|Systematic (IUPAC) name|
|Mol. mass||268.3535 g/mol|
|(what is this?)|
Remacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties. It has been studied for the treatment of acute ischemic stroke, epilepsy, 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. 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.
Remacemide is also known as remacemide hydrochloride, (±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride, or FPL 12924AA.
- 1 Mechanism of action
- 2 Enantiomers of Remacemide
- 3 Metabolites of Remacemide
- 4 Pharmacodynamics
- 5 Pharmacokinetics
- 6 Adverse effects
- 7 Toxicity
- 8 Drug interactions
- 9 Completed Clinical Trials
- 9.1 Epilepsy
- 9.2 Stroke
- 9.3 Huntington's Disease
- 9.4 Parkinson's Disease
- 10 Remacemide Salts
- 11 Drug development history
- 12 Availability
- 13 References
- 14 External links
Mechanism of action
Remacemide binds weakly and noncompetitively to the ionic channel site of the NMDA receptor complex. Remacemide binds both allosterically and in the channel. 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. That is, remacemide may actually act as a prodrug to deliver the active metabolite FPL 12495 to the central nervous system.
Generalized Absence Epilepsy
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 dischanges dose dependently. However, in contrast to most other glutamate antagonists, FPL 12495 increased the duration of the spike-wave discharges.
Enantiomers of Remacemide
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.
Metabolites of Remacemide
Much of remacemide's effect in vivo is thought to be caused by the desglycine derivative FPL 12495 (±). FPL 12495 (±) binds specifically and non-competitively to NMDAR,. Its effect on maximal electroconvulsive shock is more potent than remacemide. The S isomer (FPL 12859) is even more potent than the racemic mixture, while the R isomer is less potent than the racemate.
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.
FPL 14331 and FPL 14465
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.
FPL 15455 is an oxoacetate matabolite of remacemide, but has no demonstrated biological activity.
FPL 14991 and FPL 14981
FPL 14991 and FPL 14981 are both β-Miydroxy-desglycinates of remacemide, and they display modest efficacy against maximal electroconvulsive shock in mice. However FPL 14981 and not FPL 14991 prevents NMDLA-induced convulsions and mortality in mice.
FPL 13592 and FPL 15112
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.
FPL 14467 (p-dihydroxy-desglycine) is inactive in vivo and weak in binding NMDAR.
Comparisons to other anticonvulsants
Preclinical trials in mice showed that remacemide has a lower efficacy than some commercial anticonvulsants and a higher efficacy than others. The median effective dose (ED50) value for oral administration of remacemide was 33 mg/kg (compare to phenytoin = 11, phenobarbital = 20, carbamazepine = 13 and valproate = 631).
Crossing the Blood–Brain Barrier
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, for remacemide is 51 ± 0.9 SD.
Lack of adverse effects
Unlike many other treatments for epilepsy, remacemide does not appear to impair cognitive performance or driving performance in humans, although the evidence for effects on cognitive performance in animals has been mixed. Remacemide is not a sedative. Despite acting on the same site as phencyclidine (PCP), remacemide is not addictive and is unlikely to cause a drug-abuse problem.
Remacemide is The median toxic dose of remacemide for neural impairment tests in mice is 5.6 mg/kg. Its estimated median lethal dose is about 927.3 mg/kg in mice. It has a favorable therapeutic index of 28.1 in mice.
Remacemide and Levodopa
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).
Remacemide and Sodium Valproate
Remacemide and Carbamazepine
Remacemide and Alcohol
Completed Clinical Trials
Short Term Assessment of Remacemide Tolerability in Huntington Disease
Co-enzyme Q10 And Remacemide Evaluation in Huntington Disease
Study of Pharmacokinetic Interactions Between Remacemide And Levodopa
The first clinical study of remacemide in Parkinson's patients was SPIRAL (Study of Pharmacokinetic Interactions Between Remacemide And Levodopa), a small short-term trial which evaluated whether remacemide affected circulating plasma levdopa concentrations in Parkinson's patients. The purpose of this evaluation was to help guide the interpretation of future clinical trials. As the study found that remacemide delayed levodopa absorption somewhat but did not change average levdopa levels over time, it was concluded that the effect of remacemide on plasma levodopa levels was unlikely to be an important factor in interpreting later clinical studies of remacemide with levdopa-treated patients. The study was begun in 1997 and the results published in 1999.
