175481-36-4 Usage
Description
Different sources of media describe the Description of 175481-36-4 differently. You can refer to the following data:
1. Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsant or antiepileptic drug. It reduces the spread of seizure activity in the brain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2.? Compared to novel antiepileptic drugs, lacosamide has broader and higher efficacy, better tolerability, and improved pharmacokinetic properties. Lacosamide is in phase III clinical development for adjunctive treatment of patients with uncontrolled partial-onset seizures, and for monotherapy of patients with painful diabetic neuropathy. It is absorbed rapidly and completely after oral administration. Lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability.
Lacosamide (licensed in 2008) is a third- generation AED known with the proprietary brand name of Vimpat? (UCB Pharma, Slough) in the UK and USA.
2. Although epilepsy is a neurological disorder with varying etiology and
severity, the common feature is unprovoked, recurring seizures. Whether
classified as generalized, involving both cerebral hemispheres, or partial
with only localized portions of brain participation at onset, effective
treatment relies on accurate assessment of syndrome type to optimally
decrease the frequency, duration, and severity of seizures. The
latest weapon against partial onset epilepsy is lacosamide, formerly
known as harkoseride and erlosamide. The data also indicate that lacosamide
binds to collapsing response mediator protein 2 (CRMP2); CRMP2 is
involved in neuronal differentiation, control of axonal outgrowth, and
possibly epileptogenesis. Furthermore, lacosamide is heralded as having
a dual mode of action as it has also displayed efficacy against diabetic
neuropathy, possibly as a result of stabilization of neuronal hyperexcitability. Currently,lacosamide is approved as adjunctive treatment of partial onset seizures in patients 17 years or older and is in development as a monotherapy
for epilepsy and for neuropathic pain.
3. Lacosamide selectively enhances sodium channel slow inactivation without affecting fast inactivation. It is effective in multiple rodent models of seizure activity. The neuroprotective effects of lacosamide are also attributed to its ability to modulate collapsin response mediator protein 2 (CRMP-2), a member of the semaphorin signal transduction pathway. Formulations containing lacosamide have been used as an adjunctive or monotherapy for focal-onset seizures but, at higher doses, have a low potential for abuse. Lacosamide is regulated as a Schedule V compound in the United States.
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).
Uses
Different sources of media describe the Uses of 175481-36-4 differently. You can refer to the following data:
1. Lacosamide is an anticonvulsant and analgesic compound used for the treatment of partial-onset seizures and neuropathic pain. It can also used for the treatment of status epilepticus. Its analgesic effect is mediated by its inhibitory effect on sodium channels, which leads to neural membrane depolarization. Its interaction with the collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) may also facilitate the above process, although the detailed mechanism remains to be elucidated.
2. A potent anticonvulsant.
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.
Chemical Properties
White to Off-White Solid
Originator
Harris FRC (United States)
Brand name
Vimpat
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.
Synthetic route of lacosamide
-
Paragraph 0023, (2021/03/31)
The invention discloses a new synthesis route of lacosamide. The new synthesis route comprises the following steps: taking glycine ethyl ester hydrochloride as an initial raw material to react with methylbenzene, benzophenone and p-toluenesulfonic acid to obtain a compound of formula M1; reacting the compound of formula M1 with Xmethyl methyl ether to generate a compound of formula M2; reacting the compound of formula M2 with benzylamine under the catalytic action of sodium ethoxide to generate a compound of formula M3; reacting the compound of formula M3 under the action of acid to generate acompound of formula M4; reacting the compound of formula M4 with Ltartaric acid to generate a compound of formula M5; and enabling the compound of formula M5 to react with acetic anhydride to generate the lacosamide compound. The synthesis route has the advantages that the atom economy is high, the use of isopropyl chloroformate highly toxic products for preparing amide is avoided, the use of methylation reagents methyl iodide or dimethyl sulfate is avoided, the yield is high, and the like.
Synthetic method of (by machine translation)
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Paragraph 0032; 0035-0036; 0037; 0040-0041; 0042; 0045-0046, (2020/04/17)
The synthesis method, takes ethyl acetoacetate as a starting material, as a starting raw material and reacts the compound of the formula II with trimethyl orthoformate to form the compound; of the formula III with the compound of the formula III under the action of a catalyst and a ligand H. 2 Of asymmetric hydrogenation to produce compound; of formula IV wherein the compound of formula IV is reacted with sodium azide in Schmidt rearrangement reaction to produce compound; of formula V in which compound of formula V is reacted with benzyl amine (BnNH under alkaline conditions of sodium methoxide. 2 ) The reaction scheme of the invention has the advantages. (: the economical efficiency of the atom is high, the use, of, the methyl tert-butyl carbonate is avoided, the use, of the methyl tert-butyl peroxyformate is avoided, yield is high, and the, like. (by machine translation)
