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At least 199 records · Page 11Linked to original sources
PubMed1997

Alcohol intake decreases brain Zonisamide concentration in inbred EL mice.

This study was undertaken to evaluate the effect of ethanol intake on the anticonvulsive effects of Zonisamide (ZNS), a sulfonamide derivative. EL mice, which are highly susceptible to seizures, were given a 10% ethanol solution ad lib for 1-4 weeks. In mice given ethanol for 4 weeks, seizures were not suppressed by ZNS at a dose of 75 mg kg-1, i.p. Serum ZNS concentrations following ethanol consumption for 1-4 weeks were higher than in untreated mice; however, brain ZNS concentrations following ethanol consumption were lower than those in untreated mice. These results suggest that alcohol intake decreases the brain concentration of ZNS, but not the serum concentration.

Animals↗
PubMed2005

Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy.

The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.

Adult↗
PubMed2006

Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide.

Prolonged drug-induced cholestasis may be due to destruction and disappearance of bile ducts, sometimes referred to as vanishing bile duct syndrome. Although some of these cases progress to fibrosis, cirrhosis, and liver failure, others improve with time. We report a case of a 35-year-old man who developed vanishing bile duct syndrome after ingestion of zonisamide, an antiepileptic drug that is also prescribed for weight loss. His liver biopsy showed complete absence of bile ducts 3 weeks after starting treatment. There was no ductular reaction. The drug was stopped and a follow-up biopsy 3 months later showed strands of intermediate hepatobiliary cells at the periphery of the portal tracts that extended into lobules; these structures lacked lumina and expressed biliary cytokeratins, CK7 and CK19. A third biopsy, 7 months later, showed the presence of ductules with lumina located within portal tracts. Intermediate hepatobiliary cells were rare; although sparse clusters of hepatocytes with membrane staining for CK7 were present. Cholestasis and levels of bilirubin improved over time. The histologic features in this case document the sequence of events in restoration of the biliary tree after loss of bile ducts, which seems to be a process of maturation of intermediate hepatobiliary cells that arise from a proliferative compartment at the porto-hepatic interface.

Adult↗
PubMed2004

Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures.

PURPOSE: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures. METHODS: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It included a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investigators found that adverse effects could be reduced by gradually introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or approximately 1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and secondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a > or =50% reduction from baseline (responder rate). Patient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events. RESULTS: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated patients was 26.9%, compared with 16.2% for placebo-treated patients. At study's end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most frequently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue. CONCLUSIONS: As adjunctive treatment, ZNS was generally well tolerated and significantly improved seizure control among patients with refractory partial seizures.

Adolescent↗
PubMed2004

Dialyzability of the antiepileptic drug zonisamide in patients undergoing hemodialysis.

PURPOSE: The influence of hemodialysis on plasma zonisamide (ZNS) concentration has not been clarified. In this study, the dialyzability of ZNS during hemodialysis was investigated in four ZNS-treated women with systemic lupus erythematosus complicated by seizures. METHODS: The total and unbound plasma concentrations of ZNS were measured before and after hemodialysis. The concentration of ZNS in the spent dialysate also was determined. RESULTS: The reduction in plasma ZNS concentration after a 4.5-h hemodialysis was 52.0 +/- 7.6%, and the dialyzer (BLF-16GW) clearance of ZNS was 55.1 +/- 7.0 ml/min. Dosage was gradually increased up to 200 to 500 mg/day, and the seizures were controlled satisfactorily. CONCLUSIONS: The plasma concentration of ZNS was reduced by approximately 50% during one session of dialysis. For patients undergoing daytime hemodialysis sessions every 2 or 3 days, the usual dosage of ZNS (4-8 mg/kg/day) may be prescribed once a day in the evening. If seizures occur after hemodialysis, a supplemental daily dose may be prescribed in the morning.

Adult↗
PubMed2005

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures.

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001). The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.

Adolescent↗
PubMed1991

Monotherapy for childhood epilepsies with zonisamide.

Zonisamide was tried on 44 children, 18 girls and 26 boys, from 8 months to 15 years of age at the start of the trial. In 6 children the drug has been stopped because of side effects. The drug was introduced at a dose of 2-4 mg/kg/day and increased to 12 mg/kg/day unless a satisfactory response occurred at a lower dose. A 100% control of seizures was achieved in 5 of 5 cases of idiopathic generalized epilepsies, in 7 of 8 cases of symptomatic generalized epilepsies, in one of one case of idiopathic partial epilepsies, and in 17 of 24 cases of symptomatic partial epilepsies. The main side effect was drowsiness, especially during the introduction.

