Because remacemide has only a modest effect on seizure frequency and causes dizziness, it is no longer believed that remacemide will be an effective treatment for epilepsy.[6] Although no such statement has been made about remacemide's potential for treating stroke, Huntington's, or Parkinson's, remacemide is no longer being developed for these conditions.[citation needed]
Remacemide is also known as remacemide hydrochloride, (±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride, or FPL 12924AA.[7]
Unlike many other treatments for epilepsy, remacemide does not appear to impair cognitive performance[9][10][5] or driving performance[11] in humans, although the evidence for effects on cognitive performance in animals has been mixed.[12][13][14][15][16]
Remacemide is not a sedative.[17]
Remacemide delays the absorption of levodopa (300 mg of remacemide one hour before levodopa treatment delays mean time to peak levodopa plasma concentration by 20%) but not its total absorption (area-under-the-curve for levodopa plasma concentration was unchanged).[18]
Ramacemide does interact with carbamazepine. Remacemide inhibits the metabolism of carbamazepine, while carbamazepine induces the metabolism of remacemide and FPL 12495.[20]
Remacemide is most commonly synthesized as the salt remacemide hydrochloride. However, there has been some investigation into other remacemide salts and their crystals, as different remacemide salts might taste more pleasant or have a solubility more suitable for a pediatric suspensionformulation.[21]
Remacemide binds weakly and noncompetitively to the ionic channel site of the NMDA receptor complex.[7] Remacemide binds both allosterically and in the channel.[22]
However, because remacemide binds so weakly to NMDAR, much of remacemide's in vivo effect against excitotoxicity is thought to be caused by its metabolic transformation to the more potent desglycine derivative FPL 12495.[7] That is, remacemide may actually act as a prodrug to deliver the active metabolite FPL 12495 to the central nervous system.[23]
In a well validated and described genetic model of absence epilepsy, rats of the WAG/Rij strain, remacemide and its metabolite FPL 12495 were found to have a common for glutamate antagonist usual effect on the number of spike/wave dischargesEEG, the drugs decrease spike/wave discharges dose dependently. However, in contrast to most other glutamate antagonists, FPL 12495 increased the duration of the spike-wave discharges.[24]
The brain uptake index (BUI), a measure of a drug's ability to pass the blood–brain barrier that involves the injection of radiolabeled test and reference substances into the common carotid artery of anesthetized animals,[25][26] for remacemide is 51 ± 0.9 SD.[23]
The (-)stereoisomer of remacemide is of equal potency to the racemic mixture in preventing maximal electroshock seizures when administered orally to rats, while the (+)stereoisomer is less potent.[27]
Much of remacemide's effect in vivo is thought to be caused by the desglycine derivative FPL 12495 (±).[7]
FPL 12495 (±) binds specifically and non-competitively to NMDAR.[28] Its effect on maximal electroconvulsive shock is more potent than remacemide.[7] The S isomer (FPL 12859) is even more potent than the racemic mixture, while the R isomer is less potent than the racemate.[7]
FPL 12495 is sometimes referred to as ARL 12495AA.[29][30][31]
FPL 15053 is the N-hydroxy-desglycinate of remacemide, and exhibits modest binding to NMDAR and modest effects on convulsions and mortality in test mice and rats.[7]
FPL 14331 and FPL 14465 are the p-hydroxy-desglycinates of remacemide, and they exhibit some efficacy against maximal electroconvulsive shock after i.p. and i.v. dosing.[7]
FPL 14991 and FPL 14981 are both β-Miydroxy-desglycinates of remacemide, and they display modest efficacy against maximal electroconvulsive shock in mice.[7] However FPL 14981 and not FPL 14991 prevents NMDLA-induced convulsions and mortality in mice.[7]
The hydroxy-methyl derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevents electric shock-induced convulsions only after i.v. administration; only the desglycine derivative binds to NMDAR.[7]
Remacemide is an experimental drug most recently being developed by the British multinational pharmaceutical companyAstraZeneca. However, there has been little news of its progress since 2000. A few sources indicate that its development has been discontinued.[32][33]
Remacemide was one of the last drugs under development by the now-defunct English pharmaceutical company Fisons.[34] In 1995, it was acquired along with most of Fisons' research and development operations by the Swedish pharmaceutical company Astra,[35] which in 1999 merged with the British company Zeneca to form AstraZeneca.[36] In 2000, AstraZeneca considered possibly licensing out remacemide to some other pharmaceutical company,[37] but there has been little news about remacemide since then. Remacemide's development may have been discontinued in July 2001.[33]
By 1995, when Astra acquired remacemide, it was already in Phase IIb clinical development as an anti-epileptic drug[35] and Phase I clinical development as a treatment for Huntington's
.[39][41]
By 1998, when Astra announced its merger with Zeneca, remacemide had progressed to Phase III trials for epilepsy and Phase II trials for Parkinson's disease, and Astra was also investigating its potential for treating neuropathic pain[42]
^Santangeli S, Sills GJ, Thompson GG, Brodie MJ (March 2002). "Na(+) channel effects of remacemide and desglycinyl-remacemide in rat cortical synaptosomes". European Journal of Pharmacology. 438 (1–2): 63–8. doi:10.1016/S0014-2999(02)01297-9. PMID11906711.
