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)

Oxcarbazepine is the 10-keto analogue of carbamazepine but has a distinct pharmacokinetic profile. In contrast to the oxidative metabolism of carbamazepine, oxcarbazepine is rapidly reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. With the possible exception of the P450IIIA isozyme of the cytochrome P450 family, neither oxcarbazepine nor its monohydroxy derivative induce hepatic oxidative metabolism. Direct comparison of oxcarbazepine and carbamazepine has shown no difference in efficacy between these 2 agents in terms of reducing seizure frequency in patients with partial epilepsy with or without secondary generalisation, or with tonic-clonic seizures. Substitution of oxcarbazepine for carbamazepine in multiple antiepileptic drug regimens improved seizure control in some patients with refractory epilepsy; however, the rise in serum concentrations of concurrent antiepileptic agents secondary to elimination of carbamazepine-associated hepatic enzyme induction may have also played a role. Substitution of oxcarbazepine for carbamazepine was associated with improved cognition and alertness in some patients with epilepsy. Limited data indicate that oxcarbazepine may be a useful alternative to carbamazepine in the management of trigeminal neuralgia. Experience in patients with acute mania is promising, but the value of oxcarbazepine in managing affective disorders, particularly as a prophylactic agent, is not established. Oxcarbazepine may be better tolerated than carbamazepine; however, the current published database is small and the potential for oxcarbazepine to induce the type of serious idiosyncratic reactions occasionally associated with carbamazepine is unknown. Hyponatraemia has been reported in patients treated with oxcarbazepine. Although apparently asymptomatic, fluid restriction may be deemed necessary in some patients to reduce the risk of precipitating seizures secondary to low serum sodium. Thus, oxcarbazepine appears to be an effective substitute for carbamazepine in those patients intolerant of this agent, or experiencing significant drug interactions. Wider clinical experience should help clarify the long term efficacy and tolerability of oxcarbazepine. Pharmacokinetic advantages over current antiepileptic drugs, carbamazepine in particular, may then favour oxcarbazepine for consideration as a first-line agent in the management of partial and tonic-clonic epilepsy.
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PMID:Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. 137 59

Oxcarbazepine is a new anticonvulsant, currently undergoing clinical trials. Its spectrum of antiepileptic action, and its chemical structure, resemble those of carbamazepine, though the 2 drugs have no pharmacologically active metabolites in common. In a study of 7 adults with poorly controlled partial epilepsy, progressive substitution of oxcarbazepine for carbamazepine left seizure control unaltered in 4 and improved in 3, whilst 5 became more alert and one was rendered ataxic. Three subjects became hyponatraemic. There were no other adverse effects. Plasma levels of the drug and its pharmacologically active 10-hydroxy derivative were measured sequentially over 4 days after a single drug dose at the outset of therapy in 5 subjects. Calculated pharmacokinetic parameter values for the drug, assuming complete oral bioavailability, were: absorption lag time 2.07 +/- 1.61 h: absorption rate constant 8.328 +/- 8.941 h-1: apparent volume of distribution 3.937 +/- 2.222 L kg-1: oral clearance 2.898 +/- 1.439 L kg-1: elimination rate constant 0.609 +/- 0.261 h-1 (half-life 1.26 +/- 0.37 h), while the metabolite had a formation rate constant of 0.593 +/- 0.233 h-1, and an elimination rate constant of 0.082 +/- 0.014 h-1 (half-life 8.74 +/- 1.79 h). Even with a single dose, peak plasma metabolite levels were substantially higher than those of the parent drug. Oxcarbazepine appears to be a promising alternative to carbamazepine as an anticonvulsant, although in view of its rapid elimination it probably serves mainly as a prodrug for its 10-hydroxy metabolite.
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PMID:Oxcarbazepine: preliminary clinical and pharmacokinetic studies on a new anticonvulsant. 326 34

