Gene/Protein Disease Symptom Drug Enzyme Compound
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 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Felbamate is currently being developed as an antiepileptic agent. Although its mechanism of action has yet to be fully elucidated, felbamate appears to inhibit both the spread of seizures and increase seizure threshold in animal models. Data available in the clinical setting provide evidence that, at doses of up to 3600 mg/day as an adjunct to existing antiepileptic therapy or as monotherapy following substitution for other medications, the drug reduces the frequency of partial onset seizures in adult patients refractory to conventional antiepileptic treatments. Felbamate is also effective in the treatment of Lennox-Gastaut syndrome in children, a severe epilepsy which is usually refractory to antiepileptic agents. The effect of felbamate in the treatment of generalised tonic-clonic seizures in adults with partial onset seizures which are secondarily generalised is promising but requires clarification in large-scale trials. The most common adverse effects occurring during administration of felbamate are mild to moderate gastrointestinal (nausea, vomiting and anorexia) and central nervous system (headache, somnolence, diplopia, dizziness and insomnia) disturbances. Drug interactions with other antiepileptic agents may prove problematic in terms of adverse effects. Thus, at this stage of its development, the antiepileptic efficacy of felbamate in treatment-refractory patients with partial onset seizures and Lennox-Gastaut syndrome has been proven but efficacy in generalised tonic-clonic seizures requires further substantiation in large well controlled and well designed clinical trials. In addition, a more comprehensive base of comparative clinical trials data is necessary to further clarify issues of relative efficacy and tolerability compared with other antiepileptic agents. The clinical implications of the drug interactions associated with felbamate also require more detailed investigation. These data will be awaited with interest and when available will help to place felbamate in perspective in the management of epilepsy.
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PMID:Felbamate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. 769 93

The chemistry, pharmacology, pharmacokinetics, clinical use, adverse effects, drug interactions, and dosage of felbamate are discussed. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is chemically unrelated to any of the other currently marketed antiepileptic drugs (AEDs). It appears that felbamate, like phenobarbital and valproic acid, decreases the frequency of seizures by decreasing seizure spread and increasing seizure threshold. Oral felbamate is at least 90% absorbed, and peak concentrations are reached in one to six hours. The half-life is a little less than one day. A therapeutic range of plasma concentrations has not been determined. Felbamate has been used effectively as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization and as adjunctive therapy in children with partial or generalized seizures associated with Lennox-Gastaut syndrome. Felbamate may also be safe and effective in patients with generalized, absence, atypical absence, juvenile myoclonic, infantile, and gelastic seizures. The most frequently reported adverse effects of felbamate include nausea, anorexia, vomiting, headache, fatigue, somnolence, insomnia, and increased serum aspartate aminotransferase levels. The frequency of adverse effects is greater in patients receiving other AEDs in addition to felbamate. Felbamate affects the pharmacokinetics of phenytoin, carbamazepine, valproic acid, and methsuximide; other AEDs also affect the pharmacokinetics of felbamate. The dosage of felbamate should begin at 400 mg orally three times daily and then increase by 600 mg/day every two weeks to up to 3600 mg/day. If the patient is receiving other AEDs concurrently, their dosage should be decreased as the dosage of felbamate is increased. If the goal is to switch to felbamate, the dosage should be increased weekly as the dosages of other AEDs are reduced. Felbamate offers a safe and effective alternative to other AEDs in the treatment of partial and secondarily generalized seizures; partial and generalized seizures associated with Lennox-Gastaut syndrome; and atypical absence seizures, gelastic seizures, and other difficult to control seizures.
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PMID:Felbamate: a new antiepileptic drug. 794 90

