References
- ADI. Alzheimer’s Disease International. World Alzheimer report 2015: the global impact of dementia. 2015 [cited 2016 Aug 12]. Available from: http://www.alz.co.uk/research/world-report-2015]
- Ngo J, Holroyd-Leduc JM. Systematic review of recent dementia practice guidelines. Age Ageing. 2015;44:25–33.
- Kelley AS, McGarry K, Gorges R, et al. The burden of health care costs for patients with dementia in the last 5 years of life. Ann Intern Med. 2015;163:729–736.
- GOV.UK. Department of Health and Prime Minister’s Office. G8 dementia summit declaration 2013 [cited 2016 Aug 12]. Available from: https://www.gov.uk/government/publications/g8-dementia-summit-agreements]
- Burns A, Iliffe S. Alzheimer’s disease. BMJ. 2009;338:b158.
- WHO. World Health Organization. Dementia. Fact sheet N°362. 2015 [cited 2016 Aug 14]. Available from: https://web.archive.org/web/20150318030901/http://www.who.int/mediacentre/factsheets/fs362/en]
- McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–269.
- APA. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Arlington (VA): American Psychiatric Publishing; 2013.
- Cummings J, Mintzer J, Brodaty H, et al. Agitation in cognitive disorders: international psychogeriatric association provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27:7–17.
- Kales HC, Gitlin LN, Lyketsos CG. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62:762–769.
- Garay RP, Citrome L, Grossberg GT, et al. Investigational drugs for treating agitation in persons with dementia. Expert Opin Investig Drugs. 2016;25:973–983.
- Soto M, Abushakra S, Cummings J, et al. Progress in treatment development for neuropsychiatric symptoms in Alzheimer’s disease: focus on agitation and aggression. A report from the EU/US/CTAD task force. J Prev Alzheimers Dis. 2015;2:184–188.
- Panza F, Solfrizzi V, Seripa D, et al. Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease. Expert Opin Pharmacother. 2015;16:2581–2588.
- Antonsdottir IM, Smith J, Keltz M, et al. Advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother. 2015;16:1649–1656.
- Steinberg M. Isn’t your staff trained to manage my mother? Am J Psychiatry. 2016;173:205–207.
- Ballard C, Orrell M, YongZhong S, et al. Impact of antipsychotic review and nonpharmacological intervention on antipsychotic use, neuropsychiatric symptoms, and mortality in people with dementia living in nursing homes: a factorial cluster-randomized controlled trial by the Well-Being and Health for People with Dementia (WHELD) program. Am J Psychiatry. 2016;173:252–262.
- Gitlin LN, Kales HC, Lyketsos CG. Nonpharmacologic management of behavioral symptoms in dementia. JAMA. 2012;308:2020–2029.
- Salzman C, Jeste DV, Meyer RE, et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry. 2008;69:889–898.
- Ma H, Huang Y, Cong Z, et al. The efficacy and safety of atypical antipsychotics for the treatment of dementia: a meta-analysis of randomized placebo-controlled trials. J Alzheimers Dis. 2014;42:915–937.
- Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev. 2006;1:CD003476.
- Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14:191–210.
- Sacchetti E, Turrina C, Valsecchi P. Cerebrovascular accidents in elderly people treated with antipsychotic drugs: a systematic review. Drug Saf. 2010;33:273–288.
- Citrome L. Atypical antipsychotics, elderly patients, and mortality risk. South Med J. 2007;100:964–965.
- Avanir. Avanir pharmaceuticals announces initiation of Phase III trial of AVP-786 for agitation in patients with Alzheimer’s disease. 2015 [cited 2016 July 15]. Available from: http://www.avanir.com/press/avanir-pharmaceuticals-announces-initiation-phase-iii-trial-avp-786-agitation-patients]
- Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal. 2014;6:614–632.
- FDA. Food and Drug Administration. Nuedexta. Drug approval package. Medical review. Drugs@FDA. 2010 [cited 2016 Aug 1]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/021879Orig1s000TOC.cfm]
- Yang LPH, Deeks ED. Dextromethorphan/Quinidine: a review of its use in adults with pseudobulbar affect. Drugs. 2015;75:83–90.
- Concert. Concert Pharmaceuticals Achieves $2 Million Milestone from Avanir Pharmaceuticals for Phase 3 Initiation of AVP-786 for Agitation in Patients with Alzheimer’s Disease. 2015. Available from: http://ir.concertpharma.com/releasedetail.cfm?ReleaseID=942871]
- Avanir. Avanir Pharmaceuticals Announces Accelerated Development Path for AVP-786 Following Successful Pre-IND Meeting with FDA. 2013 [cited 2016 July 15]. Available from: http://www.avanir.com/press/avanir-pharmaceuticals-announces-accelerated-development-path-avp-786-following-successful-pre].
- Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with alzheimer disease dementia: a randomized clinical trial. JAMA. 2015;314:1242–1254.
- PubChem. Dextromethorphan. 2016 [cited 2016 July 21]. Available from: http://pubchem.ncbi.nlm.nih.gov/compound/5360696 - section=Top]
- PubChem. UNII-W9F1OD5N5J component STTADZBLEUMJRG-CDZAPMPLSA-N 2016 [cited 2016 July 21]. Available from: http://pubchem.ncbi.nlm.nih.gov/compound/90479359 - section=Top]
- Drugspider. Deudextromethorphan. Drug spider. 2016 [cited 2016 July 5]. Available from: http://drugspider.com/drug/deudextromethorphan]
- Bölcskei H, Mák M, Dravecz F, et al. Synthesis of deuterated dextromethorphan derivatives. Arkivoc. 2008;iii:182–193.
- PubChem. Quinidine. 2016 [cited 2016 July 21]. Available from: http://pubchem.ncbi.nlm.nih.gov/compound/441074 - section=Top]
- Craviso GL, Musacchio JM. High-affinity dextromethorphan binding sites in guinea pig brain. II. Competition experiments. Mol Pharmacol. 1983;23:629–640.
- Klein M, Musacchio JM. High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents. J Pharmacol Exp Ther. 1989;251:207–215.
- Meoni P, Tortella FC, Bowery NG. An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine. Br J Pharmacol. 1997;120:1255–1262.
- Werling LL, Keller A, Frank JG, et al. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol. 2007;207:248–257.
- Mendelsohn LG, Kerchner GA, Kalra V, et al. Phencyclidine receptors in rat brain cortex. Biochem Pharmacol. 1984;33:3529–3535.
- Chou YC, Liao JF, Chang WY, et al. Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Res. 1999;821:516–519.
- Fishback JA, Rosen A, Bhat R, et al. A 96-well filtration method for radioligand binding analysis of sigma receptor ligands. J Pharm Biomed Anal. 2012;71:157–161.
- Nam Y, Shin EJ, Yang BK, et al. Dextromethorphan-induced psychotoxic behaviors cause sexual dysfunction in male mice via stimulation of sigma-1 receptors. Neurochem Int. 2012;61:913–922.
- Shin EJ, Nah SY, Chae JS, et al. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats. Neurochem Int. 2007;50:791–799.
- Kim HC, Shin CY, Seo DO, et al. New morphinan derivatives with negligible psychotropic effects attenuate convulsions induced by maximal electroshock in mice. Life Sci. 2003;72:1883–1895.
- Klouz A, Sapena R, Liu J, et al. Evidence for sigma-1-like receptors in isolated rat liver mitochondrial membranes. Br J Pharmacol. 2002;135:1607–1615.
- Pubill D, Gasulla D, Sureda FX, et al. Characterization of [3H]nisoxetine binding in rat vas deferens membranes: modulation by sigma and PCP ligands. Life Sci. 1998;62:763–773.
- Taylor CP, Traynelis SF, Siffert J, et al. Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta(R)) clinical use. Pharmacol Ther. 2016;164:170–182.
- Nguyen L, Thomas KL, Lucke-Wold BP, et al. Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther. 2016;159:1–22.
- Kamei J, Iwamoto Y, Kawashima N, et al. Involvement of haloperidol-sensitive sigma-sites in antitussive effects. Eur J Pharmacol. 1992;224:39–43.
- Kotzer CJ, Hay DW, Dondio G, et al. The antitussive activity of delta-opioid receptor stimulation in guinea pigs. J Pharmacol Exp Ther. 2000;292:803–809.
- Brown C, Fezoui M, Selig WM, et al. Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004;141:233–240.
- Canning BJ. Central regulation of the cough reflex: therapeutic implications. Pulm Pharmacol Ther. 2009;22:75–81.
- Kamei J, Mori T, Ogawa M, et al. Subsensitivity to the cough-depressant effects of opioid and nonopioid antitussives in morphine-dependent rats: relationship to central serotonin function. Pharmacol Biochem Behav. 1989;34:595–598.
- Kamei H, Kameyama T, Nabeshima T. (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated sigma 1 sites. Eur J Pharmacol. 1996;299:21–28.