There are several new antiepileptic drugs undergoing extensive clinical investigation. Five new drugs--vigabatrin, lamotrigine, gabapentin, felbamate and oxcarbazepine--appear to be the most widely tested and promising agents. Vigabatrin is most effective in drug-resistant partial epilepsy. Vigabatrin is also effective in infantile spasms, but seems to have negative effects on myoclonic epilepsies and absence seizures. Lamotrigine and felbamate seem to be effective in partial epilepsy and in Lennox-Gastaut syndrome. In addition, lamotrigine and felbamate seem to have efficacy in idiopathic generalised epilepsies. Oxcarbazepine appears to be equally as effective as carbamazepine, but less toxic. Gabapentin has few adverse effects and has efficacy in some patients with drug-resistant partial epilepsy. Some of the new antiepileptic drugs modify excitatory or inhibitory amino acid transmission, but some of them may employ new, still unknown mechanisms of action. Depending on the mechanism of action, the therapeutic effectiveness of the antiepileptic drugs may differ in specific epileptic syndromes. Future antiepileptic drugs may thus give us the possibility to design rational polypharmacy for individual patients by combining agents with different spectra of effectiveness. Considering the goal of good tolerability in the development of the new antiepileptic drugs, polypharmacy with these agents is not expected to increase adverse effects significantly.
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PMID:Place of newer antiepileptic drugs in the treatment of epilepsy. 751 Jun 9

Notwithstanding pharmacokinetics has greatly increased the rational approach to the drug treatment of epilepsies, about 25% of the patients do not respond to the therapy. Therefore, a great effort has been made to discover new antiepileptic drugs effective in refractory seizures. On the basis of increased knowledge of seizure pathophysiology two principal groups of drugs have been developed: the first enhancing brain GABA activity (vigabatrin); the second inhibiting excitatory amino-acids (lamotrigine and felbamate). Oxcarbazepine has the same mechanism of action as carbamazepine, whereas gabapentin's mechanism is still uncertain. The major clinical indications of these new antiepileptic drugs are represented by partial complex seizures. Side effects (mostly regarding the central nervous system) appear mild, and clinical interactions have little importance. The role of therapeutic drug monitoring for these substances is at present not well established.
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PMID:New antiepileptic drugs. 763 Aug 54

Progress made in the development of new antiepileptics (AEs) is justified by the high percentage of refractory patients to the available medical therapy (25%), although only a minority of cases are deemed suitable for surgical therapy. Yet, the ideal AE, that is, with a well-known mechanism of action, effective in monotherapy for all epileptic fits, with a perfect pharmacokinetic profile, with no adverse or teratogenic effects, with no drug interactions and available under many formulations, is far from being developed. The new AEs arise either from modification of already marked drug molecules or clinical formulations or from the effectiveness on the excitatory/inhibitory balance of the major neurotransmitters involved in the pathogenesis of seizures, the gamma-amino-butyric acid (GABA) as the inhibitory, and the glutamate (GLU) as the excitatory one. However, the mechanism remains unknown in a few of them. Those new AEs already marketed in Portugal (Vigabatrin), soon to be (Lamotrigine, Oxcarbazepine) or available abroad only (Gabapentin, Zonisamide) are review with special emphasis on their pharmacokinetic profile, side effects, interaction with other AEs, and clinical use. In conclusion, these new drugs have brought a very important advancement in the management of refractory patients, but the development of well-designed comparative trials involving both monotherapy and polytherapy has become important in order to develop useful strategies in the drug management of epilepsy.
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PMID:[New antiepileptic medications]. 774 11

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady-state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10, 11-dihydro-10-hydroxy-carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double-blind cross-over placebo-controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.
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PMID:Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy. 780 39

