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PubMed2004

Pharmacologic treatment of the catastrophic epilepsies.

Treatment of the catastrophic epilepsies [infantile spasms (IS), Lennox-Gastaut syndrome (LGS), and progressive myoclonic epilepsy (PME)] remains a challenge to clinicians. For IS, adrenocorticotropic hormone has traditionally been the drug of choice in the United States but may be associated with serious side effects in some patients. Vigabatrin has shown promise in treating IS patients, particularly those with tuberous sclerosis. However, the drug is associated with visual field loss and is not commercially available in the United States. Newer antiepilepsy drugs (AEDs), such as zonisamide, topiramate (TPM), and lamotrigine (LTG), may be useful in patients with IS. Although LTG, TPM, and felbamate are approved in the United States for the treatment of LGS, the overall effectiveness of therapy in patients with LGS is poor. For PME, valproate is a first-line treatment. Zonisamide and levetiracetam also show promise. Supplementation with certain cofactors to correct deficiencies and increase mitochondrial function may be useful in some patients with PME, but response to such therapy is not well documented. Advances in our understanding of the etiologies, mechanisms, and genetics underlying the catastrophic epilepsies may facilitate more effective pharmacologic interventions.

Anticonvulsants↗

PubMed2005

Efficacy of levetiracetam at 12 months in children classified by seizure type, cognitive status, and previous anticonvulsant drug use.

In a retrospective study of 59 children (ages 9 months to 23 years; mean age 11 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of levetiracetam therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications (range 0-5), and the number of previous anticonvulsant drugs (range 1-12). Good to excellent seizure control (50-100% reduction) was attained in 6 (40%) patients with focal seizures, 16 (55%) patients with generalized seizures, and 8 (61%) patients with mixed seizures; these efficacy rates were not significantly different. The efficacy of levetiracetam was independent of cognitive status. Adverse effects were not associated with higher mean doses. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of levetiracetam and zonisamide had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of the mechanisms of action of levetiracetam and zonisamide and/or their pharmacodynamic interactions.

Adolescent↗

PubMed1989

Binding of sulfonamides to erythrocytes and their components.

Binding of zonisamide, a new antiepileptic sulfonamide derivative, was examined to human erythrocytes, their lysate and their carbonic anhydrase by centrifugation for cells or by ultrafiltration for the others. Scatchard plots revealed that the binding to intact and lysed cells was composed of high- and low-affinity components and that to carbonic anhydrase, of the high-affinity component alone. Parameters for high-affinity binding were similar in all three preparations and those for low-affinity binding were similar in the former two preparations. Dissociation constants for these bindings to erythrocytes were smaller than the dissociation constant for serum albumin. These results may explain the concentration of sulfonamides in red cells, and suggest the participation of cellular protein component(s) in addition to previously known carbonic anhydrase in the binding. Acetazolamide, sulthiame, zonisamide, hydrochlorothiazide and sulfanilamide inhibited carbonic anhydrase in a non-competitive manner to different extents. The Ki values of these sulfonamides were of the order of 0.1--0.2 of their respective Kd values determined by ultrafiltration, suggesting that under the present conditions, physicochemical interactions between sulfonamides and carbonic anhydrase primarily occur at common sites that affect the activity of the enzyme.

Erythrocytes↗

PubMed2002

Newer therapies in the drug treatment of epilepsy.

OBJECTIVE: To provide a review of recent developments in the pharmacotherapy of epilepsy. DATA SOURCES: A MEDLINE search was performed to identify pertinent literature (1966-June 2001). Selected articles emphasized those published from 1997 to 2001. Bibliographies of identified articles were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All identifiable sources written in English. DATA SYNTHESIS: Epilepsy is a common neurologic disorder, and antiepileptic drugs (AEDs) are the mainstays of therapy. The focus of this article is on the 3 latest AEDs--levetiracetam, oxcarbazepine, and zonisamide. We discuss human data published as both original studies and reviews from the last 4 years, except where noted. We apply a general template for all 3 drugs and provide information on clinical trials, adverse effects, pharmacokinetics, drug interactions, and clinical use. CONCLUSIONS: Levetiracetam, oxcarbazepine, and zonisamide are reasonable options for many patients whose seizures are not yet controlled or who suffer from intolerable adverse effects. All 3 agents are approved for adjunctive use in patients with partial seizures. Oxcarbazepine also has approval for monotherapy in partial seizures. All 3 drugs are well tolerated by most patients and have characteristics that potentially make them easier to use with medications other than the older AEDs. Further clinical experience is needed before specific recommendations can be given for their place among older and newer AEDs.

