newer anti-epileptics

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overview of newer drug used in epilepsy

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Pharmacotherapy of Epilepsy Newly Approved and Developmental Agents:

Pharmacotherapy of Epilepsy Newly Approved and Developmental Agents Linda J. Stephen and Martin J. Brodie CNS Drugs 2011; 25 (2): 89-107

PowerPoint Presentation:

Epilepsy is one of the most common neurological disorders, affecting around 50 million people worldwide A large proportion, perhaps up to one-third, will continue to have seizures despite adequate trials of a wide range of licensed drugs used alone or in combination

Lacosamide:

Lacosamide Lacosamide is licensed in Europe and the US as add-on therapy for adults with partial-onset seizures, with or without secondary generalization

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models By enhancing sodium channel slow inactivation, By binding to collapsin-response mediator protein 2 (CRMP-2)

PowerPoint Presentation:

effects on sodium channel slow inactivation, with no influences on fast activation, may lead to normalization of activation thresholds and a reduced pathophysiological hyper responsiveness.

PowerPoint Presentation:

CRMPs are thought to be involved in neural development, could contribute to neuronal differentiation, polarization and axonal outgrowth induced by neurotrophic factors, some of which are directly involved in the development of epilepsy

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CRMP-2 may play a part in neuronal protection from excitotoxicity and apoptosis also has a role in the downregulation of NMDA receptor subunit NR2B

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In animal studies, lacosamide was efficacious in the maximal electroshock model, in the hippocampal kindling model and in the amygdala kindling model had no effect in a model of absence seizures

Pharmacokinetics:

Pharmacokinetics completely and rapidly absorbed from the GIT with peak plasma concentrations being achieved within 4 hours of administration half-life is around 13 hours minimally bound to plasma proteins (<15%).

PowerPoint Presentation:

40% of a lacosamide dose is excreted unchanged in the urine 30% is demethylated to the pharmacologically inactive O-desmethyl metabolite, which is also excreted renally

Drug Interactions:

Drug Interactions Lacosamide does not induce or inhibit hepatic enzymes had no effect on the plasma concentrations of other AEDs Plasma lacosamide concentrations were not affected by carbamazepine or valproic acid Other enzyme inducers, such as rifampicin reduce circulating lacosamide concentrations

Efficacy:

Efficacy double-blind, placebo-controlled, multicentre trial in 418 patients given lacosamide 200, 400 or 600mg/day, the drug significantly reduced partialonset seizures in adults with refractory epilepsy

PowerPoint Presentation:

European equivalent trial in 485 patients found a median percentage reduction in seizure frequency of 35.5% with 200 mg/day (p = 0.02) and 36.4% with 400 mg/day (p = 0.03) compared with 20.5% with placebo

Safety and Tolerability:

Safety and Tolerability dizziness, headache, nausea and vomiting. Fatigue, ataxia, visual disturbance, diplopia and somnolence Rare reports of cardiac events dose-related prolongation of the PR interval with lacosamide is similar to that found with carbamazepine, lamotrigine and pregabalin

Dosage and Administration:

Dosage and Administration available as 50, 100, 150 and 200 mg tablets, as well as in a syrup formulation (15 mg/mL) and an intravenous infusion 10 mg/mL initial recommended starting dose is 50 mg twice daily

PowerPoint Presentation:

maintenance dosage of 200 or 400 mg/day according to efficacy and tolerability intravenous loading doses of lacosamide 200 and 300 mg over 15 minutes were best tolerated A 400 mg dose was more likely to lead to adverse events

Rufinamide:

Rufinamide Rufinamide is a triazole derivative Adjunctive treatment for seizures associated with Lennox-Gastaut syndrome.

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models exact mechanism of action is unclear In vitro, rufinamide prolongs the inactive state of voltage dependent sodium channels and limits sustained repetitive firing of neuronal sodium-dependent action potentials

PowerPoint Presentation:

In rodent models, oral rufinamide suppressed maximal electroshock- induced tonic-clonic seizures, and pentetrazol (pentylenetetrazol)-induced clonic seizures Intraperitoneal rufinamide suppressed pentetrazol, bicuculline- and picrotoxin-induced clonus in mice.