Remacemide As Monotherapy in Parkinson's Disease
The RAMP (Remacemide As Monotherapy in Parkinson's Disease) study was a multicenter, placebo-controlled, dose-ranging study to evaluate the safety, tolerability, and efficacy of remacemide as monotherapy in patients with early Parkinson's disease. Two hundred patients with early Parkinson's disease who were not yet receiving levodopa or dopamine agonists were randomized to receive either remacemide 150 mg, 300 mg, or 600 mg, or matching placebo daily for 5 weeks. Remacemide was found to be safe, with no serious adverse events occurring. It was also well tolerated, with the only dosage not well tolerated the 600 mg daily dose administered twice daily. Common side-effects were nausea and dizziness. However, there was no evidence of improvement in Parkinson's disease signs or symptoms associated with remacemide monotherapy. The study was begun in 1997 and the results published in 2000.
Dyskinesias And Remacemide Effects
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.
Drug development history
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.
Remacemide was one of the last drugs under development by the now-defunct English pharmaceutical company Fisons. In 1995, it was acquired along with most of Fisons' research and development operations by the Swedish pharmaceutical company Astra, which in 1999 merged with the British company Zeneca to form AstraZeneca. In 2000, AstraZeneca considered possibly licensing out remacemide to some other pharmaceutical company, but there has been little news about remacemide since then. Remacemide's development may have been discontinued in July 2001.
Discovery and Development under Fisons
In 1990, researchers at Fisons found that remacemide acted as an anticonvulsant in mice and rats . 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 and Parkinson's disease.
Continuing Trials under Astra
Planned Trials and Submissions under AstraZeneca
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
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.
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, 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" (see this external article about drug licensing.)
Remacemide is an experimental drug not available to the public and not currently undergoing clinical trials. It is available for research purposes from Tocris Bioscience, under license from AstraZeneca.
- FDA (2009-05-05). "Cumulative List of all Products that have received Orphan Designation" (excel document). FDA. Retrieved 28 April 2012.
- Santangeli, Sarah; Sills, Graeme J, Thompson, George G, Brodie, Martin J (1 March 2002). "Na+ channel effects of remacemide and desglycinyl-remacemide in rat cortical synaptosomes". European Journal of Pharmacology 438 (1-2): 63–68. doi:10.1016/S0014-2999(02)01297-9.
- MUIR, KEITH W.; LEES, KENNEDY R. (1 September 1995). "Initial Experience with Remacemide Hydrochloride in Patients with Acute Ischemic Stroke". Annals of the New York Academy of Sciences 765 (1 Neuroprotecti): 322–323. doi:10.1111/j.1749-6632.1995.tb16602.x.
- Dyker, AG; Lees, KR (1999). "Remacemide Hydrochloride: A Double-Blind, Placebo-Controlled, Safety and Tolerability Study in Patients With Acute Ischemic Stroke". Stroke 30 (9): 1796–1801. doi:10.1161/01.STR.30.9.1796. PMID 10471426.
- Wesnes, KA; Edgar, C; Dean, AD; Wroe, SJ (2009). "The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy". Epilepsy & behavior : E&B 14 (3): 522–8. doi:10.1016/j.yebeh.2008.11.012. PMID 19111629.
- Leach, JP; Marson, AG, Hutton, JL (2002). "Remacemide for drug-resistant localization related epilepsy.". Cochrane database of systematic reviews (Online) (4): CD001900. doi:10.1002/14651858.CD001900. PMID 12519561.
- "Development Pipeline as at 31 December 2011". AstraZeneca. Retrieved 15 May 2012.