Anticonvulsants↗

PubMed1994

Newer antiepileptic drugs. Towards an improved risk-benefit ratio.

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.

Acetamides↗

PubMed2006

Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.

Amines↗

PubMed2002

Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations.

BACKGROUND: To review the literature on efficacy of third generation anticonvulsants for treatment of bipolar disorder and provide clinical recommendations. METHOD: Open and controlled studies, case reports, and case series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide were located through electronic searches of several databases, by manual search of proceedings of international meetings, and through contacting authors of recent reports. RESULTS: Lamotrigine is the best studied anticonvulsant and has efficacy in acute bipolar depression and in longer term treatment of bipolar depression as well as rapid-cycling bipolar II disorder but not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct in bipolar disorder, but double-blind trials failed to confirm efficacy in acute mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is reported to be effective in acute mania and rapid-cycling bipolar disorder in several open studies, but methodological problems in a double-blind study led to a failed study in acute mania. However, topiramate may lead to weight loss in some patients. Zonisamide deserves further investigation, but tiagabine does not appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an unmet need in treating bipolar depression and rapid-cycling bipolar disorder. Other third generation anticonvulsants with the exception of tiagabine offer promise but require confirmation of their efficacy from double-blind studies.

Acetates↗

PubMed2000

Therapeutic monitoring of the new antiepileptic drugs.

OBJECTIVE: To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. METHODS: A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed. RESULTS: The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM. CONCLUSION: TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration-effect relationships of the new antiepileptic drugs are urgently needed.

Anticonvulsants↗

PubMed2006

A case of Kabuki syndrome presenting West syndrome.

A 6-month-old girl visited our hospital because of mental retardation, regression, and tonic spasms in cluster. We diagnosed her as West syndrome because of hypsarrhythmia on electroencephalogram (EEG) and tonic spasms in cluster. We also diagnosed her as Kabuki syndrome because of multiple malformations, especially a characteristic peculiar face (resembling a Kabuki actor). She was first administered clonazepam, but this was not effective. Later, she was administered vitamin B6, valproic acid, and zonisamide. Zonisamide was effective, and her tonic spasms were suppressed. Her EEG at 9 months of age showed the disappearance of hypsarrhythmia and sporadic spike and wave complexes on P3, P4, O1, and O2. At 2 years of age, she still showed mental retardation, despite the good control of West syndrome. To the best of our knowledge, Kabuki syndrome presenting West syndrome has been reported in only one previous case. We must pay attention to the occurrence of West syndrome in Kabuki syndrome.

Abnormalities, Multiple↗

PubMed2003

Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine.

BACKGROUND: Both neuropathic pain and migraine are now being treated with a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities in the pathophysiology of epilepsy, migraine, and various chronic pain disorders has further heightened interest in exploring the newer AEDs in the treatment of these conditions. OBJECTIVE: The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of 5 newer AEDs (gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these conditions; and provide a summary comparison of the dosing, tolerability, and drug-interaction potential of these agents. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1990-March 2003), American Academy of Neurology abstracts (1999-2003), and American Epilepsy Society abstracts (2000-2002). The search terms were antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide. CONCLUSIONS: The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.

Anticonvulsants↗

PubMed2001

Newer antiepileptic drugs: advantages and disadvantages.