^ abWesnes KA, Edgar C, Dean AD, Wroe SJ (March 2009). "The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy". Epilepsy & Behavior. 14 (3): 522–8. doi:10.1016/j.yebeh.2008.11.012. PMID19111629. S2CID6582499.
^ abLeach JP, Marson AG, Hutton JL (2002). "Remacemide for drug-resistant localization related epilepsy". The Cochrane Database of Systematic Reviews (4): CD001900. doi:10.1002/14651858.CD001900. PMID12519561.
^ abcdefghijklmnPalmer GC, Murray RJ, Wilson TC, Eisman MS, Ray RK, Griffith RC, et al. (June 1992). "Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide". Epilepsy Research. 12 (1): 9–20. doi:10.1016/0920-1211(92)90086-9. PMID1388119. S2CID23097783.
^ ab"A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD. Parkinson Study Group". Neurology. 54 (8): 1583–8. April 2000. doi:10.1212/wnl.54.8.1583. PMID10762497. S2CID216064344.
^Lockton J, Cole G, Hammersley M, Wesnes K (1998). "Cognitive function is unaffected by remacemide at therapeutic relevant single doses". J Psychopharmacol. 12 (A41).
^Lockton JA, Wesnes KA, Yeates N, Rolan P, Diggory G (1998). "Remacemide does not affect cognitive function following multiple dosing". J Psychopharmacol. 12 (A41).
^Ramaekers G, Lamers J, Verhey F, Muntjewerff D, Mobbs E, Sanders N, et al. (January 2002). "A comparative study of the effects of carbamazepine and the NMDA receptor antagonist remacemide on road tracking and car-following performance in actual traffic". Psychopharmacology. 159 (2): 203–10. doi:10.1007/s002130100898. PMID11862350. S2CID2774324.
^Wright LK, Pearson EC, Hammond TG, Paule MG (May–Jun 2007). "Behavioral effects associated with chronic ketamine or remacemide exposure in rats". Neurotoxicology and Teratology. 29 (3): 348–59. doi:10.1016/j.ntt.2006.12.004. PMID17291718.
^Paule MG, Fogle CM, Allen RR, Pearson EC, Hammond TG, Popke EJ (May 2003). "Chronic exposure to NMDA receptor and sodium channel blockers during development in monkeys and rats: long-term effects on cognitive function". Annals of the New York Academy of Sciences. 993 (1): 116–22, discussion 123–4. doi:10.1111/j.1749-6632.2003.tb07519.x. PMID12853303. S2CID19776727.
^ abcdeStagnitto ML, Palmer GC, Ordy JM, Griffith RC, Napier JJ, Becker CN, et al. (Sep–Oct 1990). "Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice". Epilepsy Research. 7 (1): 11–28. doi:10.1016/0920-1211(90)90050-6. PMID1963406. S2CID13657516.
^"The impact of remacemide hydrochloride on levodopa concentrations in Parkinson's disease. Parkinson Study Group". Clinical Neuropharmacology. 22 (4): 220–5. Jul–Aug 1999. PMID10442252.
^Leach JP, Blacklaw J, Jamieson V, Jones T, Richens A, Brodie MJ (November 1996). "Mutual interaction between remacemide hydrochloride and carbamazepine: two drugs with active metabolites". Epilepsia. 37 (11): 1100–6. doi:10.1111/j.1528-1157.1996.tb01031.x. PMID8917061. S2CID23489355.
^Lewis GR, Steele G, McBride L, Florence AJ, Kennedy AR, Shankland N, et al. (1 March 2005). "Hydrophobic vs. Hydrophilic: Ionic Competition in Remacemide Salt Structures". Crystal Growth & Design. 5 (2): 427–438. doi:10.1021/cg049836u.
^Subramaniam S, Donevan SD, Rogawski MA (January 1996). "Block of the N-methyl-D-aspartate receptor by remacemide and its des-glycine metabolite". The Journal of Pharmacology and Experimental Therapeutics. 276 (1): 161–8. PMID8558426.
^ abHeyn H, McCarthy DJ, Curry SH, Eisman MS, Anders MW (May–Jun 1994). "Brain uptake and biotransformation of remacemide hydrochloride, a novel anticonvulsant". Drug Metabolism and Disposition. 22 (3): 443–6. PMID8070322.
^van Luijtelaar EL, Coenen AM (April 1995). "Effects of remacemide and its metabolite FPL 12495 on spike-wave discharges, electroencephalogram and behaviour in rats with absence epilepsy". Neuropharmacology. 34 (4): 419–25. doi:10.1016/0028-3908(95)00008-T. hdl:2066/28626. PMID7566473. S2CID12067526.
^Hardebo JE, Nilsson B (October 1979). "Estimation of cerebral extraction of circulating compounds by the brain uptake index method: influence of circulation time, volume injection, and cerebral blood flow". Acta Physiologica Scandinavica. 107 (2): 153–9. doi:10.1111/j.1748-1716.1979.tb06455.x. PMID525379.
^ abGarske GE, Palmer GC, Napier JJ, Griffith RC, Freedman LR, Harris EW, et al. (September 1991). "Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat". Epilepsy Research. 9 (3): 161–74. doi:10.1016/0920-1211(91)90050-p. PMID1660399. S2CID40219442.
^Hu RQ, Davies JA (December 1995). "The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice". European Journal of Pharmacology. 287 (3): 251–6. doi:10.1016/0014-2999(95)00500-5. PMID8991798.
^Norris SK, King AE (July 1997). "Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro". Neuropharmacology. 36 (7): 951–9. doi:10.1016/S0028-3908(97)00069-5. PMID9257939. S2CID20522408.
^Norris SK, King AE (June 1997). "The stereo-isomers of the anticonvulsant ARL 12495AA limit sustained repetitive firing and modify action potential properties of rat hippocampal neurons in vitro". The Journal of Pharmacology and Experimental Therapeutics. 281 (3): 1191–8. PMID9190853.
^Palmer GC, Harris EW, Napier JJ, Stagnitto ML, Garske GE, Griffith RC, Swinyard EA (1990). "Status of PR 934-423, a novel anticonvulsant targeted for generalized tonic/clonic seizures (new designation is FPL 12924AA)". Progress in Clinical and Biological Research. 361: 435–41. PMID2290849.
^ abKieburtz K, Feigin A, McDermott M, Como P, Abwender D, Zimmerman C, et al. (May 1996). "A controlled trial of remacemide hydrochloride in Huntington's disease". Movement Disorders. 11 (3): 273–7. doi:10.1002/mds.870110310. PMID8723144. S2CID33908305.
^Greenamyre JT, Eller RV, Zhang Z, Ovadia A, Kurlan R, Gash DM (June 1994). "Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson's disease". Annals of Neurology. 35 (6): 655–61. doi:10.1002/ana.410350605. PMID8210221. S2CID21875296.
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