New antiepileptic drug therapies

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Efficacy and Safety of Antiepileptic Drugs: A Review of Controlled Trials

Summary: Twenty randomized, double-blind, controlled clinical trials of antiepileptic drugs (AEDs) in mostly adult patients with mostly partial onset and/or generalized tonic-clonic seizures have been reported, with a total of 1,336 patients. None of these studies has demonstrated significant differences in antiepileptic efficacy between available antiepileptic drugs, but the results show that there are considerable individual differences between patients' responses to the same drug. While side effects are common with all of the antiepileptic drugs currently available, these are usually mild and reversible. Although some toxic effects may occur more frequently with certain drugs, there is sufficient overlap between the effects of various antiepileptic drugs that most side effects cannot be attributed with certainty to any one drug. Since side effects are generally dose-related, they can frequently be avoided or minimized by careful dosage titration and individualization of therapy.     

Practical strategies for switching to newer antiepileptic drugs

Traditional antiepileptic drugs (AEDs) are associated with drug interactions and side effects that limit their safety and tolerability. Side effects of traditional AEDs are especially problematic for children and adolescents, women of childbearing age, and the elderly. Many patients with epilepsy may benefit from switching from a traditional AED to a newer agent because the newer agents are generally better tolerated and are less likely to cause drug interactions. Clinical studies have demonstrated improved therapeutic efficiency with better tolerability in patients switching from a traditional AED to lamotrigine, oxcarbazepine, or topiramate monotherapy or combination therapy.     

Pharmacology of Antiepileptic Drugs

Summary: Several different types of chemical compounds are useful as antiepileptic drugs. Their mechanisms of action, as well as their physical structures, differ. Compounds such as carbamazepine, phenytoin, and probably valproate act by modifying ionic conductances, particularly sodium and calcium, in excitable membranes, thus limiting sustained high-frequency neuronal discharges. In contrast, barbiturates and benzodiazepines tend to affect 7-aminobutyric acid (GABA) mediation of the chloride channel opening. Knowledge of drug mechanisms is important for choosing the proper drug for various seizure types. In addition, an understanding of antiepileptic drug pharamcokinetics, nonther-apeutic effects, and interactions is essential for optimal therapy. The lack of uniform pharmacokinetics among patients and among different formulations of a drug can make it difficult to arrive at uniform criteria for both seizure control and determinations of toxicity. Both pharmacokinetic and pharmacodynamic interactions can occur between antiepileptic medications and other drugs. Three major types of side effects with anticonvulsants can be identified: dose-related alterations of neurologic function, idiosyncratic reactions, and nonidiosyncratic direct actions on other organ systems. These effects often compromise treatment.     

Serumkonzentration von Antiepileptika Praktische Richtlinien zur Messung und sinnvollen Interpretation

The clinical relevance of being informed on the serum concentration of antiepileptic drugs has been judged very differently during the last decades. Therefore the Commission on the treatment of epilepsy (German section of the International League against Epilepsy) had the task to outline the importance of therapeutic monitoring of anticonvulsant serum concentrations. The possibility of determining the serum concentration of anticonvulsants induced the elaboration of "therapeutic drug level ranges". The usefulness of determining serum concentrations of antiepileptic drugs in clinical management of patients with epilepsy depends decisively on the following questions: Can the efficacy of antiepileptic drug treatment be increased by serum concentration monitoring? Can the rate of adverse effects of antiepileptic drugs be reduced by serum concentration monitoring? Clinical experience suggests numerous indications of therapeutic drug monitoring, scientific studies however, supporting these empirical guidelines are not available. Therefore, therapeutic drug monitoring may be restricted for some special situations which have to be justified in every single case. Tailored determinations with specific purposes are e.g.: resistance to therapy, including suspected irregular intake; suspected intoxication, particularly during combined therapy; the possibility of significant changes in the dosage-serum concentration relationship (interactions with other drugs, unusual pharmacokinetics in childhood, in pregnancy etc.).     

Levetiracetam in the treatment of epilepsy

Epilepsy is a common chronic disorder that requires long-term antiepileptic drug therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35% are refractory to medical therapy, highlighting the continued need for more effective and better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid and almost complete absorption, minimal insignificant binding to plasma protein, absence of enzyme induction, absence of interactions with other drugs, and partial metabolism outside the liver. The availability of an intravenous preparation is yet another advantage. It has been demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In addition, it was found equivalent to controlled release carbamazepine as first-line therapy for partial-onset seizures, both in efficacy and tolerability. Its main adverse effects in randomized adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children, the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is an important addition to the treatment of epilepsy.     

Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients

Multiple factors-including the efficacy of the antiepileptic drug for the particular seizure type, availability of pediatrics-friendly formulations, the ease of dosing and titration, and tolerability issues, such as possible drug interactions and adverse events-affect the selection of the best antiepileptic drug for a child with epilepsy. Behavioral problems are common in children with epilepsy and can be aggravated or initiated by antiepileptic drug therapy. The types and frequencies of antiepileptic drug-associated behavioral events can influence a clinician's drug selection, drug management, and counseling of parents. Unfortunately, appreciating differences among antiepileptic drugs in behavioral adverse event profiles is problematic because, among other reasons, methodologies for reporting, collecting, and analyzing adverse events are not uniform across trials, and there is marked heterogeneity in study design among trials. This review summarizes incidence rates for behavioral and psychiatric adverse events taken from studies of children with epilepsy. These rates are reported for the 10 most commonly prescribed antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, lamotrigine, phenytoin, levetiracetam, oxcarbazepine, topiramate, zonisamide, and gabapentin), grouped according to their predominant mechanism of action. Despite the numerous methodologic inconsistencies, some similarities in adverse event profiles among antiepileptic drugs that share mechanisms of action are apparent. Moreover, the overwhelming body of data on the behavioral effects of phenobarbital should convince clinicians that, whenever possible, it should not be used as the initial-or even the second-monotherapy in children with epilepsy.     

Epilepsy and pregnancy.

The management of the pregnant epileptic requires close cooperation between the neurologist and obstetrician. To prevent complications, knowledge is required about the natural history of epilepsy during pregnancy, the possible teratogenic effects of antiepileptic drugs, and changes in their absorption, biotransformation, and excretion. Close plasma antiepileptic drug monitoring is required because of the change in the handling of antiepileptic drugs during pregnancy. The treatment of status epilepticus with intravenous phenytoin is effective. Drug interactions which may lead to toxic plasma levels of some drugs and subtherapeutic plasma levels of others should be anticipated. The risk of problems resulting from antiepileptic drug therapy during pregnancy appears to be minor, provided that proper medical supervision is available. Newer antiepileptic drugs should not be administered to the pregnant epileptic until their safety in pregnancy is fully established.     

Pharmacotherapy of epilepsy

Antiepileptic drug treatment is essential and provides excellent therapeutic effects in more than the two-third of the epileptic patients. The antiepileptic drugs influence the chronic hyperexcitability of the brain developed during the epileptogenesis. As an effect, it decreases the excitability and/or increases the inhibition of the pathological cells, which prevents the precipitation of the epileptic seizure (anticonvulsive effect). The anticonvulsive effect comes into operation by the influence of the transport of one ore more ion-channels. The anticonvulsive effect is only symptomatic and it doesn't cure the disorder. The drug selection is based on the knowledge of the therapeutic markers and the effectiveness of the drug to be used. This can occur on the basis of the action of the drug or in syndrome-specific way. The pharmacokinetic properties of the drugs determine how they can be used in the practice. The drug interactions can take place in several levels. Among them, the change of the metabolism is the most important. Acute dose-dependent side effects, organ-specific chronic interactions and idiosyncratic reactions must be taken into consideration during the use of antiepileptic drugs. The patient's individual aspects must be considerably taken into account during the treatment. There are other medical areas that can benefit from the antiepileptic drugs. Among them, the most important diseases are: restless legs syndrome, neuropathic pain, trigeminal neuralgia, essential tremor, bulimia and bipolar disorders. There are other pharmacological (adrenocorticotropic hormone, immunoglobulins, neurosteroids) and dietary methods, which may be effective at certain epileptic syndromes. The principles of the pharmacotherapy have been changing continuously during the past decades and since. New drugs have been introduced into the marketing and new expectations are coming into the limelight concerning the treatment. As a consequence this will bring on the modification of antiepileptic drug therapeutic habits.     

Pharmacokinetic Interactions between Antiepileptic and Antidepressant Drugs

The use of antiepileptic drugs (AEDs) for the treatment of psychiatric disorders has reached a new phase of clinical interest. They are commonly used in the therapy of psychoses, mood disorders, aggression and eating disorders. Pharmacotherapy combinations involving AEDs and antidepressant drugs are used to treat co-morbid psychiatric and neurological disorders, to reduce or control the adverse effects of a medication or to increase a medication effect. Therefore, the impact of pharmacokinetic interactions of this class of drugs is quite relevant. In this paper, the available data about the mechanisms of metabolic kinetic interactions between antidepressant and antiepileptic drugs, as well as their clinical significance, has been reviewed.     

Pharmacokinetic Interactions between Antiepileptic and Antidepressant Drugs.

The use of antiepileptic drugs (AEDs) for the treatment of psychiatric disorders has reached a new phase of clinical interest. They are commonly used in the therapy of psychoses, mood disorders, aggression and eating disorders. Pharmacotherapy combinations involving AEDs and antidepressant drugs are used to treat co-morbid psychiatric and neurological disorders, to reduce or control the adverse effects of a medication or to increase a medication effect. Therefore, the impact of pharmacokinetic interactions of this class of drugs is quite relevant. In this paper, the available data about the mechanisms of metabolic kinetic interactions between antidepressant and antiepileptic drugs, as well as their clinical significance, has been reviewed.     

