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)

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.
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PMID:Topiramate: preclinical evaluation of structurally novel anticonvulsant. 815 72

The effects of topiramate, a novel antiepileptic drug, on tonic and absence-like seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) and on sound-induced seizures in DBA/2 mice were investigated. Topiramate (20 and 40 mg/kg i.p.) inhibited both tonic and absence-like seizures in a dose-dependent manner, whereas phenytoin (20 mg/kg i.p.) and zonisamide (40 mg/kg i.p.) inhibited only the tonic seizures. The inhibitory effects of topiramate on absence-like seizures were antagonized by pretreatment with haloperidol (0.5 mg/kg i.p.), but those on the tonic seizures remained unaffected. Topiramate inhibited sound-induced seizures in DBA/2 mice (ED50 = 8.6 mg/kg p.o.). These findings suggest that topiramate may be effective for treatment of both convulsive and absence seizures of human epilepsy. The inhibitory effect of topiramate on absence-like seizures in SER may be mediated through the central dopaminergic system.
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PMID:Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice. 820 19

We conducted a randomized double-blind comparison of three doses of the novel antiepileptic drug (AED) topiramate (200, 400, and 600 mg/day) and placebo as adjunctive therapy in patients with refractory partial onset epilepsy receiving one or two other AEDs at therapeutic concentrations. A total of 181 patients completed the 12-week baseline phase and were randomized to double-blind therapy. Median percent reductions from baseline in average monthly seizure rate, the principal efficacy evaluation, were 13% for placebo, 30% for topiramate 200 mg/day, 48% for topiramate 400 mg/day, and 45% for topiramate 600 mg/day. For the seizure rate comparison of active drug to placebo p values were: topiramate 200 mg/day, p = 0.051; topiramate 400 mg/day, p = 0.007; topiramate 600 mg/day, p < 0.001. Percent responders ( > or = 50% reduction in seizure rates) were 18% for placebo, 27% for topiramate 200 mg/day, 47% for topiramate 400 mg/day (p = 0.013), and 46% for topiramate 600 mg/day (p = 0.027). A significant (p = 0.003) reduction in secondarily generalized seizures compared with placebo treatment was also documented with topiramate. Topiramate plasma concentrations were closely related to dosage, and there were no significant interactions between topiramate and other AEDs. The minimal effective dose of topiramate in this study population was approximately 200 mg/day. Mild or moderate CNS symptoms were the primary treatment-emergent adverse events, but treatment-limiting adverse events occurred in only 9% of patients given topiramate compared with 7% given placebo. Results of this initial well-controlled study in patients indicate that topiramate is a very promising new AED.
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PMID:Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Topiramate YD Study Group. 864 70

Topiramate, a structurally novel anticonvulsant, and phenytoin were evaluated in a rat model of ischemia-induced epilepsy. In this model a transient global cerebral ischemia is induced by cardiac compression. By precisely controlling the experimental conditions the procedure causes reproducible neurological deficits that include audiogenic epileptic seizures. The seizures can be broadly separated into three types reflecting the degree of severity: wild running, clonic seizures, and tonic extension seizures of the forelimbs and hindlimbs. Topiramate and phenytoin blocked all three types of seizures. Calculated ED50 values for topiramate 1 hr after oral administration were 8.2, 13.0 and 36.1 mg/kg for blockade of tonic extension seizures, clonic seizures and wild running, respectively. Corresponding ED50 values for phenytoin were 5.0, 10.8 and 20.7 mg/kg. These results support the concept that the anticonvulsant activity of these drugs is due primarily to an ability to block the spread of seizures.
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PMID:Anticonvulsant activity of topiramate and phenytoin in a rat model of ischemia-induced epilepsy. 876 22

Topiramate, a chemically novel anti-epileptic drug, was evaluated in amygdala-kindled seizures in rats. Topiramate, given at doses between 0.63 and 80 mg/kg i.p. and p.o. 4 h before kindling stimulation, exhibited a dose-related inhibition on all seizure parameters measured, i.e. behavioral seizures, forelimb clonus, amygdala and cortical afterdischarges. The ED50 values obtained with topiramate on kindled seizures in all parameters tended to be lower than those observed on maximal electroshock seizures in rats. After oral drug administration, the ED50 values were: on forelimb clonus, 7.25 mg/kg; on amygdala afterdischarges 7.09 mg/kg and on cortical afterdischarges 7.12 mg/kg. After i.p. drug administration, the ED50 values were: on forelimb clonus, 10.6 mg/kg; on amygdala afterdischarges, 13.9 mg/kg and on cortical afterdischarges, 10.4 mg/kg. The data obtained after i.p. drug administration are in line with the suggestion that topiramate primarily blocks spread of seizures.
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PMID:Topiramate: a potent anticonvulsant in the amygdala-kindled rat. 879 55

Topiramate (Topamax-Janssen-Cilag Ltd) is a new drug for the treatment of adults with epilepsy. It is licensed for adjunctive treatment of partial seizures, with or without secondary generalisation, poorly controlled by conventional first-line regimens. Topiramate is the third add-on treatment for epilepsy to be marketed in the last 4 years. Does it have a specific place in the treatment of epilepsy?
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PMID:Topiramate--add-on drug for partial seizures. 881 Jan 29

