Posts Tagged AEDs

[ARTICLE] Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Full Text

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Since the introduction of bromides as the first effective antiepileptic drugs (AEDs),1 chronic AED treatment that consisted of the sustained prevention of epileptic seizures has remained the standard of epilepsy therapy.2 Before to the introduction of the newer generation of AEDs, a limited number of drugs were available that addressed the blockade of sodium channels, acting on gamma-aminobutyric acid (GABA) type A receptors, or interacting with calcium channels as the leading modes of action.3 With the introduction of the newer AEDs a heterogeneous group of drugs appeared, some of them offering new mechanisms of action2 including the blockade of GABA aminotransferase (vigabatrin [VGB]), GABA re-uptake from the synaptic cleft (tiagabine [TGB]), the modulation of calcium channels (gabapentin [GBP], pregabalin [PGB]), the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor antagonism (perampanel [PER]), and the binding to the presynaptic SV2A receptor site which is the unique mode of action of levetiracetam (LEV) and brivaracetam (BRV), the AEDs this review will cover. The authors will summarize the development of both compounds as derivatives of piracetam, review the currently available preclinical and clinical data, and discuss the question of whether BRV has the potential to be recognized as being superior to LEV and if it can replace it as the standard AED with the main mode of action both AEDs reflect.[…]

 

Continue —-> Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Bernhard J. Steinhoff, Anke M. Staack, 2019

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[Abstract] Pharmacology and epilepsy : update on the new antiepileptic drugs

New antiepileptic drugs are regularly approved for treatment and offer large therapeutic opportunities. Efficacy of these drugs is relatively similar on-label with different mechanisms to be combined for a synergic effect. Treatments such as cannabidiol have benefitted from large media coverage despite limited clinical evidence so far. The objective of antiepileptic drugs is to stop the recurrence of epileptic seizures with as few adverse events as possible. When confronted to a difficult-to-treat epilepsy, referral to a specialised centre is strongly advised. The aim is to confirm that the diagnosis is correct, that the treatment is well adapted (indication, pharmacokinetic and compliance) and to evaluate the indication for non-pharmacological treatments such as epilepsy surgery.

 

via [Pharmacology and epilepsy : update on the new antiepileptic drugs]. – Abstract – Europe PMC

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[BLOG POST] Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children

Bromley RL, Weston J, Marson AG.

JAMA 2017; 318:1700-1701.

Abstract

CLINICAL QUESTION:

Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children?

BOTTOM LINE:

Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).

Also see

Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224.

Both references are cited in the neurochecklist:

Antiepileptic drugs (AEDs): teratogenicity

Abstract link 1

Abstract link 2

Drugs firms ‘creating ills for every pill’. Publik15 on Flickr. https://www.flickr.com/photos/publik15/3415531899

via Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

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[BLOG POST] The 29 proven anti-epilepsy drugs…and their practical checklists

Neurochecklists Blog

Epilepsy is a big problem for Neurology. It is a common, and often life-long, disease. Epilepsy is like the mythical hydra in its diverse manifestations, and in its duplicitous evasion of treatment.

By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link

The pillars of epilepsy treatment are the anti-epileptic drugs (AEDs). It is however a very tricky business to wield these very powerful tools. For example, one epilepsy medication may work wonders for one form of the epilepsy, and make another type much worse.

Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511 Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511

Any successful anti-epilepsy regime must therefore be carefully thought through, requiring a strategy that keeps the following key issues in mind all the time:

Mode of action

Indications

Dosing

Side effects

Interaction with other drugs

Teratogencity

With these in mind, neurochecklists explored the difficult terrain, and came up with comprehensive, but concise, checklists for the 29 essential anti-epilepsy drugs. What better way…

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[Abstract] Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy

Abstract

Objective To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.

 

Methods Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1–3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.

 

Results AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).

 

Conclusion AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

 

via Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy | Neurology

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[Abstract] The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register

Summary

Objective

To study interactions between first‐trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs), and a history of clinical depression and/or anxiety, on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE).

Methods

We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED‐exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first‐trimester exposure to ADDs; (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD; and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data was analyzed using Fisher’s exact test.

Results

A total of 2124 pregnancy outcomes were included in the analysis; 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%, 95% confidence interval [CI] 3.9‐16.6), compared to individuals in the non–ADD‐medicated depression and/or anxiety group (7.7%, 95% CI 1.2‐14.2), or those without depression or anxiety (6.9%, 95% CI 5.7‐8.1; = 0.45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups (= 0.27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures (= 0.78), or nonconvulsive seizures (= 0.45) throughout pregnancy, did not differ across comparative groups.

Significance

Co‐medicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.