Pharmacokinetics:

Pharmacokinetics oral administration, rufinamide is 85% absorbed, with peak plasma concentrations reached in 5–6 hours 23–34% bound to plasma proteins Elimination half-life ranges from 8 to 12 hours Metabolites, none of which is active, are excreted renally and only traces of the parent drug can be found in the urine and faeces

Drug Interactions:

Drug Interactions does not inhibit most of the CYP450 enzyme system at clinically relevant concentrations, although it is a weak inhibitor of CYP2E1 Rufinamide is metabolized by carboxylesterases inducers of carboxylesterases such as carbamazepine and phenobarbital can increase the clearance of rufinamide.

PowerPoint Presentation:

Clearance of rufinamide was increased by carbamazepine (19–26% increase), phenytoin (25–46% increase), phenobarbital (25–46% increase) primidone (25–46% increase) Rufinamide reduces plasma concentrations of ethinylestradiol and norethinedrone

Efficacy:

Efficacy 28 days in 50 patients with partial-onset or primary GTCS Significantly more patients taking rufinamide than placebo had at least a 50% reduction in tonic-atonic seizure frequency

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Rufinamide significantly reduced the frequency of absence and atypical absence seizures (p < 0.03) and atonic seizures (p < 0.02) compared with placebo

Safety and Tolerability:

Safety and Tolerability somnolence, nausea, vomiting, anorexia, dizziness, diplopia and ataxia 8.1–13.5% discontinued rufinamide due to adverse events

Dosage and Administration:

Dosage and Administration available in 100, 200 and 400 mg tablets initially at a dose of 200 mg twice daily, increasing in 200 mg twice-daily increments at intervals of not less than 2 days to a maximum daily dose of 3200 mg

Eslicarbazepine Acetate:

Eslicarbazepine Acetate Eslicarbazepine acetate is a novel AED that shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, although it is structurally different at the 10,11 position

PowerPoint Presentation:

As carbamazepine- 10,11-epoxide is partly responsible for the adverse effects associated with carbamazepine, It was hoped that the differing structure of eslicarbazepine acetate would result in better efficacy with less toxicity than carbamazepine

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models Eslicarbazepine acetate competitively interacts with the inactivated state of the voltage-gated sodium channel, thereby limiting sustained repetitive firing, ictogenesis and seizure spread drug is thought to target selectively rapid-firing neurons by binding to site 2 of the inactive sodium channel

Pharmacokinetics:

Pharmacokinetics Because eslicarbazepine acetate is not metabolized to carbamazepine 10,11-epoxide, it is not susceptible to enzyme induction or autoinduction.

PowerPoint Presentation:

half-life of eslicarbazepine is 13–20 hours, with steady-state concentrations being reached within 4–5 days of once-daily dosing Eslicarbazepine is <40% protein bound Dosage reduction may be required in patients with creatinine clearance <60mL/minute

Drug Interactions:

Drug Interactions Coadministration of eslicarbazepine acetate with phenytoin resulted in reduced eslicarbazepine concentrations with increased phenytoin concentrations No pharmacokinetic interactions have been reported with other AEDs accelerates the clearance of both hormonal components of the oral contraceptive pill

Efficacy:

Efficacy Three randomized, double-blind, placebo controlled trials evaluated fixed dosages of eslicarbazepine acetate (400, 800 or 1200 mg/day) as adjunctive therapy for adults with partial seizures with or without secondary generalization

PowerPoint Presentation:

In a pooled analysis of extension studies from the three trials, there was a significant improvement in symptoms

Safety and Tolerability:

Safety and Tolerability Dizziness and somnolence headache, abnormal coordination, disturbed attention, diplopia, blurred vision, vertigo, nausea, vomiting, diarrhoea Hyponatraemia can occur, but does so less frequently than with carbamazepine and oxcarbazepine

PowerPoint Presentation:

ECG recordings during clinical trials showed an increase in PR interval in 1200mg/day dosage group contraindicated in patients with second- or third-degree atrioventricular block.