The choice of an antiepileptic drug depends firstly on its efficacy in specific seizure types and epilepsies. However, it is imperative to consider whether possible adverse events will outweigh any benefits. The advantages and disadvantages of vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine and felbamate are considered in some detail, and oxcarbazepine, stiripentol, remacemide, zonisamide and levetiracetam more briefly. Vigabatrin is effective for partial seizures and infantile spasms, but visual field defects are limiting its use. Lamotrigine has a wide spectrum, needs to be prescribed with care. Gabapentin is unlikely to cause adverse effects, but has relatively poor efficacy. Topiramate is widely effective, but can be poorly tolerated. Tiagabine is relatively untried in childhood epilepsies. The use of felbamate is restricted to severe refractory epilepsies. Stiripentol can be effective in severe myoclonic epilepsy in infancy. Zonisamide has a special place in the progressive myoclonus epilepsies. Levetiracetam, remacemide and oxcarbazepine have been used mainly for partial seizures: further studies of their roles in other circumstances are required.

Adolescent↗

PubMed2001

Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation.

PURPOSE: the choices available for patients whose partial seizures are poorly controlled include seven new antiepileptic drugs (AEDs) or vagal nerve stimulation (VNS) as add-on therapy. Comparisons are needed to help physicians and patients select among the options for treatment. METHODS: we compared efficacy and adverse events of new treatments from controlled clinical trials of patients with uncontrolled partial seizures. Response rates (> or =50% decrease in partial seizures) at doses recommended in product labeling for adjunct therapy were tabulated for overall success (placebo response rate subtracted from AED response rate). Adverse events listed in product labeling were tabulated as complaint rates (placebo events subtracted from AED events). VNS trials used low dose stimulation as a pseudo-placebo. RESULTS: overall success rates fell into two general groups with ranges of 12-20% for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), zonisamide and 27-29% for levetiracetam, oxcarbazepine, and topiramate (TPM). Summary Complaint Scores also fell into two general groups with ranges of -27 to -82 for GBP, levetiracetam, TGB, zonisamide and -113 to -205 for LTG, oxcarbazepine and TPM. VNS scores were in the lower or higher success and summary complaint categories depending on whether scores from the pseudo-placebo group were subtracted from the high dose group. CONCLUSIONS: these data allow comparisons among AEDs and VNS using similar data from standard types of clinical trials.

Anticonvulsants↗

PubMedDate not supplied

Pharmacologic management of epilepsy in the elderly.

OBJECTIVE: To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES: Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS: Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION: The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.

Absorption↗

PubMed2002

Some common issues in the use of antiepileptic drugs.

Since 1993, eight new antiepileptic drugs (AEDs) have become available in the United States for the treatment of epilepsy: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Of the older AEDs, six continue to be widely used: phenobarbital, phenytoin, primidone, ethosuximide, carbamazepine, and valproate. As a result, there is a relatively large number of alternative AEDs for the treatment of any given type of epilepsy. This has been particularly beneficial for patients with generalized epilepsies, both idiopathic and symptomatic. Given the wide availability of effective agents, the toxicity and pharmacokinetic profile of an AED have become major factors in the selection process. A number of common clinical situations may benefit from the abundance of AEDs. Chronic toxicity observed with some of the older AEDs such as osteoporosis, gingival hyperplasia, or alterations in reproductive endocrine function may be avoided with the use of the newer agents. The obese patient with epilepsy may benefit from the use of AEDs such as topiramate or zonisamide, which have a tendency to produce weight loss. In patients with a history of drug-induced skin rash, AEDs such as valproate, gabapentin, topiramate, tiagabine, and levetiracetam carry a lower risk of cross-reactivity. In patients sensitive to cognitive dysfunction, drugs with a favorable profile include gabapentin, tiagabine, lamotrigine, oxcarbazepine, and levetiracetam. A more favorable pharmacokinetic profile is observed in the majority of the newer AEDs in contraposition to the classic agents. Good absorption, linear kinetics, and low drug-drug interaction potential make these drugs easier to use. The newer AEDs are eliminated through different combinations of liver metabolism and direct renal excretion, thus providing a wider variety of choices in patients with failure of one of these organs. Some specific problems have been found with some of the newer AEDs. Hyponatremia, known to occur rarely with carbamazepine use, appears to be more common with oxcarbazepine. Felbamate has been associated with a high incidence of aplastic anemia and liver failure and should be used exceptionally. Acute angle closure glaucoma has been observed with the use of topiramate. This complication occurs early in the course of therapy and reverses rapidly with discontinuation of the drug, so physician and patient awareness of this problem is very important. In this article several common clinical situations in the management of patients with epilepsy are presented in the form of case studies. These cases illustrate some current aspects of the use of the AEDs and will give some guidelines to help the treating physician in the increasingly complex process of AED selection.