Administration, Oral↗
PubMed2000

Renal tubular acidosis associated with zonisamide therapy.

PURPOSE: We sought to report a previously undescribed adverse effect, renal tubular acidosis associated with zonisamide (ZNS) therapy. METHODS: Ammonium chloride, bicarbonate, and furosemide loading tests were performed in an epileptic patient with metabolic acidosis and episodic hypokalemia who was treated with ZNS. RESULTS: Distal renal tubular acidosis was diagnosed. On reexamination 7 weeks after ZNS had been replaced with phenytoin, the renal tubular acidosis disappeared. CONCLUSIONS: This case indicates, for the first time, that ZNS might be a potential cause of renal tubular acidosis. Blood gases and serum electrolytes should be measured in patients undergoing ZNS therapy.

Acidosis, Renal Tubular↗
PubMedDate not supplied

Effect of zonisamide (CI-912) on a synaptic system model.

The effect of the experimental antiepileptic drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide, ZNS) on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs. Intravenous administration of 10-40 mg/kg ZNS significantly depresses descending excitatory mechanisms, as well as segmental and descending inhibitory mechanisms, but has only a minor effect on segmental excitatory mechanisms. This spectrum of activity is similar to that of valproate, and suggests that ZNS should also be a broad-spectrum antiepileptic drug. In agreement with our experimental observations, it has been found that ZNS is effective against complex partial, generalized tonic clonic, and myoclonic seizures. The antiepileptic profile of ZNS in conventional screening tests resembles that of carbamazepine (CBZ) and phenytoin. However, CBZ exacerbates rather than prevents myoclonic seizures. Our experimental model thus provides a more accurate prediction of ZNS's clinical spectrum of activity. The relationship of these findings to the mechanism of action of antiepileptic drugs is discussed.

Animals↗
PubMedDate not supplied

Zonisamide-induced behavior disorder in two children.

Zonisamide (ZNS)-induced behavior disorders are reported in a 1-year-old girl and a 3-year-old boy. Both patients, who had no previous developmental or mental problems, displayed secondarily generalized motor seizures. Serum concentrations of ZNS were not high, 8.8 and 12.3 micrograms/ml (effective range 10-30 micrograms/ml) respectively. Although many cases of ZNS-related psychotic reactions and/or behavior disorders have been reported, all affected patients had complex partial seizures (CPS) and had received combination therapy with phenytoin (PHT). Thus, whether the disorders were induced only by ZNS, by an interaction between ZNS and PHT, or by CPS could not be determined. In the children reported, however, ZNS clearly induced behavior disorders at plasma ZNS levels within or even below the therapeutic range.

Anticonvulsants↗
PubMedDate not supplied

Influence of additional therapy with zonisamide (Excegran) on protein binding and metabolism of carbamazepine.

The influence of comedication with zonisamide (ZNS) on protein binding and carbamazepine (CBZ) metabolism was studied in 16 pediatric epileptic patients. Correlations were evaluated between ZNS daily dose and individual change of level per dose ratio (L/D ratio), free fraction, and carbamazepine-10,11-epoxide/CBZ level ratio (CBZE/CBZ). Statistical significant negative correlation was observed between L/D ratio and ZNS daily dose. Despite alteration in the L/D ratio, the free fraction of CBZ was unaltered in combination with ZNS. To assess the effect of addition of ZNS on CBZ metabolism, the CBZE/CBZ level ratio was compared; this ratio showed a tendency to increase with increase in ZNS dose. Consequently, ZNS is considered to have a significant effect on CBZ metabolism but not on protein binding.

Adolescent↗
PubMed1995

Zonisamide: electrophysiological and metabolic changes in kainic acid-induced limbic seizures in rats.