Clinical features, diagnosis, and treatment of dysphoric states and psychoses associated with epilepsy

Although dysphoric states and psychoses represent clinically relevant psychiatric complications in patients with epilepsy, their symptomatologies are complex and therefore frequently underrecognized and undertreated in daily psychiatric routine. Detecting dysphoric states and psychoses secondary to the psychotropic effects of various antiepileptic drugs is often challenging, even for the most experienced psychiatrists. This article gives an overview of epidemiology, clinical features, diagnosis, and therapy of interictal, peri-ictal, and alternative dysphoric states and psychoses in patients with epilepsy. Further, potential drug interactions between antiepileptic and psychiatric medications are discussed.     

New Horizons in the development of antiepileptic drugs: Innovative strategies

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or the underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma or stroke. Thus, there are at least four important goals for the future: (1) development of better antiepileptic ("anti-ictal") drugs with higher efficacy and tolerability to stop seizures compared to current medications; (2) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (3) development of disease-modifying therapies, interfering with progression of epilepsy, and (4) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The third Workshop on New Horizons in the Development of Antiepileptic Drugs explored these four goals for improved epilepsy therapy, with a focus on innovative strategies in the search for better anti-ictal drugs, for novel drugs for prevention of epilepsy or its progression, and for drugs overcoming drug resistance in epilepsy. In this conference review, the current status of antiepileptic therapies under development is critically assessed, and innovative approaches for future therapies are highlighted.     

Antiepileptic-antipsychotic drug interactions: a critical review of the evidence

The potential for drug-drug interactions in psychiatry and patients with epilepsy is very high. Moreover, antiepileptic drugs are widely used outside epilepsy as psychotropic agents and their spectrum of activity on behavior is of considerable interest to psychopharmacology. In both neurologic and psychiatric practice, pharmacotherapy combinations are commonly used to treat comorbid psychiatric and neurologic disorders, to reduce or control the adverse effects of a medication or to increase its efficacy. This paper focuses on the metabolic pharmacokinetic interactions between two classes of psychotropic drugs: antiepileptic and antipsychotic drugs. The degree of documentation varies for many interactions from clinical case-report experiences to well established research outcomes. The evidence and the clinical significance of these interactions are reviewed. In general, it is better to use as few drugs as possible, as multicolored politherapies increase the possible adverse effects of drug interactions and reduce patient compliance.     

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

OBJECTIVE: This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. METHODS: This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician's choice). Patients were converted during an 相似文献   

Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk

It is now accepted that patients with epilepsy are more prone than the general population to develop psychiatric disorders, being significantly at risk due to psychosocial reasons, the presence of electrophysiologic and anatomopathologic abnormalities mainly in the limbic system, and because they are taking antiepileptic drugs which may have negative psychotropic effects. It is also known that many patients with epilepsy sometimes receive psychotropic medications on account of their psychiatric symptoms. This review focuses on the main problems that a clinician may encompass when treating psychiatric disorders in patients with epilepsy. On one hand, the effects of antiepileptic drugs on mood and behavior for a correct differential diagnosis of psychiatric symptoms. On the other hand, the main factors that may affect choice of therapy, patients' response and compliance, when prescribing antidepressants or antipsychotic drugs, drug interactions and the potential proconvulsive risk are reviewed.     

The use of newer antiepileptic drugs in patients with renal failure

Seizures and chronic kidney disease are both common and often coexist. Treating seizures in patients with renal failure, including those on dialysis, is a challenge that is frequently encountered, especially in the inpatient setting. For the newer antiepileptic drugs, there are limited data available, so an understanding of how each drug is affected by kidney disease and dialysis is critical in order to make rational choices qualitatively (which drug) and quantitatively (dosing). Generally, newer (second-generation) antiepileptic drugs are associated with fewer systemic side effects and drug-drug interactions, so they tend to be preferred in this population. The landscape of antiepileptic drugs is constantly evolving, with new compounds being released on a regular basis. Thus, several new agents have become available since the last review of this topic (in 2006) and these are the ones discussed here. Most require dosage adjustment according to the degree of renal failure, and most require extra doses after dialysis.     

Determining the effects of antiepileptic drugs on cognitive function in pediatric patients with epilepsy

The majority of children with epilepsy are of normal intelligence; however, a significant subset suffers from temporary or permanent cognitive impairment. Factors that affect cognitive function are myriad and include the neuropathology underlying the epilepsy, seizures, epileptiform activity, psychosocial problems, and antiepileptic drug side effects. Although cognitive impairment is often wrongly attributed to the effects of antiepileptic drugs, antiepileptic drugs do impair cognition in some children. Clinicians should be aware of the differential cognitive effects of antiepileptic drugs and should monitor cognitive function closely when adding or changing therapy. Based on published data from prospective, chronic dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction.