Jump to content

Remacemide

From Wikipedia, the free encyclopedia
Remacemide
Clinical data
Trade namesEcovia[1]
Other names(±)-2-amino-N-[1,2-di(phenyl)propan-2-yl]acetamide PR 934-423
Routes of
administration		By mouth
ATC code
  • none
Identifiers
  • N-(1-methyl-1,2-diphenylethyl)glycinamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H20N2O
Molar mass268.360 g·mol−1
3D model (JSmol)
  • CC(CC1=CC=CC=C1)(C2=CC=CC=C2)NC(=O)CN
  • InChI=1S/C17H20N2O/c1-17(19-16(20)13-18,15-10-6-3-7-11-15)12-14-8-4-2-5-9-14/h2-11H,12-13,18H2,1H3,(H,19,20) ☒N
  • Key:YSGASDXSLKIKOD-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Remacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties.[2] It has been studied for the treatment of acute ischemic stroke,[3][4] epilepsy,[5] Huntington's disease, and Parkinson's disease.

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]

Adverse effects

[edit]

Lack of adverse effects

[edit]

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]

Toxicity

[edit]

The median toxic dose of remacemide for neural impairment tests in mice is 5.6 mg/kg.[17] Its estimated median lethal dose is about 927.3 mg/kg in mice.[17] It has a favorable therapeutic index of 28.1 in mice.[17]

Drug interactions

[edit]

Levodopa

[edit]

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]

Sodium valproate

[edit]

Remacemide does not interact with sodium valproate, a treatment for epilepsy.[19]

Carbamazepine

[edit]

Ramacemide does interact with carbamazepine. Remacemide inhibits the metabolism of carbamazepine, while carbamazepine induces the metabolism of remacemide and FPL 12495.[20]

Alcohol

[edit]

Remacemide salts

[edit]

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 suspension formulation.[21]

Mechanism of action

[edit]

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]

Epilepsy

[edit]

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]

Pharmacokinetics

[edit]

Blood–brain barrier

[edit]

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]

Enantiomers

[edit]

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]

Metabolites

[edit]

FPL 12495

[edit]

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]

Other metabolites

[edit]

FPL 15053

[edit]

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

[edit]

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 15455

[edit]

FPL 15455 is an oxoacetate metabolite of remacemide, but has no demonstrated biological activity.[7]

FPL 14991 and FPL 14981

[edit]

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]

FPL 13592 and FPL 15112

[edit]

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]

FPL 14467

[edit]

FPL 14467 (p-dihydroxy-desglycine) is inactive in vivo and weak in binding NMDAR.[7]

Pharmacodynamics

[edit]

The values for 50% displacement of [3H]MK801 were 68 μM for remacemide and 0.48 μM for FPL 12495AA.[7]

History

[edit]

Current status

[edit]

Remacemide is an experimental drug most recently being developed by the British multinational pharmaceutical company AstraZeneca. However, there has been little news of its progress since 2000. A few sources indicate that its development has been discontinued.[32][33]

Changing hands

[edit]

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]

Discovery and development under Fisons

[edit]

In 1990, researchers at Fisons found that remacemide acted as an anticonvulsant in mice and rats[17][27] .[38] Because of remacemide's potential as a neuroprotective agent through preventing glutamate toxicity, it was soon also under investigation as a treatment for Huntington's disease[39] and Parkinson's disease.[40]

Astra

[edit]

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]

AstraZeneca

[edit]

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]

In 1999, after the merger, AstraZeneca reported that they were investigating remacemide for its neuroprotective effects, and that they planned regulatory submissions for Huntington's disease in 2001 and for Parkinson's disease and epilepsy in 2003.[43]

Remacemide, under the trade name Ecovia, was designated an orphan drug for the treatment of Huntington's disease by the FDA in March 2000.[1]

Remacemide was last mentioned in AstraZeneca's reports on its R&D pipeline in 2000, when it was in Phase III clinical trials for remacemide in the treatment of Huntington's disease and Phase II for treatment of Parkinson's disease. At that time, the submission of the New Drug Application (NDA) to the FDA and the Marketing Authorization Application to the CHMP was projected for Huntington's in 2001 and for Parkinson's after 2003,[37] but there has been no news of such submission. In this report, it was also noted that remacemide was "under strategic review and a potential candidate for licensing activity"[37] (see this external article about drug licensing.)

Current news

[edit]

There are no clinical trials of remacemide in progress, according to the Huntington Study Group,[44] and the Parkinson Study Group.[45]

Availability

[edit]

Remacemide is an experimental drug not available to the public and not currently undergoing clinical trials.

See also

[edit]