We studied the pharmacological mechanism of zonisamide (ZNS) using an electrophysiological and autoradiographical method in a limbic seizure model in rats. Limbic seizure status epilepticus was induced by a unilateral microinjection of kainic acid (KA) into the amygdala. Initially, observed seizures were limited to the side of the injected amygdala and then propagated to bilateral sensorimotor cortex. Eighty minutes after injection, secondarily generalized seizure status epilepticus was induced, with each seizure lasting approximately 30 s and recurring every 5 min. ZNS 100 mg/kg was administered intravenously (i.v.) during the generalized seizure. Forty minutes after ZNS administration, epileptic activity was observed only at the KA-injected amygdalar site and spikes were not observed in the bilateral sensorimotor cortex. We studied local cerebral glucose utilization (LCGU) after ZNS or saline administration using an autoradiographical method in the same limbic seizure preparation. In the ZNS group, LCGU decreased in the ipsilateral sensorimotor cortex and hippocampus, whereas in the controls LCGU increased in these structures. On the other hand, ZNS did not suppress the epileptic activity of the primary focus and no decrease in LCGU was observed in the KA-injected amygdala. ZNS inhibited seizure propagation from the epileptogenic focus but did not suppress the epileptic activity of the focus. Our results suggest that ZNS is effective for the treatment of secondarily generalized seizure.

Animals↗
PubMed1996

Preliminary report on teratogenic effects of zonisamide in the offspring of treated women with epilepsy.

PURPOSE: We wished to assess the risk of teratogenicity of zonisamide (ZNS) in humans. METHODS: Pregnant epileptic women treated with ZNS and their offspring were prospectively monitored from June 1989 to December 1994. The outcome of pregnancy and status of neonates were examined based on the same standardized protocol. RESULTS: Twenty-six offspring exposed to ZNS with or without other antiepileptic drugs (AEDs) were studied. Malformations were detected in 2 offspring (7.7%) exposed to ZNS polypharmacy. Anencephaly was detected in one case at 16 weeks of gestation (case 1, artificial abortion), and atrial septal defect was detected in another case at 37 weeks of gestation (case 2, delivery by cesarean section). Serum concentrations of ZNS during the first trimester of pregnancy were 6.1 micrograms/ml in case 1 and 6.3 micrograms/ml in case 2; in both cases, the levels were below the therapeutic concentration range of ZNS. CONCLUSIONS: Teratogenic effects of ZNS were not clearly defined from these results since malformations were detected in two polypharmacy cases but not in four monopharmacy cases. The present data do not indicate that the risk of ZNS teratogenicity is greater than that of other conventional AEDs. However, such risk cannot be neglected even at therapeutic dosages or concentrations of ZNS, especially in patients receiving poly-pharmacy.

Abnormalities, Drug-Induced↗
PubMed1997

IgA and IgG2 deficiency associated with zonisamide therapy: a case report.

PURPOSE: To report a previously undescribed adverse effect, IgA/IgG subclass deficiency associated with zonisamide (ZNS) therapy. METHODS: Serum IgA and IgG subclass levels were determined by the turbidimetric immunoassay and enzyme-linked immunosorbent assay, respectively, in a 2-year-old boy with postmeningitis sequelae who was treated by ZNS. RESULTS: Four months after initiation of ZNS, combined deficiency of IgA and IgG2 was noted. After cessation of ZNS, serum IgA level was promptly increased. IgG2 level was gradually increased, but remained subnormal after 7 months. CONCLUSIONS: This case documents, for the first time, the action of ZNS on IgG immune system as well as IgA system. If patients with ZNS therapy showed IgA deficiency and recurrent infections, it is preferable to check serum IgG subclass concentrations as well.

Anticonvulsants↗
PubMed1997

Protective effect of zonisamide, an antiepileptic drug, against transient focal cerebral ischemia with middle cerebral artery occlusion-reperfusion in rats.

