Epilepsy research
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Human temporal lobe epilepsy is associated with complex partial seizures that can produce secondarily generalized seizures and motor convulsions. In some patients with temporal lobe epilepsy, the seizures and convulsions occur following a latent period after an initial injury and may progressively increase in frequency for much of the patient's life. Available animal models of temporal lobe epilepsy are produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous chronic motor seizures. ⋯ Therefore, multiple low-dose injections of kainate, which cause recurrent motor seizures for > or = 3 h, lead to the development of a chronic epileptic state that is characterized by (i) a latent period before the onset of chronic motor seizures, and (ii) a high but variable seizure frequency that initially increases with time after the first chronic seizure. This modification of the kainate-treatment protocol is efficient and relatively simple, and the properties of the chronic epileptic state appear similar to severe human temporal lobe epilepsy. Furthermore, the observation that seizure frequency initially increased as a function of time after kainate treatment supports the hypothesis that temporal lobe epilepsy can be a progressive syndrome.
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In rats, this study determined the impact of systemic hypoxia during late kainate-induced status epilepticus on hippocampal neuron loss and mossy fiber sprouting. Non-fasted Sprague Dawley rats were prepared as follows: Naive controls (n=5); rats placed 2 min in a hypoxia chamber (hypoxia only; n=6); rats that seized for more than 6 h from kainic acid (KA-status; 12 mg/kg; i.p.; n=7); and another KA-status group placed into the hypoxia chamber 75 min after the convulsions started (KA-status/hypoxia; n=16). All rats, except for half of the KA-status/hypoxia animals, were perfused 2 weeks later (short-term). ⋯ Compared to KA-status/hypoxia short-term rats, long-term animals showed no differences in ventral hippocampal neuron densities, but middle and dorsal sections demonstrated increased IML-OML GV differences and animals were observed to have spontaneous limbic epilepsy. These results indicate that rats exposed to kainate-induced status epilepticus for over 1 h and then a hypoxic insult had a shorter duration of convulsive status, decreased hippocampal neuron densities and greater FD mossy fiber sprouting than controls and the amount of neuronal damage and sprouting was slightly more than animals subjected to 6 h of kainate-induced status. This supports the hypothesis that a physiologic insult during status can shorten the convulsive episode, but still produce hippocampal pathology with a number of clinical and pathologic similarities to human mesial temporal lobe epilepsy (MTLE).
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Randomized Controlled Trial Multicenter Study Clinical Trial
A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.
In a multicentre, double-blind, parallel-group, placebo-controlled trial, a three-times daily regimen of tiagabine was evaluated as add-on therapy in 154 adult patients with refractory partial seizures. A total of 77 patients were randomised to treatment in each arm. Tiagabine HCl was titrated from an initial dose of 12-30 mg/day over 4 weeks. ⋯ Adverse event incidence was similar between tiagabine and placebo groups, except for dizziness which was more common with tiagabine (29 versus 10%, P < 0.01). Tiagabine had no significant effects on laboratory tests or vital signs. The present study shows that tiagabine, at a dose of 10 mg administered three-times daily, which is at the lower end of the usual recommended dose range (30-50 mg/day, tiagabine base), is generally well tolerated and demonstrates efficacy for the treatment of refractory partial seizures.
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Comparative Study
Anticonvulsant effect of fosphenytoin in amygdala-kindled rats: comparison with phenytoin.
Phenytoin has been reported to exert variable anticonvulsant effects in the kindling model of complex partial seizures. Phenytoin is only water soluble at a pH of more than 10, and it has been suspected that poor absorption of the drug is responsible for its lack of effect in some experiments. Recently, fosphenytoin, a prodrug of phenytoin, has been developed by phosphorylating phenytoin which makes the drug water soluble at physiological pH while it is rapidly transformed to phenytoin after injection. ⋯ Seizure severity and duration at threshold were reduced only after the highest does of fosphenytoin tested (84 mg/kg). Thus, fosphenytoin showed anticonvulsant properties similar to phenytoin in amygdala kindled rats. We conclude that fosphenytoin is an adequate and reliable substitute for the parenteral injection of phenytoin in experimental seizure models of rats.
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Multicenter Study Clinical Trial
Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin.
Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. ⋯ All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.