YOU ARE NOW CONNECTED TO THE TOXLINE (1981 FORWARD, NON-ROYALTY) FILE. ==NEURONTIN OR GABAPENTIN== 1 AUTHOR Pimentel J AUTHOR Pinto F TITLE [New antiepileptic medications] SOURCE Acta Med Port 1995 Jan;8(1):43-8 ABSTRACT 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. 2 AUTHOR Schmidt D AUTHOR Kramer G TITLE The new anticonvulsant drugs. Implications for avoidance of adverse effects. SOURCE Drug Saf 1994 Dec;11(6):422-31 ABSTRACT Several new antiepileptic drugs offer a worthwhile alternative when standard antiepileptic drugs have failed. Suggestions have been made to improve the risk-benefit ratio of the new antiepileptic agents. More specifically, vigabatrin, which is a very useful and well tolerated new antiepileptic drug for refractory partial epilepsy, should be started at a low dosage of 0.5 g/day with increments of 0.5 g/day every week. Daily dosages exceeding 3 g/day should be restricted to patients with improvement. If necessary, the daily dosage of vigabatrin should be withdrawn slowly, i.e. by not more than 1 g/week. Lamotrigine is also a beneficial new drug for refractory partial and generalized seizures. However, the drug is associated with rash. In patients also receiving valproic acid (sodium valproate) [which inhibits the metabolism of lamotrigine], the incidence of rash can be reduced by slow titration of 25mg every other day for the first week and 25mg per day for the second week. Rare hypersensitivity reactions, e.g. Stevens-Johnson syndrome, remain a problem. The risk-benefit ratio of felbamate has recently been compromised by fatal aplastic anaemia and fatal liver disease in a number of patients. In general, patients should be withdrawn from felbamate, if possible, until further clarification of its definitive risk-benefit ratio. Finally, gabapentin is a very safe add-on medication. Its remarkably low potential to cause adverse effects makes it a welcome addition for the treatment of refractory partial epilepsy. 3 AUTHOR Bruni J TITLE Antiepileptic drug selection and adverse effects: an overview. SOURCE Can J Neurol Sci 1994 Aug;21(3):S3-6 ABSTRACT In choosing an antiepileptic drug, not only efficacy but also potential adverse effects have to be considered. Adverse effects that have to be taken into account include acute and chronic systemic toxicity, cognitive side effects, and teratogenesis. Acute toxicity may be dose-related, allergic or an idiosyncratic reaction. Chronic toxicity may involve the nervous system or other organs. In determining the role of new antiepileptic drugs such as lamotrigine, vigabatrin, felbamate, and gabapentin a proper evaluation of both efficacy and adverse effects is required. 4 AUTHOR Leppik IE TITLE Antiepileptic drugs in development: prospects for the near future. SOURCE Epilepsia 1994;35 Suppl 4:S29-40 ABSTRACT Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.