Zonisamide (CI-912) and Cognition: Results from Preliminary Study

Nine patients with refractory partial seizures were evaluated in a pilot study of a new anticonvulsant compound, zonisamide (1,2-benzisoxazole-3-methanesulfonamide; CI-912). Cognitive functioning was evaluated prior to treatment with zonisamide and repeated after 12 and 24 weeks of treatment with zonisamide. At minimum steady-state plasma concentrations greater than 30 micrograms/ml, zonisamide appeared to affect specific cognitive functions such as acquisition and consolidation of new information. Previously learned material, such as vocabulary, and psychomotor performance were not affected. Verbal learning was affected, while visual-perceptual learning was unimpaired. These cognitive effects were observed in the absence of the usual clinical signs and symptoms of toxicity. A linear relationship was found between impairment of cognitive abilities and the minimum plasma concentration (r = -0.73; p less than 0.05). Findings also suggest the development of tolerance to the adverse cognitive effects.     

Effect of Cinromide on Inhibitory and Excitatory Mechanisms

The effect of the experimental anticonvulsant cinromide (3-bromo-N-ethylcinnamamide) on various inhibitory and excitatory mechanisms was investigated in the trigeminal nucleus of cats. Intravenous administration of 20-80 mg/kg cinromide depressed excitatory transmission and facilitated segmental inhibition to the same extent as phenytoin, but less than carbamazepine. These doses of cinromide also depressed periventricular inhibition, similar to valproate and ethosuximide. In addition, cinromide had a marked depressant effect on the EEG, suggesting a pronounced sedative effect. The serum levels of cinromide and of its active metabolites (3-bromocinnamamide and 3-bromocinnamic acid) were comparable to those in patients receiving long-term treatment with cinromide. Our results agree with those in other experimental models, which also suggest that cinromide is a broad-spectrum anticonvulsant, and with cinromide's effect in the clinical trials reported so far.     

Zonisamide: Review of Recent Clinical Evidence for Treatment of Epilepsy

Zonisamide is an orally administered antiepileptic drug that was first approved for clinical use in Japan in 1989. Since then, it has been licensed in Korea for a broad spectrum of epilepsies in adults and children, and in the USA for adjunctive therapy of adults with partial seizures, and in Europe for monotherapy of adults with newly diagnosed partial seizures and adjunctive therapy of adults and adolescents and children aged ≥6 years with partial seizures with or without secondary generalization. Zonisamide is a benzisoxazole derivative with a unique chemical structure, predictable dose‐dependent pharmacokinetics, and multiple complementary mechanisms of action. Treatment with zonisamide is well tolerated and is not known to be associated with clinically significant drug–drug interactions, including with oral contraceptives or other antiepileptic drugs. There have been >2 million patient‐years of experience with zonisamide for treatment of epilepsy, and this drug has International League Against Epilepsy level A evidence for efficacy/effectiveness as initial monotherapy for adults with partial‐onset seizures. This review presents the evidence for zonisamide across the spectrum of epilepsy, with emphasis on real‐world clinical practice and special populations of patients (children, elderly patients, and women of childbearing age) who are likely to be treated in daily clinical practice.     

Comparison of Progabide with Other Antiepileptic and GABAergic Drugs

The effect of the experimental antiepileptic gamma-aminobutyric acid (GABA) agonist drug progabide, [alpha-(chloro-4-phenyl)fluor-5-hydroxy-2-benzilideneamino]-4-buty ramide, on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs and with the effect of various GABA agonists and antagonists. Intravenous administration of 10-40 mg/kg progabide depressed excitatory transmission and descending periventricular inhibition, similar to carbamazepine and phenytoin. However, progabide depressed, rather than facilitated, segmental inhibition. The serum levels of progabide were comparable with those in patients receiving long-term treatment with progabide. The GABA antagonist bicuculline had the opposite effect of progabide on our experimental model, but the other GABA agonists THIP (4,5,6,7-tetrahydroisoxazolo-5,4-C-pyridine-3-ol) and muscimol did not have the same effects as progabide. THIP had no effect on excitatory transmission, periventricular inhibition, or segmental inhibition, whereas muscimol facilitated periventricular inhibition and sometimes segmental inhibition and had no effect on excitatory transmission. Our experiments thus indicate that progabide, but not THIP or muscimol, should have antiepileptic properties, in agreement with the clinical experiences that have been reported. The reason for the differential effect of these three GABA agonists remains to be elucidated.     

