Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Zonisamide: a new antiepileptic drug. 1044 47

Epilepsy is common in the elderly. The incidence of epilepsy is age-dependent, with a peak during the first year of life and higher incidence in those older than 75 years. Cerebrovascular disease is a common cause of epilepsy in the elderly. Drug treatment of the elderly is a challenge because of pharmacokinetic changes with aging, including impaired drug protein binding or displacement of drug from protein binding sites, potentially causing drug toxicity as a result of increased free drug concentrations. With aging, hepatic mass and blood flow decline along with renal function. Established anticonvulsant drugs have adverse effects and drug interactions that can make treating the elderly difficult. Newly available anticonvulsants cause fewer drug-drug interactions and less toxicity. Gabapentin is not metabolised, is not bound to protein, and has a favourable adverse effect profile and thus may be useful in the treatment of elderly patients. Lamotrigine reduced seizures between 20 and 30% in trials. Dose response was between 300mg per day and 500mg per day. This drug was well tolerated in open-label trials. Rash occurred in younger patients. Oxcarbazepine is rapidly absorbed and is converted to a monohydroxy derivative. Use with hepatic enzyme-inducing drugs necessitates an increase in dose. This drug may be substituted for carbamazepine. Hyponatraemia has been reported and monitoring is suggested. Topiramate blocks voltage-dependent sustained repetitive firing and has an effect on the gamma-aminobutyric acid (GABA) receptors. It affects glutamate responses and inhibits carbonic anhydrase. Topiramate has a dose response pattern up to 400mg per day. Cognitive effects limits its use in some patients. Nephrolithiasis has occurred with this drug. Tiagabine blocks GABA transporter proteins. Clearance is rapid and metabolism complete. Hepatic dysfunction prolongs clearance. The use of tiagabine has not been reported in the elderly. Zonisamide is rapidly absorbed and protein binding is 50%. Plasma half-life is 55 hours but is reduced to about 30 hours by hepatic enzyme-inducing drugs. Responder rate is 45%. Adverse effects include drowsiness, altered thinking and nephrolithiasis. Treatment of the elderly requires obligatory polypharmacy with potential drug interactions. Changes in body physiology alter absorption, binding, metabolism and elimination of drugs. Concomitant illness and sensitivity to drug effects narrow the therapeutic range and complicate pharmacokinetics in elderly patients. Newer anticonvulsant drugs have advantages that may outweigh risks and have therapeutic profiles that may aid in the treatment of this special population of patients.
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PMID:Choice and use of newer anticonvulsant drugs in older patients. 1120 Mar 5

A brief review of epilepsy as a disease, anti-epileptic drugs and methods of evaluation of anti-epileptic drugs are presented as a background for assessment of zonisamide, which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. Chemically, zonisamide is classified as a sulphonamide and is unrelated to other anti-epileptic drugs. The mode of action of zonisamide remains unclear, but likely mechanisms are blockade of sodium and T-type calcium channels. It is also shown to have some neuroprotective effect against hypoxia and ischaemia. It has a liner pharmacokinetics with excellent oral bioavailability. Zonisamide has been approved for use in Japan for ten years prior to approval in USA and Europe. Clinical experience with zonisamide in Japan has documented its efficacy in the treatment of partial seizures (partial-onset generalised tonic-clonic, simple partial and/or complex partial seizures) and to a more variable extent, generalised tonic-clonic, generalised tonic (mainly seen in symptomatic generalised epilepsies including Lennox-Gastaut Syndrome) and compound/combination seizures. The efficacy and safety was confirmed in trials conducted in USA and Europe in adults as well as children. Zonisamide compares favourably with other newly introduced drugs and has the potential for development as a monotherapy for epilepsy.
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PMID:An assessment of zonisamide as an anti-epileptic drug. 1124 91

We evaluated racemic zopiclone, its (S)- and (R)-enantiomers and a metabolite, (S)-desmethylzopiclone, for their actions on locomotor activity, rotarod performance, the elevated plus maze and the Vogel conflict test of anxiety, and electroconvulsive shock-induced seizures duration. Zopiclone and its (R)- and (S)-enantiomers reduced locomotor activity, and zopiclone and its (S)-enantiomer disrupted rotarod performance at 10 mg/kg. (S)-desmethylzopiclone did not alter these measures at doses of less than 200 mg/kg. (S)-desmethylzopiclone altered plus maze performance at the lowest dose of all the zopiclone derivatives tested, caused a dose-related effect on the Vogel conflict test and caused a dose-related reduction of electroconvulsive shock-induced seizure durations. The data indicate that (S)-desmethylzopiclone can bring about an anxiolytic effect without a substantial degree of central nervous system depression, and suggest that the agent may be particularly useful clinically in the treatment of anxiety.
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PMID:Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite. 1127 97

The effects of phenobarbital (PB; doses, 5, 10, and 25 mg/kg, intraperitoneally (i.p.)) and zonisamide (ZNS; doses, 30, 75, and 150 mg/kg, i.p.) on nitric oxide (NO) production, and those of coadministration of PB (5 mg/kg, i.p.) and ZNS (75 mg/kg, i.p.) on monoamines in the brain of the seizure-susceptible EL mouse were investigated. Nitric oxide production was obtained by measuring the combined level of nitrite plus nitrate (NOx). Zonisamide and PB dose-dependently suppressed the seizure of the EL mouse, and coadministration of PB (5 mg/kg) and ZNS (75 mg/kg) induced a greater degree of seizure suppression than treatment with ZNS or PB alone. Although PB (5 mg/kg) had no effect on brain NOx levels, ZNS (150 mg/kg) and coadministration of ZNS (75 mg/kg) and PB (5 mg/kg) decreased NOx levels significantly. Phenobarbital (5 mg/kg) did not influence monoamines, while coadministration of PB (5 mg/kg) and ZNS (75 mg/kg) decreased dihydroxyphenylacetic acid and increased 5-HT concentrations. The effect of the coadministration of two drugs on monoamines were similar to that of ZNS alone. These results suggest that one of the anticonvulsant effects of coadministration of PB and ZNS may be caused by changes in NOx levels.
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PMID:Alterations of nitric oxide and monoamines in the brain of the EL mouse treated with phenobarbital and zonisamide. 1144 80