Epilepsy is one of the most common neurological disorders. Even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications. There is, therefore, a need for more potent and effective antiepileptic drugs and drugs with fewer adverse effects, particularly CNS effects. Drugs for the treatment of partial seizures are particularly needed. With major advances in our understanding of the basic neuropathology, neuropharmacology and neurophysiology of epilepsy, numerous candidate novel antiepileptic drugs have been developed in recent years. This review comparatively evaluates the pharmacokinetics, efficacy and adverse effects of 12 new antiepileptic drugs namely vigabatrin, lamotrigine, gabapentin, oxcarbazepine, felbamate, tiagabine, eterobarb, zonisamide, remacemide, stiripentol, topiramate and levetiracetam (ucb-L059). Of the 12 drugs, vigabatrin, lamotrigine and gabapentin have recently been marketed in the UK. Five of these new drugs have known mechanisms of action (vigabatrin, lamotrigine, tiagabine, oxcarbazepine and eterobarb), which may provide for a more rational approach to the treatment of epilepsy. Oxcarbazepine, remacemide and eterobarb are prodrugs. Vigabatrin, gabapentin and topiramate are more promising on the basis of their pharmacokinetic characteristics in that they are excreted mainly unchanged in urine and not susceptible to significant pharmacokinetic interactions. In contrast, lamotrigine, felbamate and stiripentol exhibit significant drug interactions. Essentially, all the drugs are effective in partial or secondarily generalised seizures and are effective to varying degrees in other seizure types. Particularly welcome is the possible effectiveness of zonisamide in myoclonus and felbamate in Lennox-Gastaut syndrome. In relation to adverse effects, CNS effects are observed with all drugs, however, gabapentin, remacemide and levetiracetam appear to exhibit least. There is also the possibility of rational duotherapy, using drugs with known mechanisms of action, as an additional therapeutic approach. The efficacy of these 12 antiepileptic drug occurs despite the fact that candidate antiepileptic drugs are evaluated under highly unfavourable conditions, namely as add-on therapy in patients refractory to drug management and with high seizure frequency. Thus, whilst candidate drugs which do become licensed are an advance in that they are effective and/or are associated with less adverse effects than currently available antiepileptic drugs in these patients, it is possible that these drugs may exhibit even more improved risk-benefit ratios when used in normal clinical practice.
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PMID:Newer antiepileptic drugs. Towards an improved risk-benefit ratio. 791 80

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. 904 81

Oxcarbazepine (OCBZ) has been accepted for registration as a first-line antiepileptic drug (AED) in several countries. However, because of changing regulations, further studies confirming statistically significant proof of efficacy are necessary in accordance with new standards. Therefore, Ciba has initiated a worldwide clinical development program to achieve registration. Four different types of design to demonstrate statistically significant proof of efficacy in partial seizures will be initiated. These studies are a "classical" polytherapy add-on study, a monotherapy substitution trial, a high-dose/low-dose active-control monotherapy study, and a study in presurgical patients.
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PMID:Clinical development outlook of oxcarbazepine. 815 75

In drug-resistant epilepsy the use of VGB, LTG, oxcarbazepine, FBM and GBP resulted in at least a 50% improvement in 20% to 60% of such patients treated and in 7% led to complete seizure control. In the long term, VGB may lose its efficacy and give rise to tolerance phenomena. Another frequent disadvantage of VGB is poor compliance owing to the large number of tablets needed to achieve the necessary dose (2-3 g). VGB may also induce a worsening of myoclonic epilepsies and seems ineffective in absences; whereas it can induce a good response in West's syndrome. LTG and FBM yielded a good response in idiopathic generalized epilepsies and were effective in refractory partial seizures, West's syndrome and Lennox-Gastaut's syndrome. After being suspended because of the risks of bone-marrow aplasia and liver toxicity, FBM trials began again in 1995, use of the drug being restrict to drug-resistant partial epilepsies and to Lennox-Gastaut's syndrome. Oxcarbazepine has an efficacy equal to that of CBZ, but had fewer side effects and very few interactions with other drugs. Although GBP has few side effects and acts as an anticonvulsant in subjects with resistant partial epilepsy, some reports suggest that it can lose its efficacy around the 18th or 19th month.
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PMID:[New antiepileptic drugs: a review and personal contribution]. 876 54


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