Topiramate is a recently licensed and marketed antiepileptic drug in the UK for use as add-on therapy for refractory partial epilepsy. It has multiple modes of action involving voltage-dependent sodium channels, GABA receptors and glutamate receptors. Topiramate has very favourable pharmacokinetics as it is primarily excreted unchanged. Its metabolism is, however, increased by enzyme inducers, and it can inhibit the metabolism of phenytoin in some patients. Its efficacy as adjunctive treatment in refractory partial epilepsy in adults appears good, over 40% of patients have a 50% or greater reduction in seizure frequency when topiramate is added to their regime with up to 7% becoming seizure free. The main adverse events are ataxia, impaired concentration, confusion, dizziness, fatigue, parasthesia, somnolence and "thinking abnormal'. Most of these occurred during rapid titration. During long-term treatment, weight loss also occurred and nephrolithiasis occurred in 1.5% of patients receiving topiramate. Topiramate is a useful and well-tolerated addition to our treatment of refractory epilepsy, but it should be titrated slowly in order to avoid adverse events.
Seizure 1996 Sep
PMID:Topiramate: a new antiepileptic drug for refractory epilepsy. 890 21

The spontaneously epileptic rat (SER), a double mutant, manifests both tonic and absence-like seizures. The effect of topiramate, a novel antiepileptic drug, on the extracellular levels of excitatory amino acids (EAA) in the hippocampus of SER was investigated using in vivo microdialysis. The basal levels of glutamate and aspartate in dialysates of hippocampus in SER were 2- to 3-fold higher than those in normal Wistar rats. Both the dose-response relationship and the time course of the suppression of tonic seizures by topiramate were similar to the attenuation of glutamate level in SER. Topiramate (40 mg/kg i.p.) significantly (P < 0.05) reduced both glutamate and aspartate levels in SER while showing no effect on normal Wistar rats. These findings suggest that topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of SER. This effect may, at least in part, be related to the anticonvulsant activity of topiramate.
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PMID:Topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of spontaneously epileptic rats (SER). 891 26

Topiramate, a new antiepileptic drug effective in controlling partial-onset seizures, was administered to humans for the first time as single oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phase I safety and pharmacokinetic study. Model-independent pharmacokinetic data analysis was performed on plasma concentration and renal excretion data for topiramate. Maximum plasma concentrations (Cmax) were observed between 1.4 and 4.3 hours after administration. Mean values for plasma Cmax and area under the concentration-time curve (AUC) increased linearly with dose; however, a greater-than-proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes. Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Approximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportionally over the 200 mg to 1,200 mg dose range. Elimination half-life (t1/2) values calculated from plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and independent of dose. Intersubject variability was low for all parameters. Renal clearance was 13.9 mL/min, suggesting that renal tubular reabsorption may be prominently involved in the renal handling of topiramate. The elimination profile of topiramate indicated that longer sampling times are necessary in future studies to more accurately determine the t1/2. Food effect studies indicated a slight reduction in the rate (approximately 10% decrease in mean Cmax and mean tmax approximately 2 hours later) but not the extent of absorption when topiramate was given with food. Topiramate demonstrates a number of favorable pharmacokinetic features, including linear and predictable dose-concentration relationships, excretion mainly as unchanged drug by the kidney, a dose-independent t1/2, low intersubject variability in pharmacokinetic parameters, and lack of clinically significant effect of food on bioavailability.
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PMID:Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. 893 Jul 74

1. After a hiatus of over 20 years, several new antiepileptic drugs (vigabatrin, lamotrigine, gabapentin, oxcarbazepine, topiramate, felbamate, zonisamide and tiagabine) have reached or approached the registration phase. 2. Compared with older agents, many new drugs exhibit simpler pharmacokinetics. This is especially true for vigabatrin and gabapentin, which are renally eliminated and have a low interaction potential. 3. Unlike most of the older agents, vigabatrin, lamotrigine, gabapentin and tiagabine are devoid of significant enzyme inducing or inhibiting properties. Topiramate, oxcarbazepine and felbamate may induce the metabolism of steroid oral contraceptives. In addition, felbamate also acts as a metabolic inhibitor. 4. To date, the efficacy of new drugs has been evaluated extensively only under add-on conditions in patients with partial seizures (with or without secondary generalization) refractory to conventional treatment. However, there is evidence that lamotrigine, zonisamide, felbamate and, possibly, topiramate may also be effective in generalized epilepsies. 5. In placebo-controlled studies, typically between 15 and 40% of patients with difficult-to-treat partial epilepsy have shown an improvement (defined as a 50% or greater decrease in seizure frequency) after addition of a new drug. Only a small minority of these patients achieved complete seizure control. 6. Compared with older agents, some of the new drugs may have a better tolerability profile. Felbamate, however, has been associated with a high risk of aplastic anaemia and hepatotoxicity. 7. At present, the main use of the new agents is in patients refractory to first-line drugs such as carbamazepine or valproate, and further studies are required to characterize their activity spectrum as well as their potential value in monotherapy. In most patients, new drugs cannot be recommended for first-line use until evidence is obtained that potential advantages in tolerability or ease of use outweigh the drawback of their high cost.
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PMID:The new generation of antiepileptic drugs: advantages and disadvantages. 895 Nov 84


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