Influence of Additional Therapy with Zonisamide (Excegran) on Protein Binding and Metabolism of Carbamazepine

Summary: 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 (CBZEKBZ). Statistical significant negative correlation was observed between LID 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.     

Preliminary Report on Teratogenic Effects of Zonisamide in the Offspring of Treated Women with Epilepsy

Summary: Purpose: We wished to assess the risk of terato-genicity 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 septa1 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 μg/ml in case 1 and 6·3μ/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 polypharmacy.     

Protective Effect of Zonisamide, an Antiepileptic Drug, Against Transient Focal Cerebral Ischemia with Middle Cerebral Artery Occlusion-Reperfusion in Rats

Summary: 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 chloridenegative stained area of the serial brain sections 1 day after MCAo.
Results : The pre- or postischemic treatment with ZNS [(10–100 mgkg 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 mgkg p.0. 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 mgkg 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.     

Neuroprotective Effect of Felbamate After Kainic Acid-Induced Status Epilepticus

Summary: Felbamate (FBM), a newly developed antiepileptic drug (AED), was previously shown to offer some neuroprotective effects against hypoxic injury in both in vivo and in vitro studies. We administered FBM (100 or 300 mg/kg) to 30-day-old rats 1 h after they received a convulsant dosage of kainic acid (KA). Animals were then tested at age 80 days in the water maze, open field, and handling tests. Seizure latency was then tested by flurothyl inhalation. Animals that received 300 mg/kg FBM performed better in all three tests and had longer latencies to flurothyl-induced seizures than did animals that received vehicle. This study suggests that FBM may have some neuroprotective effects after KA-induced status epilepticus (SE).     

Effects of Zonisamide (AD-810) on Tungstic Acid Gel-Induced Thalamic Generalized Seizures and Conjugated Estrogen-Induced Cortical Spike-Wave Discharges in Cats

Effects of zonisamide (AD-810, CI-912) were examined on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spike-wave discharges in gallamine-immobilized cats. Zonisamide prolonged the interictal periods of the generalized seizures by thalamic (centralis lateralis) application of tungstic acid gel (50 microliters) and, at the higher doses, abolished the seizures; its potency was near that of phenobarbital. Zonisamide abolished the spike-wave discharges by cortical (posterior lateralis) application of 2% conjugated estrogens (CE); its potency was stronger than that of dipropylacetate or trimethadione, but slightly less than that of phenytoin, phenobarbital, or carbamazepine. Zonisamide did not affect the posttetanic potentiation of the monosynaptic reflexes (ventral root potentials) in urethane-chloralose-anesthetized spinal rats. From these results, it is suggested that zonisamide suppresses both seizures originating from the thalamus and the cortex through the mechanism differing from that of phenytoin. Zonisamide appears to be effective in primary generalized seizures, especially the grand mal epilepsies, in addition to being effective in cortical epilepsies.     

Triazolines XV. Anticonvulsant Profile of ADD 17014, a Potentially Unique 1,2,3-Triazoline Antiepileptic Drug, in Mice and Rats

ADD 17014[1-(4-chlorophenyl)-5-(4-pyridyl) delta 2-1,2,3-triazoline], is a representative member of a hitherto unknown, structurally novel family of anticonvulsant agents. The anticonvulsant profile of ADD 17014 following intraperitoneal (i.p.) and oral administration in mice and rats was evaluated using a battery of well-standardized anticonvulsant tests and compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). The results indicate that ADD 17014 is effective in nontoxic i.p. doses in mice by the maximal electroshock seizure (MES), Metrazol (subcutaneous, s.c. Met), bicuculline (s.c. Bic) and picrotoxin (s.c. Pic) tests, but ineffective against strychnine-induced seizures; it is also effective after nontoxic oral doses in both mice and rats by the MES and s.c. Met tests. Protective indices (PI = TD50/ED50), calculated from i.p. data in mice, were highest for ADD 17014 by the s.c. Met (26.02) and s.c. Bic (93.93) tests; the PIs, after oral administration in mice and rats, were equal to or higher than those of the prototype agents. In vitro receptor binding studies of ADD 17014 and potential metabolites indicated no significant inhibitory activity except for the beta-amino alcohol, which displaced almost 93% of [3H]glutamate from the glutamate receptors, suggesting that ADD 17014 may be functioning as a prodrug and an excitatory amino acid antagonist. The overall results indicate that ADD 17014 is a relatively nontoxic agent that more closely resembles PB and VPA, with a broad and unique spectrum of anticonvulsant activity.     

A New Experimental Model for Drug Studies: Effects of Phenobarbital and Phenytoin on Photosensitivity in the Lateral Geniculate-Kindled Cat

Photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and the GL-kindled cat pretreated with DL-allylglycine showed a stable level of photosensitivity. To test the usefulness as a model for the evaluation of anticonvulsant drugs, the effects of phenobarbital (PB) and phenytoin (PHT) on photosensitivity were studied in the GL-kindled cat under DL-allylglycine. PB (5 and 10 mg/kg intravenously, i.v.) completely suppressed photically induced seizures in most subjects at plasma concentrations of 7-16 micrograms/ml, and this anticonvulsant action persisted for at least 4 h after the injection. PHT (15 mg/kg, i.v.) at plasma concentrations of 9-15 micrograms/ml produced toxic signs, e.g., pupil dilatation, hypersalivation, and tachypnea. At this dose, PHT was inactive against photically induced myoclonus but prevented the elicitation of a generalized tonic-clonic convulsion. From these results showing that the effects of anticonvulsant drugs on photically induced seizures can be assessed in relation to plasma concentration and acute neurologic toxicity, we suggest that the GL-kindled cat is a potentially useful animal model of epilepsy for testing the efficacy of anticonvulsant drugs.     

Effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced convulsions: Possible mechanism of action

Cyclooxygenase (COX) is reported to play a significant role in neurodegenerative and neuropsychiatric disorders, and may play a significant role in the pathogenesis of epilepsy. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy. The objective of the present study was to elucidate the effect of cyclooxygenase inhibitors on pentylenetetrazol (PTZ)-induced (80 mg/kg) convulsions in mice with possible mechanism of action. Various COX-inhibitors were administered 45 min prior to the PTZ administration. Onset, duration of clonic convulsions and percentage mortality/recovery were recorded. Pretreatment with COX-inhibitors aspirin (10 and 20 mg/kg, p.o.), naproxen (7 and 14 mg/kg, p.o.), nimesulide (1–5 mg/kg, p.o.) or rofecoxib (1–4 mg/kg, p.o.) dose-dependently showed protection against PTZ-induced convulsions. COX-2 inhibitors were more effective as compared to non-selective COX-inhibitors. Rofecoxib (1 mg/kg) or nimesulide (1 mg/kg) also enhanced the sub-protective effect of diazepam or muscimol showing GABAergic modulation of COX-2 inhibitors. COX-2 inhibitors also antagonized the effect of flumazenil (4 mg/kg)- against PTZ-induced convulsions further confirming the GABAergic mechanism.

In conclusion, the results of the present study strongly suggest the possible role of cyclooxygenase isoenzymes in the pathophysiology of epilepsy and the use of COX-inhibitors as an adjuvant therapy in the treatment of epilepsy.     

Suppression of pentylenetetrazole seizures by oral administration of a dihydropyridine Ca2+ antagonist

We previously demonstrated that the dihydropyridine calcium channel blocker, nimodipine, is an effective anticonvulsant in experimental seizures when administered parentally. Reported now are the results for the oral administration of nimodipine in pentylenetetrazole (PTZ)-induced seizures in the rabbit. Twenty rabbits were randomly assigned into 10 controls and 10 treated with nimodipine 5 mg/kg/day orally for 5 days. All animals received increasing doses of the convulsant PTZ intravenously (i.v). The epileptogenecity of this agent was assessed in all animals (mg/kg) by four electrocorticographic criteria: first seizure greater than 5 s, two seizures within 5 min, epileptiform activity for 1 h, and status epilepticus. In all four categories, nimodipine increased the seizure threshold by 50-60%. The dose of PTZ required to produce the first seizure was 27.0 +/- 5.4 mg/kg in controls and 49.6 +/- 9.9 mg/kg in treated animals (p less than 0.001). Similar values were obtained for the other three electrocorticographic categories. There were no observable adverse side effects. The results confirm our previous findings that calcium influx is critical for seizure induction, and that selective central nervous system (CNS) calcium channel blockers may emerge as a new class of anticonvulsants.     

