Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present work is a review of the new anti-epileptic drug felbamate. Felbamate is a dicarbonate with antiepileptic effects in partial attacks and in Lennox-Gastaut syndrome. This new drug is especially interesting since its pharmacological action on test animals would indicate a wider anti-epileptic spectrum of activity than most other such drugs. We review the clinical pharmacology of felbamate, its development as a new antiepileptic and the new clinical control type trials carried out into epilepsy. We also give a summary of clinical trial experiments performed using felbamate in the treatment of partial refractory attack and of Lennox-Gastaut syndrome. Felbamate has turned out to be the first anti-epileptic with specific efficacy in Lennox-Gastaut syndrome. Felbamate was approved as an anti-epileptic by the United States Food And Drug Administration in July 1993 for clinical use with children suffering from Lennox-Gastaut syndrome and with adults having partial epileptic attacks. 1994 saw some cases of aplastic anaemia and liver failure associated with treatment using felbamate which called for a reevaluation of the benefit-risk factors of the drug. Its use in the European Union was restricted to Lennox-Gastaut syndrome, and rigorous liver function and haematological controls were set up in patients so treated. In the United States the FDA also allows treatment using felbamate of partial attacks not responding to any type of medicine.
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PMID:[Felbamate: perspectives for new antiepileptic treatment]. 855 22

A totally automated analysis of felbamate was developed by using a robotized PrepStation for extraction, followed by automated liquid chromatographic (LC) analysis and data reduction. This is one of the newer direct-sample analysis approaches by LC. Felbamate was a previously approved antiepileptic agent used to treat partial seizures with and without generalization and to treat Lennox-Gastaut syndrome in pediatric patients. However, due to the reported incidences of aplastic anemia, its clinical application was recently restricted to the treatment of the latter syndrome. The automated assay using Bench Supervisor, PrepStation, and LC, based on a previously developed manual method, used 200 microliters of serum standards, quality control, or patients' plasma. These were mixed with 600 microliters of internal standard (IS) W509 dissolved in acetonitrile for protein precipitation. After axial centrifugation and standing, aliquots of the clear supernatant were transferred and washed with hexane. Aliquots of the supernatant were transferred and injected into a high-performance liquid chromatograph (HPLC). HPLC parameters included an mu Bondapak C-18 column, phosphate/acetonitrile (8:2) as mobile phase, and detection at 214 nm. Retention times were 2.9 and 4.2 min for felbamate and IS, respectively. Calibration was linear for concentrations from 10 to 200 mg/L with r > 0.994. Precision studies showed coefficients of variation ranging from 2.7% to 8.8%. Correlation with the manual method showed that r = 0.934, slope = 1.048, intercept = -2.642, and n = 21. Phenobarbital coeluted with the IS. This study demonstrated the feasibility of using a robotized, automated method for monitoring felbamate, readily extended to monitoring other antiepileptic drugs with minimal modification.
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PMID:Totally automated analysis by robotized PrepStation and liquid chromatography: direct-sample analysis of felbamate. 888 22

We evaluated the use of felbamate in 379 adults and children with refractory epilepsies in an open-label, compassionate clinical use setting. Prior to the termination of the program, because of reports of aplastic anemia, 351 patients had completed 2 months of treatment with felbamate at a dose of 2400-3600 mg/day for adults or 30-45 mg/kg/day for children. Of the 246 patients who had a diagnosis of therapy-refractory localization-related epilepsy with or without secondary generalization, 52% (126/246) achieved a seizure reduction of 50% or more, including 10% (25/246) who became seizure free. There was no difference in response rate between adults and children. Of the 80 patients who had a diagnosis of Lennox-Gastaut syndrome (LGS), 60% (48/80) achieved a seizure reduction of 50% or more, including 6% (5/80) who became seizure free. Of the 25 patients with a diagnosis of generalized epilepsy (other than LGS) or undetermined epilepsy whether focal or generalized, 60% (15/25) achieved a seizure reduction of 50% or more, including 12% (3/24) who became seizure free. The results of this uncontrolled study suggest that felbamate could be useful in patients with epilepsies which are refractory to other antiepileptic drugs after careful risk-benefit assessment and consideration of all circumstances involved.
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PMID:Felbamate in therapy-resistant epilepsy: an Italian experience. Felbamate Italian Study Group. 895 23

Felbamate, 2-phenyl-1,3-propanediol dicarbamate, is an antiepileptic drug recently approved by the United States Food and Drug Administration. It has a novel mechanism of action whereby it may decrease excitation by inhibiting glycine binding at the NMDA receptor, and it appears to have neuroprotective properties in addition to antiepileptic ones. A number of animal models have demonstrated felbamate to have a broad range of efficacy as well as a favorable safety profile. In humans it has been potentially linked to some cases of aplastic anemia. It is effective in the treatment of partial and secondarily generalized tonic-clonic seizures as well as seizures associated with the Lennox-Gastaut syndrome, especially drop attacks. It may also be effective against atypical absence as well as other seizure types. Felbamate monotherapy is generally well tolerated, with such side effects as insomnia and anorexia occurring most commonly. Felbamate shows great promise as a useful antiepileptic drug, but its role in clinical practice awaits further investigation of recently reported cases of aplastic anemia.
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PMID:Felbamate pharmacology and use in epilepsy. 931 88