- Kamei H, Kameyama T, Nabeshima T. (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma 1 sites. Eur J Pharmacol. 1996;309:149–158.
- Nguyen L, Robson MJ, Healy JR, et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One. 2014;9:e89985.
- Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274:1263–1270.
- Choi DW. Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity. Brain Res. 1987;403:333–336.
- Leander JD. Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-D-aspartic acid antagonists in mice. Epilepsy Res. 1989;4:28–33.
- Ferkany JW, Borosky SA, Clissold DB, et al. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol. 1988;151:151–154.
- Leander JD, Rathbun RC, Zimmerman DM. Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism. Brain Res. 1988;454:368–372.
- Damaj MI, Flood P, Ho KK, et al. Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity. J Pharmacol Exp Ther. 2005;312:780–785.
- Lee JH, Shin EJ, Jeong SM, et al. Effects of dextrorotatory morphinans on alpha3beta4 nicotinic acetylcholine receptors expressed in Xenopus oocytes. Eur J Pharmacol. 2006;536:85–92.
- Gao XF, Yao JJ, He YL, et al. Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. PLoS One. 2012;7:e49384.
- Annels SJ, Ellis Y, Davies JA. Non-opioid antitussives inhibit endogenous glutamate release from rabbit hippocampal slices. Brain Res. 1991;564:341–343.
- Lin TY, Lu CW, Wang SJ. Inhibitory effect of glutamate release from rat cerebrocortical synaptosomes by dextromethorphan and its metabolite 3-hydroxymorphinan. Neurochem Int. 2009;54:526–534.
- Lu CW, Lin TY, Wang CC, et al. sigma-1 Receptor agonist SKF10047 inhibits glutamate release in rat cerebral cortex nerve endings. J Pharmacol Exp Ther. 2012;341:532–542.
- Ellis Y, Davies JA. The effects of sigma ligands on the release of glutamate from rat striatal slices. Naunyn Schmiedebergs Arch Pharmacol. 1994;350:143–148.
- Kim HC, Pennypacker KR, Bing G, et al. The effects of dextromethorphan on kainic acid-induced seizures in the rat. Neurotoxicology. 1996;17:375–385.
- Shin EJ, Bach JH, Lee SY, et al. Neuropsychotoxic and neuroprotective potentials of dextromethorphan and its analogs. J Pharmacol Sci. 2011;116:137–148.
- Trube G, Netzer R. Dextromethorphan: cellular effects reducing neuronal hyperactivity. Epilepsia. 1994;35(Suppl 5):S62–7.
- Shin EJ, Nah SY, Kim WK, et al. The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. Br J Pharmacol. 2005;144:908–918.
- Steinberg GK, George CP, DeLaPaz R, et al. Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits. Stroke. 1988;19:1112–1118.
- Steinberg GK, Kunis D, DeLaPaz R, et al. Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile. Neurol Res. 1993;15:174–180.
- Britton P, Lu XC, Laskosky MS, et al. Dextromethorphan protects against cerebral injury following transient, but not permanent, focal ischemia in rats. Life Sci. 1997;60:1729–1740.
- Liu Y, Qin L, Li G, et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther. 2003;305:212–218.
- Zhang W, Wang T, Qin L, et al. Neuroprotective effect of dextromethorphan in the MPTP Parkinson’s disease model: role of NADPH oxidase. FASEB J. 2004;18:589–591.
- Drachtman RA, Cole PD, Golden CB, et al. Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol. 2002;19:319–327.
- Kimiskidis VK, Mirtsou-Fidani V, Papaioannidou PG, et al. A phase I clinical trial of dextromethorphan in intractable partial epilepsy. Methods Find Exp Clin Pharmacol. 1999;21:673–678.
- Fisher RS, Cysyk BJ, Lesser RP, et al. Dextromethorphan for treatment of complex partial seizures. Neurology. 1990;40:547–549.
- Gredal O, Werdelin L, Bak S, et al. A clinical trial of dextromethorphan in amyotrophic lateral sclerosis. Acta Neurol Scand. 1997;96:8–13.
- Blin O, Azulay JP, Desnuelle C, et al. A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis. Clin Neuropharmacol. 1996;19:189–192.
- Askmark H, Aquilonius SM, Gillberg PG, et al. A pilot trial of dextromethorphan in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1993;56:197–200.
- Schmitt B, Bauersfeld U, Fanconi S, et al. The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study. Neuropediatrics. 1997;28:191–197.