Lamotrigine (LTG) inhibits repetitive high frequency firing in depolarised neurones by selectively prolonging slow inactivation of the sodium channel, thereby suppressing the release of excitatory amino acids. It has been shown to be effective in 11 pivotal double-blind add-on trials in patients with refractory partial seizures with or without secondary generalisation. Subsequent anecdotal data support its efficacy for typical and atypical absences, myoclonic jerks, tonic or clonic seizures, Lennox-Gastaut syndrome and infantile spasms. Most recently LTG has been compared with carbamazepine and phenytoin in double-blind trials in patients with newly diagnosed partial and primary and secondary generalised tonic-clonic seizures. At the doses used, its efficacy was similar to the older agents for all seizure types, but LTG was better tolerated than both of the older agents. The commonest side-effects with LTG include headache, nausea, diplopia, dizziness, ataxia and tremor. Rash occurs in fewer than 5% patients. Its incidence can be reduced by starting treatment with a low dose, particularly in patients receiving concomitant sodium valproate which inhibits LTG metabolism. Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but LTG itself has no effect on hepatic metabolic processes. A pharmacodynamic interaction with carbamazepine necessitates a dosage reduction in some patients when LTG is introduced. LTG is a new antiepileptic agent with a long elimination half-life, a broad spectrum of activity, and a wide therapeutic ratio.
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PMID:Lamotrigine--an update. 895 Dec 13

Benign occipital epilepsy of childhood is an idiopathic partial epilepsy syndrome with elementary visual symptomatology, frequently associated with other ictal phenomena. Seizures are usually followed by postictal headache and are often associated with interictal occipital rhythmic paroxysmal EEG activity that appears only after eye closure. In some children the ictal visual symptoms or the interictal EEG abnormalities may not be demonstrated. The clinical and/or EEG manifestations of other forms of idiopathic partial or generalized epilepsy may be found in association. Occipital spikes in non-epileptic children with defective vision, occipital slow spike-and-wave found in some patients with the Lennox-Gastaut syndrome, focal epilepsy due to occipital lesions, seizures originating in the temporal lobe secondary to an occipital abnormality, and complicated or basilar migraine must be considered in the differential diagnosis. Early-onset benign occipital epilepsy or seizure susceptibility syndrome deserves to be considered separately. It has been defined by Panayiotopoulos as consisting of brief, infrequent attacks or prolonged status epilepticus and characterized by ictal deviation of the eyes and/or head and vomiting, occurring in children usually between the ages of 3 and 7 years. Advances in molecular genetics will help decide whether these two disorders are indeed distinct. Benign occipital and benign rolandic epilepsy are commonly associated with migraine. The selective involvement of the occipital lobe in migraine has not been fully explained. The association between benign occipital epilepsy and migraine is likely related to this underlying mechanism as well. The "fixation off" phenomenon or blocking of occipital epileptic discharges by eye opening is not specific to benign occipital epilepsy of childhood and may be found in symptomatic epilepsies as well. Migraine and epilepsy are distinct disorders, both as far as their pathophysiologic mechanisms and clinical symptomatology are concerned. There is however an overlap in some patients and a causal relationship may exist in some, leading to clinically distinct migraine epilepsy syndromes. Here too, clarification of the molecular basis of migraine and of epilepsy will throw light on the nature of the relationship between the two conditions.
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PMID:The benign occipital epilepsies of childhood: an overview of the idiopathic syndromes and of the relationship to migraine. 1048

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.
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PMID:[Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy]. 1084 3

Accumulating data suggest that the antiepilepsy drug lamotrigine, which has been available for adult use for more than a decade, also confers broad-spectrum, well-tolerated control of epilepsy in children. The current study--the open-label continuation phase of several short-term clinical trials--was conducted to assess the long-term tolerability and efficacy of lamotrigine as open-label adjunctive therapy or monotherapy in pediatric patients for a variety of seizure types and syndromes including partial seizures, absence seizures, and Lennox-Gastaut syndrome. Clinic visits occurred every 24 weeks throughout the treatment period. A total of 252 patients under 16 years of age were enrolled in the study. The numbers of patients exposed to at least 48 weeks, 96 weeks, and 144 weeks of treatment with lamotrigine were 185 (73.4%), 119 (47.2%), and 60 (23.8%), respectively, for an average duration of exposure of 96.7 weeks. The most common adverse events considered by the investigator to be drug related were dizziness (9.1%), somnolence (7.9%), nausea (6.3%), vomiting (5.2%), and headache (5.2%). The most common serious adverse events (regardless of suspected cause) included pneumonia (3.0%) and infection (1.9%). Investigators judged that the overall clinical status of three-fourths of the patients had improved at treatment weeks 48 and 96 relative to prelamotrigine clinical status. Lamotrigine administered as monotherapy or adjunctive therapy for an average of 2 years (96.7 weeks) was well tolerated and effective in pediatric patients with partial or generalized epilepsy. These results complement and extend the large body of data demonstrating the tolerability and efficacy of lamotrigine with short- and long-term use in adults.
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PMID:Long-term tolerability and efficacy of lamotrigine in pediatric patients with epilepsy. 1208 84

Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. Rufinamide was profiled for anticonvulsant activity at the National Institutes of Health and showed broad-spectrum anticonvulsant properties at nontoxic doses in animal models. The principal mechanism of action of rufinamide is considered to be the modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide provides an efficacious and well-tolerated treatment option for use as adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS). In LGS, rufinamide is effective in controlling multiple seizure types and in reducing the severity of the seizures. The most commonly observed (> or =10%) adverse experiences seen in association with rufinamide are headache, dizziness, fatigue, somnolence and nausea. Rufinamide is generally well tolerated, and its safety profile is well-established.
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PMID:Rufinamide. 1719 32

Rufinamide is a new antiepileptic drug that is effective in acute animal seizure models and also in the kindling model of epilepsy with a high protective index. Its mechanism of action is largely unknown; studies suggest an effect at voltage-gated sodium channels, but whether this is its main mode of action remains to be determined. Rufinamide can be administered twice daily and has minimal drug interactions (it does, however, interact with the contraceptive pill). Food markedly increases absorption, which may complicate clinical use. Trials indicate that rufinamide is effective as adjunctive therapy in partial epilepsy and the Lennox-Gastaut syndrome with minimal adverse effects including headache, dizziness and fatigue. In addition, rufinamide has a favorable cognitive side-effect profile. However, it remains uncertain whether rufinamide offers significant advantages over other current antiepileptic drugs, and the results of further clinical trials are awaited.
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PMID:Rufinamide. 1772 46

Rufinamide, a triazole derivative that is structurally distinct from currently marketed antiepileptic drugs (AEDs), is in development for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in children and adults. Rufinamide is well absorbed after oral administration, demonstrates low protein binding, and is metabolized by enzymatic hydrolysis without involvement of cytochrome P450 enzymes, conferring a low drug interaction potential. In a randomized, double-blind trial involving 138 adult and pediatric patients with LGS, compared with placebo, rufinamide 45 mg/kg/day resulted in significantly superior reductions in drop attacks (median change -42.5% vs +1.4% with placebo) and total seizures (-32.1% vs -11.7% with placebo), accompanied by significantly higher responder rates. These results are comparable with findings reported for other AEDs in randomized, controlled clinical trials in patients with LGS. Rufinamide produced statistically significant seizure reduction which was maintained during long-term therapy and accompanied by good tolerability. The most frequently reported adverse events from a pooled safety database evaluating short- and long-term therapy were headache (22.9% and 29.5%), dizziness (15.5% and 22.5%) and fatigue (13.6% and 17.7%). Rufinamide therefore presents a favorable efficacy and tolerability profile and is a promising candidate for the adjunctive therapy of LGS.
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PMID:Role of rufinamide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy). 1930 May 35

Rufinamide is a novel antiepileptic agent recently approved in the United States for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. To help inform clinical decision making, the authors analyzed safety and tolerability data from the entire pediatric population in the rufinamide epilepsy clinical development program. The analysis population comprised 212 rufinamide-treated (age range 3-16 years) and 197 placebo patients (age range 4-17 years) in the double-blind studies, and 391 patients receiving rufinamide in the double-blind and/or open-label extensions. The most common adverse effects observed in rufinamide-treated patients in the double-blind studies were somnolence, vomiting, and headache. Changes in laboratory values, vital signs, and weight were generally clinically insignificant. This pooled analysis of data from pediatric patients in clinical studies of rufinamide for the treatment of seizures, mainly as adjunctive therapy, suggests a favorable safety and tolerability profile in this patient population.
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PMID:Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. 1995 44


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