175481-36-4 Usage
Description
Lacosamide, also known as SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, harkoseride, or ADD 234037, is a functionalized amino acid specifically synthesized as an anticonvulsant or antiepileptic drug. It is a third-generation AED with the proprietary brand name Vimpat, licensed in 2008. Lacosamide has a dual mode of action, selectively enhancing sodium channel inactivation and modulating collapsin response mediator protein-2 (CRMP-2). It is effective in reducing the spread of seizure activity in the brain and has broader and higher efficacy, better tolerability, and improved pharmacokinetic properties compared to other novel antiepileptic drugs.
Uses
Used in Pharmaceutical Industry:
Lacosamide is used as an anticonvulsant for the treatment of partial-onset seizures and neuropathic pain. Its anticonvulsant effect is attributed to its selective enhancement of sodium channel inactivation and modulation of CRMP-2, which is involved in neuronal differentiation, control of axonal outgrowth, and possibly epileptogenesis.
Used in Neurological Treatment:
Lacosamide is used as an adjunctive treatment for patients with uncontrolled partial-onset seizures, aged 17 years or older. It is also in development as a monotherapy for epilepsy and neuropathic pain. Its analgesic effect is mediated by its inhibitory effect on sodium channels, leading to neural membrane depolarization.
Used in Epilepsy Management:
Lacosamide is used in the management of epilepsy, particularly for patients with partial-onset seizures. It has been found to be effective in multiple rodent models of seizure activity and is regulated as a Schedule V compound in the United States.
Used in Neuroprotection:
The neuroprotective effects of lacosamide are attributed to its ability to modulate CRMP-2, a member of the semaphorin signal transduction pathway. This modulation may contribute to its efficacy against diabetic neuropathy, possibly as a result of stabilization of neuronal hyperexcitability.
Used in Status Epilepticus Treatment:
Lacosamide can also be used for the treatment of status epilepticus, a life-threatening condition characterized by continuous or near-continuous seizures.
Generic formulation
MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (incl. generic products):
It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.
Indications
Epilepsy: Adjunctive treatment of focal seizures with or without secondary generalization.
Dose titration
Epilepsy— adjunctive therapy: 50 mg bd for 7 days, then increased by 50 mg bd every 7 days; usual maintenance 100 mg bd (max. 200 mg bd).
Epilepsy— adjunctive therapy (loading dose regimen when it is necessary to rapidly attain therapeutic plasma concentrations, under close medical supervision): 200 mg bd for 1 day, followed by maintenance dose of 100 mg bd after 1 day, then increased if needed by 50 mg bd every 7 days (max. 200 mg bd).
Side effects
Lacosamide was generally well tolerated in adult patients with partial-onset seizures.[11] The side-effects most commonly leading to discontinuation were dizziness, ataxia, diplopia (double vision), nystagmus, nausea, vertigo and drowsiness. These adverse reactions were observed in at least 10% of patients.[9] Less common side-effects include tremors, blurred vision, vomiting and headache.
Cautions
Patients with conduction problems (contraindicated in patients with second- or third- degree A– V block).
Patients with severe cardiac disease.
Patients at risk of PR- interval prolongation.
Elderly patients.
Interactions
With AEDs
Concomitant treatment with other AEDs known to be enzyme inducers (such as carbamazepine, phenobarbital, phenytoin) decreases the overall systemic exposure of lacosamide by 25%.
With other drugs
Nil.
With alcohol/food
Although no pharmacokinetic data on the interaction of lacosamide with alcohol are available, a pharmacodynamic effect cannot be excluded.
There are no specific foods that must be excluded from diet when taking lamotrigine.
Special populations
Hepatic impairment
Titrate with caution in mild- to- moderate impairment if co- existing renal impairment.
Caution in severe impairment.
Renal impairment
Loading dose regimen can be considered in mild- to- moderate impairment (titrate above 200 mg with caution).
Titrate with caution in severe impairment (max. 250 mg daily).
Pregnancy
There are no adequate data from the use of lacosamide in pregnant women and the potential risk for humans is unknown.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus). If a woman decides to become pregnant, the use of lacosamide should be carefully re- evaluated. In case of treatment with lacosamide, the dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
Lacosamide has been found to be present in milk in animal studies and it is recommended that it should be avoided during breastfeeding
Behavioural and cognitive effects in patients with epilepsy
For this third- generation agent, clinical experience is still limited and little is known about its positive and negative psychotropic properties and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of depression, irritability and agitation, and psychotic symptoms. Reports of cognitive effects (mainly affecting attention and memory) are rare and usually not severe.
Psychiatric use
Lacosamide has no indications for the treatment of psychiatric disorders. There is insufficient experience with lacosamide to draw any conclusion regarding its psychotropic profile.
References
[1] B. K. Beyreuther, J. Freitag, C. Heers, N. Krebsf?nger, U. Scharfenecker, T. St?hr (2007) Lacosamide: a review of preclinical properties, CNS Drug Reviews, 13, 21-42
[2] Beyreuther, Bettina K., et al. "Lacosamide: A Review of Preclinical Properties." Cns Drug Reviews 13.1(2007):21.