 

via The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register – Sivathamboo – – Epilepsia – Wiley Online Library

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[Abstract] Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

Abstract

Backgrounds:

Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Since 1989, 18 new AEDs have been licensed for clinical use and there are now 27 licensed AEDs in total for the treatment of patients with epilepsy. Furthermore, several AEDs are also used for the management of other medical conditions, e.g., pain and bipolar disorder. This has led to an increasingly widespread application of therapeutic drug monitoring (TDM) of AEDs, making AEDs among the most common medications for which TDM is performed. The aim of this review is to provide an overview of the indications for AED TDM, to provide key information for each individual AED in terms of the drug’s prescribing indications, key pharmacokinetic characteristics, associated drug-drug pharmacokinetic interactions and the value and the intricacies of TDM for each AED. The concept of the reference range is discussed as well as practical issues such as choice of sample types (total vs free concentrations in blood vs saliva) and sample collection and processing.

Methods:

The present review is based on published articles and searches in PubMed and Google Scholar, last searched March in 2018, in addition to references from relevant papers.

Results:

In total, 171 relevant references were identified and used to prepare this review.

Conclusions:

TDM provides a pragmatic approach to epilepsy care in that bespoke dose adjustments are undertaken based on drug concentrations so as to optimize clinical outcome. For the older first generation AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone and valproic acid), much data has accumulated in this regard. However, this is occurring increasingly for the new AEDs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin and zonisamide).

via Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

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[Abstract] Pharmacotherapy of epilepsy

Pharmacotherapy of epilepsy is usually initiated after two or more unprovoked seizures, a decision that should be made after assessment of the individual risk of further seizures. Antiepileptic drugs (AEDs) are selected based on documented efficacy for the type of seizures, the epilepsy and possible epilepsy syndrome of the patient, taking potential adverse effects and comorbidity into account. For many AEDs, the mechanisms of action are incompletely understood. More than half of patients with newly diagnosed epilepsy achieve sustained seizure freedom with their first or second drug trials. After a prolonged time of seizure freedom discontinuation of therapy may be considered; the risk of relapse after drug withdrawal can be estimated on the basis of a number of clinical factors. The informed patient’s attitude is essential in all therapy decisions. Treatment is still largely symptomatic, but the future may involve a greater degree of disease-modifying precision medicine.

via [Pharmacotherapy of epilepsy]. – Abstract – Europe PMC

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[Slideshow] Comparing the Safety of Antiepilepsy Drugs in Pregnancy

Comparing the Safety of Antiepilepsy Drugs in Pregnancy

Mar 26, 2018

What are the risks of birth defects and perinatal outcomes for infants exposed to various AEDs in utero?

Source: http://www.neurologytimes.com/slideshows/comparing-safety-antiepilepsy-drugs-pregnancy

 

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[WEB SITE] Antiepileptic Drugs – Medscape

Overview

Modern treatment of seizures started in 1850 with the introduction of bromides, which was based on the theory that epilepsy was caused by an excessive sex drive. In 1910, phenobarbital (PHB), which then was used to induce sleep, was found to have antiseizure activity and became the drug of choice for many years. A number of medications similar to PHB were developed, including primidone.

In 1938, Houston Merrit and Tracy Putnam described animal models for screening multiple compounds for antiepileptic activity in the Journal of the American Medical Association. In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures.

In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. Ethosuximide has been used since 1958 as a first-choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. Valproate (VPA) was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world. It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures.

These anticonvulsants were the mainstays of seizure treatment until the 1990s, when newer AEDs with good efficacy, fewer toxic effects, better tolerability, and no need for blood level monitoring were developed. A study of live-born infants in Denmark found that exposure to the newer-generation AEDs lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam in the first trimester was not associated with an increased risk in major birth defects. [1]

The new AEDs have been approved in the United States as add-on therapy only, with the exception of topiramate and oxcarbazepine (OXC); lamotrigine (LTG) is approved for conversion to monotherapy. A meta-analysis of 70 randomized clinical trials confirms the clinical impression that efficacy does not significantly differ among AEDs used for refractory partial epilepsy. [2]

Antiepileptic drugs should be used carefully, with consideration of medication interactions and potential side effects. This is particularly important for special populations, such as patients with HIV/AIDS. [3]

For more information, see Epilepsy and Seizures.

Mechanism of Action

It is important to understand the mechanisms of action and the pharmacokinetics of antiepileptic drugs (AEDs) so that these agents can be used effectively in clinical practice, especially in multidrug regimens (see the image below).

Pearls of antiepileptic drug use and management.
Pearls of antiepileptic drug use and management.

Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses. The AEDs are designed to modify these processes so as to favor inhibition over excitation and thereby stop or prevent seizure activity (see the image below).

Dynamic target of seizure control in management of epilepsy is achieving balance between factors that influence excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action (see the image below).

Antiepileptic drugs can be grouped according to th
Antiepileptic drugs can be grouped according to their major mechanism of action. Some antiepileptic drugs work by acting on combination of channels or through some unknown mechanism of action.

[…]

For more Visit site —>  Antiepileptic Drugs: Overview, Mechanism of Action, Sodium Channel Blockers

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