Effect of Phenytoin on Semen

Summary: Male patients receiving antiepileptic drugs (AEDs) have often complained of hyposexuality. Few studies have been done on semen analysis, which is relevant for assessment of potential and possible reproductive outcome in such cases. We evaluated the effect of epilepsy itself and/or phenytoin (PHT) on the male reproductive system. Fifty-five patients with epilepsy (42 with PHT and 13 untreated) and 28 healthy normal controls were studied by semen analysis. Serum samples from 21 of the 55 patients were also analyzed for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone. Results showed lower volume of seminal fluid, spermatozoa concentration, and total sperm count in untreated and PHT-treated patients as compared with controls, although no difference was evident between the patient groups. Morphologically abnormal sperm were more increased in untreated patients than in PHT treated and control subjects. Hormonal analysis showed lower levels of testosterone in 9 patients. LH levels were increased in one third of the patients. Our results suggests an effect of seizures on the male reproductive system, and PHT may have a slight additive (if any) influence.     

Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial

The safety and preliminary efficacy of trigeminal nerve stimulation (TNS) for epilepsy was evaluated in a pilot feasibility study of transcutaneous stimulation of the infraorbital and supraorbital branches of the trigeminal nerve. TNS was well tolerated. Four (57%) of seven subjects who completed >or=3 months experienced a >or=50% reduction in seizure frequency. The results of this pilot study support further investigation into the safety and efficacy of TNS for epilepsy.     

Pilot Study of Zonisamide (1,2-Benzisoxazole-3-methanesulfonamide) in Patients with Refractory Partial Seizures

A new anticonvulsant compound, zonisamide (1,2 benzisoxazole-methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were higher than plasma concentrations because of red blood cell binding. Steady-state plasma concentrations were higher than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose-related reversible side effects in the central nervous and gastrointestinal systems were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day.     

Effect of anticonvulsants on cortical focal seizure in cats.

Electrical stimulation of the visual cortex evoked the cortical focal seizure restricted in the neighbor cortex of the stimulated area in gallamine-immobilized cats. The present experiment was performed to clarify the participation of anticonvulsants in the cortex itself. Phenytoin and carbamazepine depressed the focal seizure, as indicated by the shortening of seizure duration and the suppression of spreading. In addition, the high-frequency components in seizure disappeared with the use of these drugs. Phenobarbital and diazepam also shortened the seizure duration. However, the high-frequency components did not disappear although seizure amplitude was depressed. Trimethadione, acetazolamide, and dipropylacetate facilitated the focal seizure. From these results, the participation of the drugs affecting grand mal and partial epilepsies in the cortex is suggested. In addition, this experimental model is though to be useful in elucidating possible modes or mechanisms of anticonvulsant action on cortical neurons by analyzing, after drug administration, the changes in seizure patterns which seem to reflect underlying neuronal changes.     

Comparison of Midazolam and Diazepam by the Intramuscular Route for the Control of Seizures in a Mouse Model of Status Epilepticus

A model system is described in which sustained clonic seizures are produced by a combination of phenytoin (PHT) and pentylenetetrazol (PTZ) in the mouse, the former agent preventing the terminal tonic spasms produced by the latter. In this system, midazolam (MDL), a water-soluble benzodiazepine, was compared with diazepam (DZP), a sparingly soluble agent which is widely used to treat status epilepticus (SE) in humans. Both agents were administered intramuscularly (i.m.) in approximately equieffective doses in animals exhibiting clonic seizure activity. MDL proved to be about twice as potent as DZP. Whereas control animals convulsed for a period of approximately 90 min, those treated with DZP 0.2 and 0.4 mg/kg convulsed for 7.8 and 3.9 min, respectively; mice receiving MDL 0.1 and 0.2 mg/kg convulsed for 1.9 and 1.4 min, respectively. MDL arrested seizures substantially more rapidly than diazepam (p less than 0.05). These data suggest that MDL has sufficiently rapid anticonvulsant action to merit evaluation for control of SE in humans when a rapidly absorbed antiepileptic drug (AED) is needed and intravenous (i.v.) administration is not feasible.     

Synaptic connections of a periodontal primary afferent neuron within the subnucleus oralis of the cat

The central axon of a primary afferent neuron that responded to light mechanical stimulation of the lower premolar teeth in a fast adapting fashion was intra-axonally injected with horseradish peroxidase in the cat. The labeled terminals within the rostrodorsomedial (Vo.r) and dorsomedial (Vo.dm) parts of subnucleus oralis were examined electron microscopically. The labeled ending had pale axoplasm, contained clear spherical synaptic vesicles, and formed multiple synapses with dendrites and/or unlabeled axonal endings with pleomorphic vesicles (P-endings). In these synaptic contacts, the labeled primary ending was presynaptic to dendrites and postsynaptic to P-endings. Labeled endings simultaneously synapsing with both dendrites and P-endings were more frequent in Vo.dm (28%) than in Vo.r (8.3%).