References

[edit]
  1. ^ a b FDA (2009-05-05). "Cumulative List of all Products that have received Orphan Designation" (excel document). FDA. Retrieved 28 April 2012.
  2. ^ 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. PMID 11906711.
  3. ^ Muir KW, Lees KR (September 1995). "Initial experience with remacemide hydrochloride in patients with acute ischemic stroke". Annals of the New York Academy of Sciences. 765 (1 Neuroprotecti): 322–3. Bibcode:1995NYASA.765..322M. doi:10.1111/j.1749-6632.1995.tb16602.x. PMID 7486631. S2CID 7573258.
  4. ^ Dyker AG, Lees KR (September 1999). "Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke". Stroke. 30 (9): 1796–801. doi:10.1161/01.STR.30.9.1796. PMID 10471426.
  5. ^ a b Wesnes 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. PMID 19111629. S2CID 6582499.
  6. ^ a b Leach 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. PMID 12519561.
  7. ^ a b c d e f g h i j k l m n Palmer 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. PMID 1388119. S2CID 23097783.
  8. ^ a b "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. PMID 10762497. S2CID 216064344.
  9. ^ Lockton J, Cole G, Hammersley M, Wesnes K (1998). "Cognitive function is unaffected by remacemide at therapeutic relevant single doses". J Psychopharmacol. 12 (A41).
  10. ^ Lockton JA, Wesnes KA, Yeates N, Rolan P, Diggory G (1998). "Remacemide does not affect cognitive function following multiple dosing". J Psychopharmacol. 12 (A41).
  11. ^ 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. PMID 11862350. S2CID 2774324.
  12. ^ 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. Bibcode:2007NTxT...29..348W. doi:10.1016/j.ntt.2006.12.004. PMID 17291718.
  13. ^ Popke EJ, Allen RR, Pearson EC, Hammond TG, Paule MG (1 July 2001). "Differential effects of two NMDA receptor antagonists on cognitive-behavioral development in nonhuman primates I". Neurotoxicology and Teratology. 23 (4): 319–32. Bibcode:2001NTxT...23..319P. doi:10.1016/S0892-0362(01)00156-8. PMID 11485835.
  14. ^ Popke EJ, Allen RR, Pearson EC, Hammond TG, Paule MG (1 July 2001). "Differential effects of two NMDA receptor antagonists on cognitive--behavioral performance in young nonhuman primates II". Neurotoxicology and Teratology. 23 (4): 333–47. Bibcode:2001NTxT...23..333P. doi:10.1016/S0892-0362(01)00138-6. PMID 11485836.
  15. ^ Popke EJ, Patton R, Newport GD, Rushing LG, Fogle CM, Allen RR, et al. (1 March 2002). "Assessing the potential toxicity of MK-801 and remacemide: chronic exposure in juvenile rhesus monkeys". Neurotoxicology and Teratology. 24 (2): 193–207. Bibcode:2002NTxT...24..193P. doi:10.1016/S0892-0362(02)00206-4. PMID 11943507.
  16. ^ 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. PMID 12853303. S2CID 19776727.
  17. ^ a b c d e Stagnitto 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. PMID 1963406. S2CID 13657516.
  18. ^ "The impact of remacemide hydrochloride on levodopa concentrations in Parkinson's disease. Parkinson Study Group". Clinical Neuropharmacology. 22 (4): 220–5. Jul–Aug 1999. PMID 10442252.
  19. ^ Leach JP, Girvan J, Jamieson V, Jones T, Richens A, Brodie MJ (June 1997). "Lack of pharmacokinetic interaction between remacemide hydrochloride and sodium valproate in epileptic patients". Seizure. 6 (3): 179–84. doi:10.1016/S1059-1311(97)80003-9. PMID 9203245. S2CID 18469302.
  20. ^ 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. PMID 8917061. S2CID 23489355.
  21. ^ 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.
  22. ^ 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. PMID 8558426.
  23. ^ a b Heyn 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. PMID 8070322.
  24. ^ 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. PMID 7566473. S2CID 12067526.
  25. ^ 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. PMID 525379.
  26. ^ Oldendorf WH, Pardridge WM, Braun LD, Crane PD (May 1982). "Measurement of cerebral glucose utilization using washout after carotid injection in the rat". Journal of Neurochemistry. 38 (5): 1413–8. doi:10.1111/j.1471-4159.1982.tb07920.x. PMID 7062059. S2CID 44670571.
  27. ^ a b Garske 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. PMID 1660399. S2CID 40219442.
  28. ^ 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. PMID 8991798.
  29. ^ 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. PMID 9257939. S2CID 20522408.
  30. ^ Leach JP, Sills GJ, Butler E, Forrest G, Thompson GG, Brodie MJ (July 1997). "Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain". British Journal of Pharmacology. 121 (5): 923–6. doi:10.1038/sj.bjp.0701219. PMC 1564774. PMID 9222548.
  31. ^ 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. PMID 9190853.
  32. ^ "remacemide () UKMi New Drugs Online Database". Retrieved 2 May 2012.
  33. ^ a b "remacemide AstraZeneca discontinued, Europe, USA, Canada (epilepsy)". R & D Focus Drug News. March 15, 2004. Archived from the original on May 18, 2013. Retrieved 2 May 2012.
  34. ^ "FISONS DISCONTINUES TIPREDANE DEV'T". the pharma letter. 12 April 1993. Retrieved 28 April 2012.
  35. ^ a b "Sweden's Astra Buys Most Of Fisons R&D Ops". the pharma letter. 27 March 1995. Retrieved 28 April 2012.
  36. ^ "AstraZeneca History". AstraZeneca. Retrieved 29 April 2012.
  37. ^ a b c "AstraZeneca R&D Pipeline: NCEs". AstraZeneca. 2000. Retrieved 28 April 2012.
  38. ^ 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. PMID 2290849.
  39. ^ a b Kieburtz 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. PMID 8723144. S2CID 33908305.
  40. ^ 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. PMID 8210221. S2CID 21875296.
  41. ^ "Completed Clinical Trials". Huntington Study Group. 2010. Archived from the original on 28 June 2012. Retrieved 29 April 2012.
  42. ^ "Astra 98 Annual Report" (PDF). Stellan Ståls Grafiska AB. Retrieved 28 April 2012.
  43. ^ Polinsky R. "AstraZeneca CNS". AstraZeneca. Retrieved 27 April 2012.
  44. ^ "Clinical Trials and Observational Studies in Progress". Huntington Study Group. 2010. Archived from the original on 18 May 2009. Retrieved 29 April 2012.
  45. ^ "Clinical Trials in Progress - Parkinson Study Group". Archived from the original on 11 September 2011. Retrieved 2 May 2012.
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Remacemide&oldid=1250073274"