileptic drugs-levetiracetam, oxcarbazepine, and zonisamide--are reviewed here. Their individual characteristics, including mechanism of action, efficacy, safety, and pharmacokinetics, are compared, and their effectiveness in treating specific seizure types is noted. As with all antiepileptic drugs, the efficacy, side-effect, and pharmacokinetic profiles must be matched to each individual's clinical profile to attain the maximum benefit. All three are unique and will be useful in expanding the aggregate of therapies available to clinicians treating diverse epilepsy syndromes and seizure types. This review focuses on results in adults; pediatric experience is reported in other articles in this supplement.

Anticonvulsants↗
PubMed2002

Long-term response to zonisamide in patients with West syndrome.

The long-term effectiveness of zonisamide (ZNS) was evaluated in 11 patients with West syndrome (7 symptomatic) who had cessation of spasms with ZNS monotherapy. During the follow-up period (24 to 79 months, mean = 53 months), this response was maintained in 7 patients (3 symptomatic, relapse rate = 36%), including 2 children in whom ZNS was successfully discontinued. No serious adverse reactions were noted. ZNS may be both effective and well tolerated for the treatment of West syndrome.

Adolescent↗
PubMed1996

The necessity of adjusting the dosage of zonisamide when coadministered with other anti-epileptic drugs.

Zonisamide (ZNS), a new anti-epileptic drug that exhibits a wide anti-epileptic spectrum, is commonly prescribed concomitantly with other anti-epileptic drugs. The interaction between ZNS and other anti-epileptic drugs was investigated in epileptic patients. The steady state plasma levels of all the anti-epileptic drugs were measured by high-performance liquid chromatography. The concomitant administration of phenobarbital (PB), phenytoin (PHT), or carbamazepine (CBZ) with ZNS significantly decreased the ratio of the steady state plasma concentration to the administered dose (C/D ratio) of ZNS, whereas clonazepam (CZP) and valproic acid (VPA) when administered concomitantly with ZNS did not change the C/D ratio. Significant negative correlations were observed between the C/D ratio of ZNS and the doses of PB, PHT, CBZ, and VPA. On the other hand, the ratio of the plasma concentration of carbamazepine-10,11-epoxide (CBZ-E), the major active metabolite of CBZ, to the plasma concentration of CBZ was significantly decreased by concomitant administration with ZNS, indicating that ZNS inhibits the metabolism of CBZ. These findings show that when ZNS is administered concomitantly with these anti-epileptic drugs, it is necessary to monitor the plasma concentration of ZNS in order to adjust its dosage.

Adolescent↗
PubMed1997

Utility of a rectal suppository containing the antiepileptic drug zonisamide.

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15:S-55 = 3:1) as a lipophilic base and the other polyethylene glycol (PEG, 4000:1500 = 4:1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

Administration, Oral↗
PubMed1992

Factors influencing serum concentration of zonisamide in epileptic patients.

The relationship between daily dose and serum concentration of zonisamide (ZNS) and the effects of patient age on the serum level/dose (L/D) ratio for ZNS were studied in epileptic patients (mean age +/- S.D. = 10.6 +/- 6.2 years) who chronically received ZNS. The influence of phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ) and valproic acid (VPA) on the serum protein binding of ZNS in vitro and the correlation between total and unbound serum levels of ZNS in patients were also examined. Significant correlations were obtained between daily dose per body weight or per body surface area and serum level of ZNS. The correlation coefficient of the latter was higher than that of the former. There was no effect of age on the L/D ratio on the basis of body surface area, whereas that on the basis of body weight increased significantly with age. No significant increase in the free fraction of ZNS was observed in the presence of PHT, PB and CBZ except VPA in vitro. There were significant correlations between total and unbound serum levels of ZNS in the two patient groups coadministered with and without VPA. Although the free fraction of ZNS in the former was significantly higher than that of the latter, the increase was small. These results suggest that dosage regimens on the basis of body surface area would be more accurate than those on a body weight basis and that there is little effect of other antiepileptics on the serum protein binding of ZNS.

Adolescent↗
PubMed2004

Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinson's disease.