Adolescent↗

PubMed2002

New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.

Animals↗

PubMed2003

Therapeutic drug monitoring of the newer antiepileptic drugs.

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.

Anticonvulsants↗

PubMed1996

The new generation of antiepileptic drugs: advantages and disadvantages.

1. After a hiatus of over 20 years, several new antiepileptic drugs (vigabatrin, lamotrigine, gabapentin, oxcarbazepine, topiramate, felbamate, zonisamide and tiagabine) have reached or approached the registration phase. 2. Compared with older agents, many new drugs exhibit simpler pharmacokinetics. This is especially true for vigabatrin and gabapentin, which are renally eliminated and have a low interaction potential. 3. Unlike most of the older agents, vigabatrin, lamotrigine, gabapentin and tiagabine are devoid of significant enzyme inducing or inhibiting properties. Topiramate, oxcarbazepine and felbamate may induce the metabolism of steroid oral contraceptives. In addition, felbamate also acts as a metabolic inhibitor. 4. To date, the efficacy of new drugs has been evaluated extensively only under add-on conditions in patients with partial seizures (with or without secondary generalization) refractory to conventional treatment. However, there is evidence that lamotrigine, zonisamide, felbamate and, possibly, topiramate may also be effective in generalized epilepsies. 5. In placebo-controlled studies, typically between 15 and 40% of patients with difficult-to-treat partial epilepsy have shown an improvement (defined as a 50% or greater decrease in seizure frequency) after addition of a new drug. Only a small minority of these patients achieved complete seizure control. 6. Compared with older agents, some of the new drugs may have a better tolerability profile. Felbamate, however, has been associated with a high risk of aplastic anaemia and hepatotoxicity. 7. At present, the main use of the new agents is in patients refractory to first-line drugs such as carbamazepine or valproate, and further studies are required to characterize their activity spectrum as well as their potential value in monotherapy. In most patients, new drugs cannot be recommended for first-line use until evidence is obtained that potential advantages in tolerability or ease of use outweigh the drawback of their high cost.

Anticonvulsants↗

PubMedDate not supplied

Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies.

The aim of this paper is to review a number of new antiepileptic agents (i.e. felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide) for their inducing and/or inhibitory properties in humans, mainly considering the interactions where they are involved as the cause rather than the object of such interactions. Two aspects have been particularly taken into account: the changes or absence of changes in plasma/serum concentrations of concomitant drugs and the direct or indirect evidence of induction, inhibition or lack of effect on the six major human hepatic CYP isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4), as well as on other CYP isozymes or enzyme systems. Felbamate clearly affects the pharmacokinetics of a number of drugs, generally increasing but also decreasing their concentrations. It induces enzymes such as CYP3A4 and inhibits enzymes such as CYP2C19 and those of the beta-oxidation pathway. Topiramate is not devoid of potential interaction properties: it decreases the plasma concentrations of ethinylestradiol, induces CYP3A4 and inhibits CYP2C19. For oxcarbazepine, no inhibitory, only inductive effects have been observed thus far. Felbamate. topiramate and oxcarbazepine may induce the metabolism of steroidal oral contraceptives. In this respect, tiagabine has been studied at a rather low dose. Pharmacodynamic or pharmacokinetic interaction seems to exist between lamotrigine and carbamazepine. Lamotrigine appears to be a weak inducer of UGTs, whereas induction of CYP3A4 seems improbable as the compound does not change the concentrations of oral contraceptives or the urinary excretion of 6beta-hydroxycortisol. Zonisamide has very peculiar pharmacokinetics and an extensive metabolism. Additional information on its enzyme inducing or inhibiting properties would be necessary, as data so far collected on its effect on the pharmacokinetics of other drugs are conflicting. Gabapentin, vigabatrin and in particular levetiracetam appear to be devoid of significant enzyme inducing or inhibiting properties.

Anticonvulsants↗