Dosage and Administration:

Dosage and Administration 800 mg tablets initial recommended dose is 400 mg once daily, increasing after 1–2 weeks to 800 mg once daily maximum tolerated daily dose of 1200 mg according to efficacy and tolerability

Retigabine:

Retigabine Mechanisms of Action and Activity Profile in Animal Models opening of neuronal voltage-gated potassium channels, enhancing the M-type potassium current. M current is a low-threshold, noninactivating, voltage-dependent neuronal potassium current.

PowerPoint Presentation:

It slowly inactivates when an excitatory stimulus depolarises the neuron towards spike threshold, repolarising the membrane back towards resting potential and suppressing repetitive firing The M current is produced by the Kv7 channel family, one of a group of voltage-gated potassium channels at which retigabine acts

PowerPoint Presentation:

Retigabine also has a direct positive modulatory action on GABA A receptors,which is believed to contribute to its CNS adverse effects no effect on cardiac voltage-gated potassium channels

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Retigabine had potent anticonvulsant activity in a variety of animal models, including electrically, sound- and chemically induced seizures, and genetic epilepsy models Effectiveness in models of partial-onset and generalized seizures, as well as the status epilepticus model, was demonstrated.

Pharmacokinetics:

Pharmacokinetics Retigabine is rapidly absorbed following oral administration with a bioavailability approaching 60%. peak plasma concentrations within 60–90 minutes Protein binding is <80%.

PowerPoint Presentation:

The primary metabolite of retigabine is a monoacetylated metabolite, formed by N-acetylation Both the parent drug and its metabolite have a half-life of approximately 8 hours. In patients with modest or severe hepatic impairment, clearance is decreased by 30–50%.

Drug Interactions:

Drug Interactions has modest potential to inhibit the CYP2A6 isoform higher retigabine doses, phenytoin and carbamazepine may increase the clearance of retigabine by 30% Retigabine does not alter the metabolism or pharmacokinetics of ethinylestradiol or norgestrel

Efficacy:

Efficacy median percentage reduction in monthly total partial seizure frequency from baseline was 23% for 600 mg/day, 29% for 900 mg/day and 35% for 1200 mg/day Retigabine has recently been shown to significantly improve symptoms of restless legs syndrome compared with placebo in adults

Safety and Tolerability:

Safety and Tolerability somnolence, confusion, dizziness, tremor, amnesia, abnormal thinking, vertigo, speech disorders and asthenia discontinuation rates due to adverse events were 4.5% with placebo, 8.7% with 400 mg/day, 11.6% with 800 mg/day 19.3% with 1200mg/day.

Brivaracetam:

Brivaracetam The discovery of levetiracetam binding to synaptic vesicle protein 2A (SV2A) as its likely site of action triggered the search for other compounds with greater affinity Brivaracatem, the n-propyl analogue of levetiracetam, 10-fold higher affinity for SV2A than levetiracetam

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models Compared with levetiracetam, brivaracetam has a broader spectrum of activity in animal models, including against maximal electroshock and pentetrazol-induced rodent seizure models

PowerPoint Presentation:

The drug is 6 and 12 times more potent than levetiracetam in the kindled rat and audiogenic mouse seizure models, respectively The drug also inhibits neuronal voltage-gated sodium channels, with effects comparable to carbamazepine, but of a lower magnitude

Pharmacokinetics:

Pharmacokinetics brivaracetam is rapidly absorbed half-life of 7–8 hours Around 5–8% of the parent drug is recovered in the urine, with 33–49% recovered as two metabolites

Drug Interactions:

Drug Interactions Brivaracetam reduces plasma concentrations of carbamazepine and phenytoin brivaracetam decreases the estrogen and progestin concentrations of low dose oral contraceptives without any impact on suppression of ovulation.