- Palmer, GC; Murray, RJ, Wilson, TC, Eisman, MS, Ray, RK, Griffith, RC, Napier, JJ, Fedorchuk, M, Stagnitto, ML, Garske, GE (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.
- 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.
- 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: the biological fate of chemicals 22 (3): 443–6. PMID 8070322.
- Van Luijtelaar, E.L.J.M.; Coenen, A.M.L. (1 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): 419–425. doi:10.1016/0028-3908(95)00008-T.
- Garske, GE; Palmer, GC, Napier, JJ, Griffith, RC, Freedman, LR, Harris, EW, Ray, R, McCreedy, SA, Blosser, JC, Woodhead, JH (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.
- Hu, Ruo Qi; Davies, John A. (1 December 1995). "The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice". European Journal of Pharmacology 287 (3): 251–256. doi:10.1016/0014-2999(95)00500-5.
- Norris, S.K.; King, A.E. (1 July 1997). "Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro". Neuropharmacology 36 (7): 951–959. doi:10.1016/S0028-3908(97)00069-5.
- 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.
- 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.
- Stagnitto, ML; Palmer, GC, Ordy, JM, Griffith, RC, Napier, JJ, Becker, CN, Gentile, RJ, Garske, GE, Frankenheim, JM, Woodhead, JH (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.
- 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.
- 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.
- Parkinson Study Group (2000-04-25). "A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD.". Neurology 54 (8): 1583–8. doi:10.1212/wnl.54.8.1583. PMID 10762497.
- Lockton, JA; 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 O; Diggory G (1998). "Remacemide does not affect cognitive function following multiple dosing". J Psychopharmacol 12 (A41).
- Wesnes, K.A.; Edgar, C., Dean, A.D.P., Wroe, S.J. (1 March 2009). "The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy". Epilepsy & Behavior 14 (3): 522–528. doi:10.1016/j.yebeh.2008.11.012. PMID 19111629.
- J., Ramaekers; C., Lamers, F., Verhey, N., Muntjewerff, E., Mobbs, N., Sanders, J., Lewis, J., Lockton (1 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): 203–210. doi:10.1007/s002130100898.
- Wright, LK; Pearson, EC; Hammond, TG; Paule, MG (May–Jun 2007). "Behavioral effects associated with chronic ketamine or remacemide exposure in rats". Neurotoxicol Teratol 29 (3): 348–59. doi:10.1016/j.ntt.2006.12.004. PMID 17291718.
- Popke, E.J; Allen, R.R, Pearson, E.C, Hammond, T.G, Paule, M.G (1 July 2001). "Differential effects of two NMDA receptor antagonists on cognitive–behavioral development in nonhuman primates I". Neurotoxicology and Teratology 23 (4): 319–332. doi:10.1016/S0892-0362(01)00156-8.
- Popke, E.J; Allen, R.R, Pearson, E.C, Hammond, T.G, Paule, M.G (1 July 2001). "Differential effects of two NMDA receptor antagonists on cognitive–behavioral performance in young nonhuman primates II". Neurotoxicology and Teratology 23 (4): 333–347. doi:10.1016/S0892-0362(01)00138-6.
- Popke, E.J; Patton, R, Newport, G.D, Rushing, L.G, Fogle, C.M, Allen, R.R, Pearson, E.C, Hammond, T.G, Paule, M.G (1 March 2002). "Assessing the potential toxicity of MK-801 and remacemide:". Neurotoxicology and Teratology 24 (2): 193–207. doi:10.1016/S0892-0362(02)00206-4.
- PAULE, MERLE G.; FOGLE, C. MATTHEW, ALLEN, RICHARD R., PEARSON, EDWIN C., HAMMOND, TIMOTHY G., POPKE, E. JON (1 May 2003). "Chronic Exposure to NMDA Receptor and Sodium Channel Blockers during Development in Monkeys and Rats". Annals of the New York Academy of Sciences 993 (1): 116–122. doi:10.1111/j.1749-6632.2003.tb07519.x.