PURPOSE: The antiepileptic effects of zonisamide (ZNS) have been well documented experimentally and clinically. The purpose of this study was to examine whether ZNS reduces cerebral damage after transient focal ischemia in rats. METHODS: Ischemia was induced by a transient occlusion of the left middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. Neurological evaluation was performed by measuring the event of neurological deficit of the contralateral forepaw and hindpaw at 10 min and 1 day after MCA occlusion (MCAo). Brain infarct size was determined by measuring triphenyltetrazonium chloride-negative stained area of the serial brain sections 1 day after MCAo. RESULTS: The pre- or postischemic treatment with ZNS [(10-100 mg/kg p.o.), 30 min before and 4 h after or 15 min and 4 h after the occlusion] markedly reduced cerebral damage in the ipsilateral hemisphere and the neurological deficit induced by transient ischemia. The reducing effect on the damage was observed in the cortical and subcortical regions. Preischemic treatment with carbamazepine (CBZ 60 mg/kg p.o. twice 30 min before and 4 h after MCAo) tended to reduce the cerebral damage and neurological deficit, but the lower dose (20 mg/kg p.o. twice) did not. Valproate (VPA 1,000 mg/kg p.o. twice) also had no effect. CONCLUSIONS: ZNS at the anticonvulsant dose, unlike CBZ and VPA, ameliorated the brain infarction and the event of neurological deficit after transient focal cerebral ischemia. These data suggest that ZNS has therapeutic potential in protecting against ischemic cerebral damage, such as stroke.

Animals↗
PubMed1997

Zonisamide monotherapy in newly diagnosed infantile spasms.

PURPOSE: We determined the short-term efficacy of zonisamide (ZNS) monotherapy in newly diagnosed patients with infantile spasms (IS). METHODS: Eleven hospitals participated in this open, prospective trial. ZNS 3-10 mg/kg/day was administered as the second-choice drug to 11 newly diagnosed patients with IS (cryptogenic 3, symptomatic 8) who failed to respond to high-dose vitamin B6. RESULTS: Four infants with symptomatic IS had cessation of spasms and disappearance of the hypsarrhythmia. In these responders, the spasms ceased after a few days (1-5 days) of treatment at a dose of ZNS 4-5 mg/kg/day which produced plasma ZNS concentrations ranging from 5.2 to 16.3 microg/ml (mean 9.8 microg/ml). There were two relapses (50%) 4-6 weeks after cessation of seizures, however. Relapse was predicted by effects of ZNS on EEG; the 2 infants in whom an abnormal EEG persisted had relapses, whereas the 2 whose EEG normalized remained seizure-free (follow-up 20 and 26 months). No adverse reactions were noted. CONCLUSIONS: ZNS may be effective in the initial treatment of selected patients with IS.

Adrenocorticotropic Hormone↗
PubMed1999

Zonisamide.

Zonisamide (ZNS) is a broad-spectrum antiepileptic drug in both animal models of epilepsy and patients with epilepsy. It is effective for both localization-related and generalized epilepsies and appears to be particularly potent in progressive myoclonic epilepsy syndromes. Its pharmokinetic profile is favorable, with a long half-life and low protein binding. However, its insolubility may make the development of a parenteral formulation difficult. Its safety profile is good, although teratogenicity in animal models is of concern. Adult doses of 400-600 mg per day in two doses, with blood levels from 20 to 30 mg/ml, appear to be effective.

Adult↗
PubMed2000

Zonisamide reduces the increase in 8-hydroxy-2'-deoxyguanosine levels formed during iron-induced epileptogenesis in the brains of rats.

PURPOSE: To examine the change of 8-hydroxy-2'deoxyguanosine (8-OHdG) levels, which are used as a marker for oxidative DNA damage, in iron-induced epileptogenic foci of the rat cerebrum. METHOD: Male Wistar rats were given a cortical injection of ferric chloride, and their 8-OHdG levels were determined over time. Additional animals were pretreated with the antiepileptic drug zonisamide (ZNS) before the ferric chloride injection, and their 8-OHdG levels were compared with the nonpretreated rats. RESULTS: Fifteen minutes after ferric chloride solution injection, the level of 8-OHdG increased, reaching a maximum 30 minutes after injection. Sixty minutes after injection, the levels coincided with those of controls. ZNS, in concentrations of 50 and 100 mg/kg body weight, prevented the increase of 8-OHdG levels within the cerebrum 30 minutes after iron solution injection. CONCLUSIONS: These results indicate that the formation of iron-induced epileptogenic foci in rats is related to DNA-damage-induced reactive oxygen species and that the inhibition of 8-OHdG formation by ZNS after iron injection may be due to the drug's antioxidant activity. The data suggest that free radical species known to be formed during iron salts-induced focal epileptogenesis cause damage to isocortical DNA. Furthermore, ZNS appears to inhibit the focal injuring response to DNA that occurs following iron salts-induced acute epileptogenesis.

8-Hydroxy-2'-Deoxyguanosine↗