The choice of an antiepileptic drug depends firstly on its efficacy in specific seizure types and epilepsies. However, it is imperative to consider whether possible adverse events will outweigh any benefits. The advantages and disadvantages of vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine and felbamate are considered in some detail, and oxcarbazepine, stiripentol, remacemide, zonisamide and levetiracetam more briefly. Vigabatrin is effective for partial seizures and infantile spasms, but visual field defects are limiting its use. Lamotrigine has a wide spectrum, needs to be prescribed with care. Gabapentin is unlikely to cause adverse effects, but has relatively poor efficacy. Topiramate is widely effective, but can be poorly tolerated. Tiagabine is relatively untried in childhood epilepsies. The use of felbamate is restricted to severe refractory epilepsies. Stiripentol can be effective in severe myoclonic epilepsy in infancy. Zonisamide has a special place in the progressive myoclonus epilepsies. Levetiracetam, remacemide and oxcarbazepine have been used mainly for partial seizures: further studies of their roles in other circumstances are required.
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PMID:Newer antiepileptic drugs: advantages and disadvantages. 1150 96

Zonisamide is a novel anticonvulsant that is structurally and mechanistically unique, compared with other antiepilepsy drugs. Available in Japan and South Korea since 1989, it was approved in the United States in the year 2000 as adjunctive therapy for partial seizures in adults. There has been extensive clinical trial and clinical practice experience with zonisamide therapy in Japanese children. Open-label data from pediatric clinical trials conducted in Japan suggest that zonisamide is well tolerated and effective against partial- and generalized-onset seizures in children. Despite this wealth of open-label data, no formal pharmacokinetic studies and only one well-controlled trial of zonisamide's efficacy and safety in Japanese children have been completed to date. No controlled clinical trials of zonisamide in children have been completed in the United States or Europe. Additional controlled trials in children with partial- or generalized-onset seizures, infantile spasms, and Lennox-Gastaut syndrome are warranted to further delineate zonisamide's broad spectrum of efficacy and tolerability in children.
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PMID:Zonisamide in pediatric epilepsy: review of the Japanese experience. 1195 83

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.
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PMID:[Urolithiasis induced by combined ACTH and zonisamide treatment in a patient with startle induced epilepsy]. 1223 54

We treated 27 children with idiopathic epilepsy with zonisamide monotherapy over a period of 2 years and observed behaviour disturbances in a prospective study. In all cases, seizure control was excellent; however, two cases (7.4%) had behaviour disturbances. The first (Case 1) was a 14-year-old girl with partial epilepsy which began at age 4 years. Zonisamide was administered at age 6 years, which was effective against her seizures, but selective mutism, violent behaviour, and lack of concentration developed at age 10 years. The second (Case 2) was a 15-year-old girl with generalized tonic-clonic seizures which began at age 10 years. Zonisamide was also effective against her seizures, but obsessive compulsive disorders (OCD) developed at age 13 years. The patients have had no other physical or mental problems and decreasing the dosage of zonisamide reduced the problems. There are few reports of behaviour disturbances provoked by zonisamide monotherapy in epileptic children who are neither physically nor mentally disturbed. While problems can develop several years later, in the present study, decreasing the zonisamide dosage maintained adequate prevention of seizures and eliminated the behaviour disturbances. Zonisamide is still a useful anticonvulsant for epileptic seizures, but physicians should be wary of its adverse behavioural side effects, which may arise several years later.
Seizure 2002 Oct
PMID:Selective mutism and obsessive compulsive disorders associated with zonisamide. 1223 77

We investigated the characteristics of the flurothyl-induced seizures and the effects of antiepileptic drugs on the flurothyl-induced seizure model in a previously untested Mongolian gerbil species. Mongolian gerbils demonstrated tonic extension immediately after or within 1 min after the appearance of clonic convulsion. Very high amplitude spike waves appeared in these regions concurrent with the appearance of clonic convulsion. When the tonic extension appeared immediately after the clonic convulsion, the high amplitude spike waves continued during tonic convulsion. When the tonic extension occurred, high amplitude spike waves appeared in these three regions within a very short time, and afterward Mongolian gerbils died. Administration of valproic acid-Na (200 mg/kg), ethosuximide (100 and 200 mg/kg), clonazepam (2 mg/kg) and diazepam (0.5, 1 and 2 mg/kg) significantly prolonged the latency of clonic convulsion. Zonisamide-Na, phenytoin and carbamazepine, however, had no such effect. In Mongolian gerbils, tonic extension was demonstrated immediately after the appearance of clonic convulsion, yet, this effect was inhibited by all these drugs in a dose-dependent manner. Diazepam completely blocked the appearance of any behavioral changes in animals. These findings suggest that diazepam has a significant effect on flurothyl-induced seizures. Flurothyl-induced convulsions are associated with GABA receptors; hence, benzodiazepine (BDP) suppression may result from the strong relation between BDP and GABAnergic neurons.
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PMID:Characteristics of flurothyl-induced seizures and the effect of antiepileptic drugs on flurothyl-induced seizures in Mongolian gerbils. 1237 61


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