Within the last years five new antiepileptics have become available in Germany. Vigabatrin is a second choice drug against partial seizures, West syndrome and epilepsies in infant encephalopathy syndromes. Lamotrigine and Gabapentin can be used as add-on therapy in partial seizures in children above 12 years of age Felbamate has a high incidence of severe side-effects like aplastic anemia and liver failure. Therefore it should be restricted to the treatment of Lennox-Gastaut syndrome. Oxcarbazepine is not yet on the German market, but is available by import from Austria. Its therapeutic range is similar to carbamazepine with less side-effects. The new antiepileptics discussed have turned out to be useful additional therapeutics, especially in focal epilepsies. There is, however, still limited experience with these drugs in children. So none can as yet be considered a drug of first choice in any epileptic childhood disorder. The classical antiepileptic drugs remain essential in antiepileptic therapy.
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PMID:[Value of the new anticonvulsants in pediatrics]. 952 99

Felbamate was launched in 1993 in the U.S. as a "new generation" antiepileptic drug (AED) with a unique mechanism of action. It proved efficacious in patients refractory to other AEDs and was particularly beneficial in children suffering from Lennox-Gastaut syndrome, being the first drug shown to be effective at treating this condition in controlled trials. Following the occurrence of rare cases of aplastic anemia and of hepatic failure associated with the use of felbamate during early 1994, a "black-box" warning was added to the drug's package insert. Despite this, felbamate continues to be used in many patients, although not as a first-line treatment. Felbamate's dual mechanism of action--enhancing the GABA system while inhibiting excitatory amino acid responses--may explain its efficacy in a broad range of epileptic patients. A better understanding of this mechanism may lead to the development of felbamate-like drugs with a better side effect profile.
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PMID:Felbamate: clinical and molecular aspects of a unique antiepileptic drug. 984 55

Felbamate (2-phenyl-1,3-propanediol dicarbamate), a representative of novel antiepileptic drugs (AESs), proved to have broad-spectrum anticonvulsive activity. Particularly beneficial efficacy was found against partial seizures and Lennox-Gastaut syndrome. Therefore, felbamate started to be indicated not only as an adjunctive antiepileptic drug but also in monotherapy. Unfortunately, it was also evidenced that the drug may induce aplastic anemia or hepatic failure. The former complication was frequently described in patients with previously diagnosed hematopoetic disturbances. Thirty-four cases of well-documented bone marrow suppression, occurred fatal in thirteen cases. Subsequently, felbamate's usage was essentially restricted and at present felbamate is not a first-line AED. However, excluding anemia-prone individuals, new possibilities may open for felbamate position in add-on therapy of drug-resistant epilepsy. Experimental studies provide a good theoretical basis for this kind of treatment.
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PMID:Is there any future for felbamate treatment? 1521 58

Felbamate is a derivative of meprobamate used in second-line partial epilepsy and in the Lennox-Gastaut syndrome. Felbamate is well absorbed and has linear kinetics: C(max) and AUC increasing linearly with dose. The metabolism takes place in the liver. Metabolites represent 40 to 60% of excretion and are eliminated via the urine. The half-life is between 15 and 23 hours. Clearance is dependent on renal function. There is a concentration - efficacy and concentration - toxicity relationship. These arguments are in favour of a TDM but the therapeutic range is not clearly established. Potentially fatal side effects can be caused by felbamate (aplastic anemia, acute liver failure), which limits its use because they are dose-independant.
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PMID:[Therapeutic drug monitoring of felbamate]. 2020 93

In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, especially intravenous levetiracetam. The pharmacokinetic profiles of levetiracetam, gabapentin, and pregabalin are favorable: these drugs exhibit minimal protein binding, do not undergo hepatic metabolism, are not involved in any clinically relevant drug interactions, and rarely lead to the development of serious adverse effects. In general, levetiracetam is probably the closest to being the ideal AED because of its broad-spectrum favorable pharmacokinetic profile and safety profile as well as because of the availability of its parenteral formulation. Among the injectable AEDs, fosphenytoin is a water-soluble prodrug and is used to treat patients with status epilepticus. Systemic and local side effects of this drug are fewer than those of phenytoin. Lorazepam, a benzodiazepine is used as the first-line AED for the treatment of patients with status epilepticus. The effects of this drug are more prolonged than those of diazepam. Intravenous administration of valproic acid is regarded as a new treatment option for patients with status epilepticus, because sedative and negative effects on the cardiorespiratory system of this drug are lesser than those of the traditional injectable AEDs. These novel medications will aid the improvement of the quality of life of epileptic patients through improved seizure control and reduced adverse effects.
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PMID:[Antiepileptic drugs in North America]. 2045 99

The antiepileptic drug felbamate has demonstrated efficacy against a variety of seizure types in the pediatric population, particularly seizures associated with Lennox-Gastaut syndrome. Postmarketing experience, however, revealed serious idiosyncratic adverse effects not observed during clinical trials, including aplastic anemia and liver failure. As a result, many physicians have been hesitant to prescribe felbamate. This retrospective study evaluated the efficacy of felbamate in a pediatric population with intractable epilepsy. Of 38 patients, 22 had Lennox-Gastaut syndrome (58%); 6 had myoclonic-astatic epilepsy of Doose (16%); 5 had symptomatic generalized epilepsy, not otherwise specified (13%); and 5 had symptomatic localization-related epilepsy (13%). Most patients had multiple seizure types and had been tried on a variety of antiepileptic medications. With felbamate treatment, 6 patients (16%) became seizure free, including 4 of the 6 patients with myoclonic-astatic epilepsy of Doose; 24 patients (63%) had a greater than 50% reduction in seizure frequency. In this population felbamate appeared to be safe, with minimal adverse effects. The study is limited by the small number of patients and by its retrospective nature, but nonetheless adds to the evidence that felbamate is an important antiepileptic drug for medically refractory epilepsy in children and is well tolerated with few adverse effects.
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PMID:Efficacy of felbamate in the treatment of intractable pediatric epilepsy. 2047 90


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