Efficacy:

Efficacy mixed results were reported from the phase III clinical trial programme in April 2009, with only one of the two studies meeting the primary endpoint for efficacy A small subject-blind, placebo-controlled study in 18 patients showed the drug suppresses generalized photoparoxysmal electroencephalographic responses

Safety and Tolerability:

Safety and Tolerability 200, 400 or 800mg/day dizziness, headache and somnolence. Neutropenia occurred in four patients taking brivaracetam 50mg/day and in two taking 20mg/day.

Perampanel:

Perampanel Perampanel was designed as a selective noncompetitive (allosteric) AMPA-type glutamate receptor antagonist

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models Glutamate receptors, found in abundance in the excitatory synapses of the CNS, have a key function in mediating glutaminergic transmission in the cortex. divided into ionotropic receptors and metabotropic receptors

PowerPoint Presentation:

three types of ionotropic receptor: NMDA, kainate and AMPA It has been shown that AMPA receptors are involved in the pathophysiology of epileptic seizures Perampanel is a highly selective antagonist of the AMPA receptor

PowerPoint Presentation:

In animal models, perampanel has broad-spectrum antiseizure effects, being effective in the mouse maximal electroshock seizure test following oral administration also had efficacy in the model for self-sustaining status epilepticus

Pharmacokinetics:

Pharmacokinetics peak concentration achieved 1-hour post-dose long half-life of around 52–129 hours following a single dose 66–90 hours with multiple dosing (1–6mg once daily for 14 days)

Efficacy:

Efficacy In the 206 study, themajority of patients tolerated perampanel 4mg/day. Of patients taking perampanel, 31% had at least a 50% reduction in seizure frequency compared with 22% in the placebo group

PowerPoint Presentation:

responder rate, defined as th proportion of patients with >50% seizure reduction, was 40% in the perampanel arm and 22% in the placebo arm. Perampanel is also being evaluated in patients with postherpetic neuralgia, and painful diabetic neuropathy

Safety and Tolerability:

Safety and Tolerability dizziness, fatigue and somnolence, with no serious clinical adverse events being reported to date

Ganaxolone:

Ganaxolone Ganaxolone (3 α -hydroxy-3 β -methyl-5 α -pregnan- 20-one) belongs to a novel class of neurosteroids called epalons Epalons are chemically related to progesterone, but are devoid of any hormonal activity, and have potent antiepileptic, anxiolytic, sedative and hypnotic properties in animals

Mechanisms of Action and Activity Profile in Animal Models:

Mechanisms of Action and Activity Profile in Animal Models acts directly to specifically modulate GABA A receptors containing the d-subunit in the CNS It is active against seizures in maximal electroshock, pentetrazol-, bicuculline-, aminophylline- t butylbicyclophosphorothionate and corneal kindling-induced seizure animal models

Pharmacokinetics:

Pharmacokinetics only partially absorbed following oral administration

Efficacy:

Efficacy In a randomized, double-blind study, ganaxolone, in dosages up to 1875 mg/day, had significant efficacy for refractory partial-onset seizures in 52 patients

Safety and Tolerability:

Safety and Tolerability dizziness and somnolence, Nervousness, headache, malaise, diarrhoea, constipation and vomiting

Conclusions:

Conclusions Despite the introduction of more than 12 AEDs over the past 20 years, prognosis in the common epilepsies and the rarer childhood epilepsy syndromes has only minimally improved with only a handful of reported successes

PowerPoint Presentation:

What we now require, therefore, are unique methods of developing new chemical entities that do not mirror pharmacologically the currently available AEDs We also need to develop different approaches to the identification and testing of novel treatments using multiple models of refractory epilepsy as opposed to focusing on preventing seizures in rodent models

PowerPoint Presentation:

Coupled to this, a better understanding of the various neurobiologies under pinning pharmacoresistance in individual patients is essential to improve the overall prognosis of seizure disorders in children and adults

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