We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

Animals↗
PubMed1999

[Efficacy of zonisamide in West syndrome].

The efficacy of zonisamide (ZNS) was studied in 16 patients (11 males, 5 females) with West syndrome (WS), symptomatic in 13 and cryptogenic in 3. They did not respond to pyridoxal phosphate (12 cases) or valproate (16 cases). The mean age of onset of WS was 4.4 (2-9) months. ZNS was administered from 3 to 9 months of age (mean 6.1). Four cases (2 cryptogenic and 2 symptomatic) became seizure free. Two had more than 50% seizure reduction. Ten infants remained unchanged or showed less than 50% seizure reduction. In the 4 responders, the effective dose was 4-8 mg/kg (mean 5.8), and the serum ZNS concentration was 10-21 micrograms/ml (mean 13.8). One had relapse of WS after 4 months. Three with normalized EEG remained seizure-free during the follow-up period (12-26 months). One case developed a transient drowsiness, but no serious side effects were observed. These data suggest ZNS may be regarded as a therapy of choice before synthesized ACTH therapy in the management of WS.

Anticonvulsants↗
PubMedDate not supplied

Zonisamide: a new antiepileptic drug.

Zonisamide (ZNS) is a relatively new antiepileptic medication currently available in Japan. Attempts to market the drug in the United States were thwarted by reports of nephrolithiasis by European and American investigators. However, successful marketing of the drug in Japan has resulted in a renewed interest in bringing the drug to the United States. Japanese experience with ZNS showed a broad spectrum of efficacy in the treatment of seizures, including infantile spasms and myoclonic seizures. A neuroprotective role and an antimanic effect have also been reported. The exact antiepileptic mechanism of action of ZNS is not known, but it has dose-dependent sodium channel blocking and T-type calcium channel blocking properties and free radical scavenging actions. Recommended initial adult dosage in Japan is 100-200 mg/d, increased if necessary to 200-400 mg/d, up to a maximum of 600 mg/d. In children, initial dosage is 2-4 mg/kg/d, increased if necessary to 4-8 mg/kg/d up to a maximum of 12 mg/kg/d. The recommended therapeutic plasma ZNS concentration is 10-20 mg/L. Adverse events, most notably drowsiness, loss of appetite, gastrointestinal problems, and CNS toxicity, have been noted with plasma ZNS concentrations of > 30 mg/L. A drug rash also has been reported.

Adult↗
PubMed1999

Zonisamide inhibits nitric oxide synthase activity induced by N-methyl-D-aspartate and buthionine sulfoximine in the rat hippocampus.

The antiepileptic zonisamide (ZNS) is known to be effective in protecting against epilepsy in a wide variety of animal epilepsy models and in humans with epileptic seizures, with both partial and generalized seizures. ZNS scavenges hydroxyl radicals (OH*) and nitric oxide (NO) in a dose-dependent manner. The mechanism of the antiepileptic effect of ZNS may involve protection of neurons from free radical damage and stabilization of neuronal membranes. In this study, the effect of ZNS on nitric oxide synthase (NOS) activity in the hippocampus of rats induced by N-methyl-D-aspartate (NMDA) with/without L-buthionine-[S, R]-sulfoximine (BSO) was examined. NOS activity was accelerated significantly (plus 93%) in the hippocampus 3 hours after NMDA injection (30 mg/Kg, i.p.), and (plus 220%) 3 hours after NMDA (30 mg/Kg, i.p.) injection into BSO-pretreated rats (150 mg/Kg, i.p.). NOS activity was not affected by ZNS itself. ZNS reduced NOS activity, accelerated by NMDA- with/without BSO-treatment, to the control level in the hippocampus. This suggests that ZNS may inhibit initiation and propagation of seizures by inhibiting NOS activity, and also may protect neurons from free radical damage by NO and/or OH*.

Animals↗
PubMed2002

[A case of infantile epileptic encephalopathy with frequent focal motor status convulsivus: successful treatment with zonisamide].

We reported a 41-day-old girl starting with partial status convulsivus. She had suffered from infantile epileptic encephalopathy manifesting with recurrent focal motor status convulsivus, eventually requiring general anesthesia for the treatment. She had had never myoclonic seizures nor tonic spasms. The examinations including brain MRI scan and metabolic screening tests were all negative. The ictal EEGs showed the onset of the seizures from the left frontal region. Interictal EEG demonstrated multifocal spike discharges as well as discontinuous abnormal EEG pattern resembling suppression-burst during sleep. The seizures were resistant to the multiple antiepileptic drugs, but zonisamide achieved full seizure control as well as improvement of the EEG. Her psychomotor development was severely retarded at 3 years of age.

Anticonvulsants↗
PubMed2002

[Urolithiasis induced by combined ACTH and zonisamide treatment in a patient with startle induced epilepsy].

A 5-year-old boy had periodic spasms and startle-induced drop attacks. Zonisamide (ZNS) was partially effective for the former seizures, and propranolol for the latter. An add-on therapy with ACTH resulted in a transient disappearance of seizures and an improvement of EEG. However, the patient developed urolithiasis with resultant hematuria and pyelectasis during ACTH therapy. ZNS can induce urolithiasis by increasing urinary pH and calcium (Ca) excretion, and ACTH may facilitate this rare adverse effect of ZNS by further increasing the urinary Ca. Hydrochlorothiazide could resolve the urolithiasis by decreasing the urinary Ca excretion.

Adrenocorticotropic Hormone↗
PubMed2003

[Effect of zonisamide on resting tremor resistant to antiparkinsonian medication].

The antiparkinsonian effect of zonisamide (ZNS), an antiepileptic agent, has been reported. Generally, resting tremor of patients with Parkinson's disease is not the main therapeutic target in this disease. However, depending on the social situation of the patient, the amelioration of the tremor may be necessary. In this study, we examined the effect of ZNS on tremor in nine patients who desired amelioration of their tremor. Except for tremor, they seemed to be under optimal therapeutic condition based on their daily activities. By the add-on administration of ZNS, the degree of tremor was reduced in seven out of nine patients (p < 0.0017). Although one patient felt sleepiness and two patients had a transient loss of appetite, all the patients tolerated the eight-week ZNS administration period. The final dose of ZNS was 100 mg/day in the majority of the patients. Although the mechanism of the antitremulous effect of ZNS is not yet clear, other than the enhancement of dopaminergic transmission, some specific action of the drug on tremor may exist. A more detailed random examination should be carried out.

Aged↗
PubMedDate not supplied

Zonisamide: a new antiepileptic drug.

Although the significant progress in pharmacotherapy of epilepsy during last decade was achieved, about one third of patients are resistant to the current treatment. When the monotherapy is not efficient, the polytherapy should be applied. Zonisamide (ZNS) is a new antiepileptic drug (AED) efficient in treating refractory epilepsy. Its efficacy in different types of seizures was confirmed in various animal studies as well as in clinical conditions. ZNS inhibits voltage-dependent Na(+) channels and Ca(2+) channels of T-type. The drug influences also monoamine neurotransmission and exhibits free radical scavenging properties. ZNS has a linear and favorable pharmacokinetics with excellent oral bioavailability. Furthermore, ZNS treatment, compared to other anticonvulsants, is relatively safe and well tolerated. Since ZNS is often used in polytherapy, its interactions with other AEDs seem to be of particular importance. However, the experimental data are rather inconsistent and further studies are necessary to elucidate exact effects of coadministration of ZNS with other AEDs. Recently, the clinical and experimental studies have suggested some new indications for ZNS administration, as mania, neuropathic pain, Parkinson's disease or migraine prophylaxis. Nowadays, it is also well established that ZNS exerts neuroprotective properties.

Animals↗
PubMed2004

Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy.

