Friday, September 2, 2016

Lacosamide | Treatment of Partial-Onset Seizures | Slow Inactivator of Voltage Gated Sodium Channels (VGSCs) | Modulator of Collapsin-Response Mediator Protein-2 (CRMP-2)

Lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropionamide] also referred to as harkoseride is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. Later, experimental studies proved Lacosamide to be an efficacious anticonvulsant in animal models [1, 2].
Lacosamide demonstrated broad anticonvulsant effects in murine seizure models for generalized seizures, complex partial-onset seizures, and status epilepticus. In the maximal electroshock seizure (MES) test, Lacosamide was more potent than phenytoin or phenobarbital.

Lacosamide: 2D and 3D Structure

It causes a general decrease in neuronal discharge frequency and synaptic excitability in laboratory testing. Since these actions are not mediated at major excitatory (AMPA/NMDA) or inhibitory (GABAA) postsynaptic receptors, the mechanism of action of Lacosamide was initially unknown [2].
Later, two different probable mechanisms of action were discovered. Lacosamide selectively enhances slow inactivation of sodium channels. Second, Lacosamide binds to the collapsin response mediator protein-2 (CRMP-2) and modulates mCRMP2 function in vitro [2].
Lacosamide tablets are indicated for use alone or as add-on therapy in the treatment of partial-onset (focal) seizures in patients with epilepsy who are 17 years of age or older (in EU it is 16 years and older).
In August 2008, Lacosamide was granted market authorization by the European Commission as an adjunctive therapy for partial-onset seizures with or without secondary generalization in patients with epilepsy. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October 2008.

Epilepsy and Antiepileptic Drugs (AEDs) 
Epilepsy is one of the most common neurological disorders, and is estimated to affect ~3% of the general population at some point in their lives1. There are three clinical types of partial seizures including simple partial, complex partial, and partial seizure evolving into secondarily generalized seizures.
In general, carbamazepine is considered firstline therapy for partial-onset seizures. However, less than 50% of patients will remain seizure-free after beginning initial antiepileptic drug (AED) therapy. If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide may be either added to carbamazepine or used as monotherapy. Although these agents have demonstrated similar efficacy for the treatment of partial-onset seizures, they are not always well tolerated by patients. In fact, 20-30% of patients will discontinue therapy because of intolerable adverse drug effects (ADEs). Based upon the percentage of patients with epilepsy who are refractory to or unable to tolerate AEDs due to ADEs, it is evident that effective AEDs with minimal adverse drug reactions are needed. Therefore, a need remains for AEDs with improved effectiveness and tolerability [1].

Lacosamide has Dual Mode of Action
Experimental results suggest that Lacosamide has a dual mode of action underlying its anticonvulsant and analgesic activity.  Lacosamide appears to selectively enhance sodium channel slow inactivation, with no effects on fast inactivation. Classical sodium channel modulators selectively enhance fast inactivation. Since slow inactivation of sodium channels is an endogenous mechanism by which neurons reduce ectopic hyperactivity, this modulation represents an effective mechanism to selectively reduce pathophysiological hyperactivity, while leaving physiological activity intact.
In contrast, some antiepileptic drugs (AEDs), such as carbamazepine, phenytoin, and lamotrigine, affect the fast inactivation of voltage-gated sodium channels. The enhancement of slow inactivation induced by Lacosamide may help normalize activation thresholds and decrease pathophysiological neuronal activity, thus controlling neuronal hyperexcitability [3, 4].
Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of Lacosamide with CRMP-2 in vitro. It is unclear whether the effect on this protein is stimulatory or inhibitory, but as a consequence, Lacosamide appears to attenuate the effects of neurotrophic factors on axon outgrowth.

Dosages and Approvals:
Lacosamide (Tradename: Vimpat) should be initiated at 50 mg twice daily for the adjunctive treatment of partial-onset seizures. The dose can be increased weekly by 100 mg daily given as two divided doses, up to the recommended total daily dose of 200 or 400 mg. The Food and Drug Administration (FDA) did not approve the 600 mg total daily dose, due to no additional benefit and the increased risk of additional side effects over a 400 mg total daily dose.
Patients receiving IV Lacosamide can receive a dosage equivalent to their oral Lacosamide dose. The IV dose should be infused over 30-60 min. The injection may be injected without further dilution and is compatible with sodium chloride injection 0.9%, lactated ringers, and dextrose.
Lacosamide is available as 50 mg, 100 mg, 150 mg, and 200 mg tablets. It is also available in a 200 mg/20 mL single dose vial, which is stable at room temperature.
Lacosamide was discovered at the University of Houston and developed initially by Schwarz Bioscienes. Union Chimique Belge (UCB) later acquired Schwarz and developed Lacosamide for the adjunctive treatment of partial-onset seizures and also trying Lacosamide as a therapy for neuropathic pains.

Reported Activities for Lacosamide
Lacosamide (10-100 uM) did not significantly bind (greater than 50% inhibition of radioligand binding) to any of more than 100 receptors, channels, or enzymes tested, including molecular targets of other drugs with analgesic and antiepileptic activity. Lacosamide did not modulate the uptake of the neurotransmitters: norepinephrine, dopamine, or serotonin into synaptosomes, and did not bind to GABA transporters or influence the activity of GABA transaminases.
Lacosamide did bind weakly (25-50% inhibition of radioligand binding) to the sodium channel at batrachotoxin site 2. Lacosamide did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, Nor P-type).
Moreover, its major desmethyl metabolite exerted no significant binding to the receptors tested [5].

Common name: SPM 927; SPM-927; SPM927; ADD 234034; ADD234034; ADD-234034; Harkoseride; LCM; Lacosamide
Trademarks: Vimpat
Molecular Formula: C13H18N2O3
CAS Registry Number: 175481-36-4
CAS Name: R-2-acetamido-N-benzyl-3-methoxypropionamide
Molecular Weight: 250.30
SMILES: O=C(N[C@@H](C(=O)NCc1ccccc1)COC)C
InChI: InChI=1S/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1
Mechanism of Action: Slow Inactivator of Voltage Gated Sodium Channels (VGSCs); Modulator of Collapsin-Response Mediator Protein-2 (CRMP-2)
Activity: Treatment of Partial-Onset Seizures in Adults with Epilepsy; Antiepileptic Drugs
Status: Launched 2008 (US, EU)             
Chemical Class: Amides; Amino Acids; Benzene; Small-molecules; D-serine
Originator: University of Houston/Union Chimique Belge
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