[3]Chung, S, et al. "Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial." Epilepsia 51.6(2010):958–967.
[4]Kellinghaus, C, et al. "Intravenous lacosamide for treatment of status epilepticus." Acta Neurologica Scandinavica 123.2(2011):137–141.
Originator
Harris FRC (United States)
Clinical Use
#N/A
Synthesis
The most common adverse events were diplopia, headache, dizziness, and nausea. As typical with AEDs, lacosamide may increase the risk of suicidal thoughts or behavior. Patients should, therefore, be monitored for the emergence or worsening of depression. Caution should also be exercised in patients with known conduction problems or severe cardiac disease (myocardial ischemia or heart failure) since dose-dependent prolongations in PR interval have been observed in clinical studies.
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: anticonvulsant effect antagonised;
avoid with St John’s wort.
Antimalarials: mefloquine antagonises
anticonvulsant effect.
Antipsychotics: anticonvulsant effect antagonised.
Orlistat: possibly increased risk of convulsions.
Metabolism
The metabolism of lacosamide has not been completely
characterised. Lacosamide is a CYP2C19 substrate.
Metabolites are inactive.
About 95% of a dose is excreted in the urine, about 40%
as unchanged drug and less than 30% as the inactive
O-desmethyl metabolite. Less than 0.5% of a dose is
excreted in the faeces
Check Digit Verification of cas no
The CAS Registry Mumber 175481-36-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,7,5,4,8 and 1 respectively; the second part has 2 digits, 3 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 175481-36:
(8*1)+(7*7)+(6*5)+(5*4)+(4*8)+(3*1)+(2*3)+(1*6)=154
154 % 10 = 4
So 175481-36-4 is a valid CAS Registry Number.
InChI:InChI=1/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
175481-36-4Relevant articles and documents
An enantioselective approach to functionalized amino acids: Total synthesis of antiepileptic drug (R)-lacosamide
Garg, Yuvraj,Pandey, Satyendra Kumar
, p. 4201 - 4203 (2015)
A short and highly efficient synthetic approach to enantiopure functionalized amino acids (FAAs) 1 skeleton from racemic butadiene monoepoxide as a starting material and its application to the total synthesis of an antiepileptic drug (R)-lacosamide 2 are described. The synthesis utilizes the palladium catalyzed Trosts Dynamic Kinetic Asymmetric Transformation (DYKAT) as key step.
Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid
Zhang, Jian,Wang, Yi-Yan,Sun, He,Li, Shao-Yu,Xiang, Shao-Hua,Tan, Bin
, p. 47 - 54 (2020)
A catalytic enantioselective three-component Ugi reaction was developed. SPINOL-derived phosphoric acid with bulky 2,4,6-tricyclohexylphenyl groups at the 6,6′ positions was found to be the best catalyst to afford α-amino amide derivatives in good to excellent yields (62% to 99%) and enantiocontrol (81% to >99% enantiomeric excess). This asymmetric reaction was applicable well to an array of aliphatic aldehydes. The gram-scale synthesis, modification of dapsone, and enantioselective synthesis of (R)-Lacosamide underline the general utility of this methodology Influence of dihedral angles and substituents of the chiral phosphoric acids on the enantioselectivity was also discussed in this article.
Total synthesis of lacosamide
Stecko, Sebastian
, p. 6342 - 6346 (2014)
Total synthesis of anticonvulsant amino acid, lacosamide, is reported. The key step is stereospecific allyl cyanate-to-isocyanate rearrangement, which proceeds with chirality transfer. The enantiopure starting material for the rearrangement step was accessed from ethyl l-lactate.
Novel preparation method of lacosamide
-
, (2021/07/09)
The invention relates to a preparation method of high-purity lacosamide, and belongs to the technical field of organic synthesis. The technical problem to be solved by the invention is to provide a preparation method of lacosamide with mild reaction conditions and high optical purity. The preparation method comprises the following steps: carrying out condensation reaction on a carboxylic acid compound with a protecting group and benzylamine to generate an amide compound, carrying out deprotection under the condition of phosphoric acid, and introducing acetyl to prepare the lacosamide. The invention provides a novel industrial synthesis selection mode, the synthesis mode has the characteristics of simple process, mild reaction conditions, environmental friendliness and the like, can be used for preparing an optical high-purity target compound, and is beneficial to industrial production.
Preparation method of lacosamide
-
Paragraph 0029-0030, (2020/07/02)
The invention provides a novel methylation method of a lacosamide synthesis intermediate, which comprises the following steps: methylating a compound I in a reaction solvent at a proper temperature byusing trimethyloxyonium tetrafluoroborate as a methylation reagent under alkaline condition to obtain a methylation product II. The reaction formula is shown in the specification. The method has theadvantages of mild reaction condition, simple post-treatment, green methylation reagent, no high toxicity and high reaction yield, and conforms to the safe and environment-friendly green chemical concept. The method is suitable for laboratory small-scale preparation and large-scale industrial production.