- Hudzik, TJ; Freedman, L, Palmer, GC (June 1996). "Remacemide hydrochloride and ARL 15896AR lack abuse potential: additional differences from other uncompetitive NMDA antagonists.". Epilepsia 37 (6): 544–50. doi:10.1111/j.1528-1157.1996.tb00607.x. PMID 8641231.
- The Parkinson Study Group (Jul–Aug 1999). "The impact of remacemide hydrochloride on levodopa concentrations in Parkinson's disease. Parkinson Study Group.". Clin Neuropharmacol 22 (4): 220–5. PMID 10442252.
- Leach, J.P.; Girvan, J., Jamieson, V., Jones, T., Richens, A., Brodie, M.J. (1 June 1997). "Lack of pharmacokinetic interaction between remacemide hydrochloride and sodium valproate in epileptic patients". Seizure 6 (3): 179–184. doi:10.1016/S1059-1311(97)80003-9.
- Leach, John Paul; Blacklaw, Jackie, Jamieson, Virginia, Jones, Tracey, Richens, Alan, Brodie, Martin J. (1 November 1996). "Mutual Interaction Between Remacemide Hydrochloride and Carbamazepine: Two Drugs with Active Metabolites". Epilepsia 37 (11): 1100–1106. doi:10.1111/j.1528-1157.1996.tb01031.x.
- "Parkinson Study Group: Completed Trials: SPIRAL". Retrieved 2 May 2012.
- "Parkinson Study Group: Completed Clinical Trials: RAMP". Retrieved 2 May 2012.
- Lewis, Gareth R.; Steele, Gerry, McBride, Lorraine, Florence, Alastair J., Kennedy, Alan R., Shankland, Norman, David, William I. F., Shankland, Kenneth, Teat, Simon J. (1 March 2005). "Hydrophobic vs. Hydrophilic: Ionic Competition in Remacemide Salt Structures". Crystal Growth & Design 5 (2): 427–438. doi:10.1021/cg049836u.
- "remacemide () UKMi New Drugs Online Database". Retrieved 2 May 2012.
- "remacemide AstraZeneca discontinued, Europe, USA, Canada (epilepsy)". R & D Focus Drug News. March 15, 2004. Retrieved 2 May 2012.
- "FISONS DISCONTINUES TIPREDANE DEV'T". the pharma letter. 12 April 1993. Retrieved 28 April 2012.
- "Sweden's Astra Buys Most Of Fisons R&D Ops". the pharma letter. 27 March 1995. Retrieved 28 April 2012.
- "AstraZeneca History". AstraZeneca. Retrieved 29 April 2012.
- "AstraZeneca R&D Pipeline: NCEs". AstraZeneca. 2000. Retrieved 28 April 2012.
- 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.
- Kieburtz, Karl; Feigin, Andrew, McDermott, Michael, Como, Peter, Abwender, David, Zimmerman, Carol, Hickey, Charlyne, Orme, Constance, Claude, Kathy, Sotack, Jennie, Greenamyre, J. Timothy, Dunn, Cynthia, Shoulson, Ira (1 May 1996). "A controlled trial of remacemide hydrochloride in Huntington's disease". Movement Disorders 11 (3): 273–277. doi:10.1002/mds.870110310.
- 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.
- "Completed Clinical Trials". Huntington Study Group. 2010. Retrieved 29 April 2012.
- "Astra 98 Annual Report". Stellan Ståls Grafiska AB. Retrieved 28 April 2012.
- Polinsky, Ron. "AstraZeneca CNS". AstraZeneca. Retrieved 27 April 2012.
- "Clinical Trials and Observational Studies in Progress". Huntington Study Group. 2010. Retrieved 29 April 2012.
- "Clinical Trials in Progress - Parkinson Study Group". Retrieved 2 May 2012.
- "Remacemide hydrochloride Cat. No. 1622". Tocris. Retrieved 29 April 2012.