- Montastruc JL, Fabre N, Rascol O, et al. N-methyl-D-aspartate (NMDA) antagonist and Parkinson’s disease: a pilot study with dextromethorphan. Mov Disord. 1994;9:242–243.
- Hollman A. Quinine and quinidine. Br Heart J. 1991;66:301.
- FDA. Food and Drug Administration. Nuedexta. Label information. Drugs@FDA. 2015 [cited 2016 Aug 2. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021879s005lbl.pdf]
- FDA. Food and Drug Administration. Quinidine sulfate. Drugs@FDA. 2016 [cited 2016 Aug 2]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm]
- Tung R. The development of deuterium-containing drugs. Innovations Pharmaceutical Technol. 2010;32:24–28.
- Avanir. Avanir Corporate Presentation. September 2013. 2013 [cited 2016 Aug 4]. Available from: http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9MjAzMTAzfENoaWxkSUQ9LTF8VHlwZT0z&t=1]
- Schadel M, Wu D, Otton SV, et al. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol. 1995;15:263–269.
- Capon DA, Bochner F, Kerry N, et al. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther. 1996;60:295–307.
- Pope LE, Khalil MH, Berg JE, et al. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol. 2004;44:1132–1142.
- Schmid B, Bircher J, Preisig R, et al. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther. 1985;38:618–624.
- Gonzalez FJ, Meyer UA. Molecular genetics of the debrisoquin-sparteine polymorphism. Clin Pharmacol Ther. 1991;50:233–238.
- Woodworth JR, Dennis SR, Moore L, et al. The polymorphic metabolism of dextromethorphan. J Clin Pharmacol. 1987;27:139–143.
- Duche JC, Querol-Ferrer V, Barre J, et al. Dextromethorphan O-demethylation and dextrorphan glucuronidation in a French population. Int J Clin Pharmacol Ther Toxicol. 1993;31:392–398.
- Hollander D, Pradas J, Kaplan R, et al. High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies. Ann Neurol. 1994;36:920–924.
- Yu A, Haining RL. Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? Drug Metab Dispos. 2001;29:1514–1520.
- Chen ZR, Somogyi AA, Bochner F. Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man. Ther Drug Monit. 1990;12:97–104.
- Avanir. Avanir Pharmaceuticals Announces Positive Interim Data From Pharmacokinetic Study With Next Generation Compound AVP-786. 2013 [cited 2016 July 15]. Available from: http://www.avanir.com/press/avanir-pharmaceuticals-announces-positive-interim-data-pharmacokinetic-study-next-generation]
- Bem JL, Peck R. Dextromethorphan. An overview of safety issues. Drug Saf. 1992;7:190–199.
- Pender ES, Parks BR. Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases. Pediatr Emerg Care. 1991;7:163–165.
- Burns JM, Boyer EW. Antitussives and substance abuse. Subst Abuse Rehabil. 2013;4:75–82.
- Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J. 1986;111:1088–1093.
- Redfern WS, Carlsson L, Davis AS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32–45.
- Schoedel KA, Morrow SA, Sellers EM. Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect. Neuropsychiatr Dis Treat. 2014;10:1161–1174.
- EMA. European Medicines Agency. Human medicines. European public assessment reports. Nuedexta 2016 [cited 2016 Aug 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/03/WC500203195.pdf]
- Wilson MP, Pepper D, Currier GW, et al. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project beta psychopharmacology workgroup. West J Emerg Med. 2012;13:26–34.
- Defrancesco M, Marksteiner J, Fleischhacker WW, et al. Use of Benzodiazepines in Alzheimer’s disease: a systematic review of literature. Int J Neuropsychopharmacol. 2015;18:pyv055.
- Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311:682–691.
- Kogut C, Crouse EB, Vieweg WVR, et al. Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports. Ther Adv Drug Saf. 2013;4:189–198.
- FDA. Food and Drug Administration. Drugs@FDA (FDA approved drug products). Celexa 2014. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020822Orig1s046lbl.pdf]
- Mullard A. Deuterated drugs draw heavier backing. Nat Rev Drug Discov. 2016;15:219–221.
- Thomsen MS, El-Sayed M, Mikkelsen JD. Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6:e27014.
- Valles AS, Borroni MV, Barrantes FJ. Targeting brain alpha7 nicotinic acetylcholine receptors in Alzheimer’s disease: rationale and current status. CNS Drugs. 2014;28:975–987.
- Zawertailo LA, Kaplan HL, Busto UE, et al. Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol. 1998;18:332–337.