The recommended treatment for juvenile myoclonic epilepsy (JME) is valproate (VPA). Recently, topiramate and lamotrigine have also been shown to be effective. The objective of this study was to evaluate the efficacy and tolerability of zonisamide (ZNS) in the treatment of JME. We retrospectively analyzed the records of 15 patients (three M, 12 F, ages 11-20 years) diagnosed with JME at our institution during 2001-2003, and treated with ZNS. Generalized tonic-clonic (GTC), myoclonic and absence seizure response was assessed. The ZNS dose range was 200-500 mg/day (2.0-8.5 mg/kg/day). ZNS was started as the first drug, and as monotherapy, in 13 and was added to VPA in two patients. Follow-up range was 2-24 months (mean 12 months). Overall, 80% of patients on ZNS monotherapy showed good control (> or = 50% seizure reduction). Sixty-nine, 62 and 38% of patients were free of GTC, myoclonic, and absence seizures, respectively. Seizure control was achieved within four to eight weeks of attaining the maintenance dose. One patient on polytherapy had a 75% reduction in seizure frequency, whereas the other patient showed no response. There were no ZNS-VPA interactions. One patient stopped ZNS and was switched to VPA because of poor seizure control. Three patients (20%) experienced side effects (weight loss, headache, dizziness) during escalation, which resolved during maintenance. In this open-label, retrospective study, ZNS was shown to be an effective and well-tolerated drug in the treatment of patients with JME. The ease of titration, good safety profile, once-a-day dosing, lack of significant drug interaction, and short latency for onset of efficacy make ZNS an attractive therapeutic alternative for the treatment of JME.

Adolescent↗
PubMed2006

[New medications; zonisamide].

Zonisamide is an adjuvant for the treatment of patients with partial epilepsy, with or without secondary generalisation. It affects, among other things, the voltage-sensitive sodium and calcium channels, thus disrupting synchronised neuronal firing; as a result, it diminishes the spread of seizure discharges.

Anticonvulsants↗
PubMed2007

[Valproate sodium and zonisamide associated interstitial pneumonitis in an infant].

A six month-old female infant developed dyspnea when she was treated with valproate sodium (VPA) and zonisamide (ZNS) for epileptic spasms. Two weeks after its onset, her dyspnea was exacerbated by respiratory syncytial virus (RSV) infection. We diagnosed interstitial pneumonitis (IP) based on her chest CT and high serum concentrations of KL-6 and surfactant protein D. Her dyspnea improved with the treatment which included steroids, neutrophil elastase inhibitor and discontinuation of VPA and ZNS. An allergic reaction probably explains the IP in our patient because steroids were effective. Her IP might have been exacerbated by several factors including the use of two anticonvulsants (VPA, ZNS), RSV infection, and physiological low serum IgA level of infants. Drug-induced interstitial lung disease should be remembered as a possible complication of anticonvulsant treatment, such as VPA and ZNS.

Anticonvulsants↗
PubMed1990

Competitive binding enzyme immunoassay for zonisamide, a new antiepileptic drug, with selected paired-enzyme labeled antigen and antibody.

We assessed the competitive binding between zonisamide (ZNS) in serum samples and beta-galactosidase-labeled ZNS derivatives, using competing antibodies to ZNS derivatives, and selected the best enzyme-labeled antigen and antibody for accurate enzyme immunoassay (EIA) of ZNS in serum without interference from its metabolites or from other antiepileptic drugs. This EIA, based on use of antibody linked to bacterial cell walls, has advantages over HPLC in simplicity, speed (50 samples per hour), and lack of requirement for special equipment. The concentrations of ZNS in serum as measured by the EIA correlated well with those by HPLC (n = 33, r = 0.977).

Antibodies↗
PubMed1996

[Oligohidrosis caused by zonisamide].

We studied 70 patients who took zonisamide (ZNS) in August 1994, to clarify the relation between ZNS and oligohidrosis. Twelve of the 70 patients were revealed to have oligohidrosis by the interview with patients' mothers. Six of these 12 patients were evaluated by heat loading test, which showed a decreased sweat response in all patients. Five of the 12 oligohidrotic patients were evaluated by acetylcholine (Ach) loading test and all of them showed a decreased sweat response. On two patients poor sweat responses to heat loading and Ach loading recovered after discontinuation of ZNS. These results suggest that ZNS causes dysfunction of sweat glands.

Acetylcholine↗