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ใช้ยาแก้แพ้ dimebon ในโรคสมองเสื่อมอัลไซเมอร์ Print E-mail
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ศุกร์, 01 สิงหาคม 2008

        Dimebon in Alzheimer’s disease: old drug for new indicationAlzheimer’s disease, the commonest cause of dementia,is a chronic neuropsychiatric disorder that aff ects25 million people worldwide and costs £17 billion eachyear in the UK alone.1,2 Current management is directedat improving, or at least controlling, symptoms (such asmemory loss, agitation, and depression), maintaining independence,and supporting patients and their families.Available drugs, which are moderately eff ective overallbut can sometimes provide substantial improvement,include the cholinesterase inhibitors (donepezil, rivastigmine,and galantamine) and the glutamatergic agentmemantine.

        The cost-eff ectiveness of these drugs hasbeen examined by the UK’s National Institute for Healthand Clinical Excellence (NICE), leading to their use onlyfor people with moderate Alzheimer’s disease in theNational Health Service (NHS) in England and Wales.The cause of Alzheimer’s disease is unknown but depositionof the amyloid protein is a key event. Whilst theneurotransmitter-based approaches of cholin esterasesand memantine will probably be the mainstay of treatmentfor the foreseeable future, alternative approachesdirected at clearing amyloid deposition are developing,and include vaccination,3 passive immunotherapy, secretasemodulation, and heavy metal chelation.4Prevention, largely on the basis of adequate controlof vascular risk factors, especially blood pressure, isa reality in view of the common abnormalities thatunderlie vascular and Alzheimer’s dementias. However,the evidence that important eff ects will arise here is notyet strong.5,6
         In today’s Lancet, Rachelle Doody and colleaguesreport a clinical trial of dimebon in patients withmild-to-moderate Alzheimer’s disease.7 This drugbegan life as a non-selective antihistamine but waswithdrawn when more selective agents becameavailable. For Alzheimer’s disease, the drug’s actionsseem to cover all bases, with weak cholinesterase, weakglutamatergic, and neuroprotective activity. The study,a double-blind placebo-controlled trial in 183 patientsin 11 centres in Russia, used established and acceptedmethods and diagnostic criteria. The results, analysedon an intention-to-treat basis, were highly statisticallysignifi cant at 6 months, with dimebon–placebo bene-fi t of –4・0 (95% CI –5・73 to –2・28) on the cognitivesubscale of the Alzheimer’s disease assessment scale. Improvements were seen across all domains (cognition,activities of daily living, psychiatric symptoms, andglobal assessment), and were a positive eff ect of thedrug and not a refl ection of declining function in theplacebo group. 85% of participants completed thetrial, and dry mouth in less than one in fi ve participantswas the only signifi cant side-eff ect. 86% of the groupelected to continue for a further 6 months and thetreatment eff ect was strengthened with no new safetyor tolerability concerns.Doody and colleagues’ report raises several issues.First, this report is the most high-profi le study to dateof dementia in Russia. The practice of psychiatry inRussia is very diff erent from that in countries of thedeveloped world in that it is still based on being incustodial care and reliant on drug treatment. Wards forpatients with dementia are large, with populations ofaround 70. Occupational therapy and rehabilitation forsuch patients is virtually unknown.Second, the ethics of a 6-month or 12-monthplacebo-controlled trial when established treatmentsare available is pertinent—enshrined in the question ofclinical equipoise, in which it is unethical to deny bestavailable treatment as a result of enrolment in a trial.In Russia, antidementia drugs are available only to thefew who can pay for them. This situation applies toall modern psychiatric drugs, and it is probably only aminority who can aff ord them. Perhaps this point makesthe present study ethical. Have placebo-controlledtrials suddenly become ethical for people with mildAlzheimer’s disease in England and Wales, for whomantidementia drugs are now unavailable on the NHSafter the pronouncement from NICE?Third, is dimebon a drug looking for an indication?Testing readily available drugs makes economic sense, anddrugs developed in this way will probably be cheaper thannewly developed compounds. Other drugs with a soundrationale for use in Alzheimer’s disease should be trialledand the most made of existing technologies. For instance,the tetracycline minocycline has several biological actionsthat aff ect amyloid and attenuates learning and memorydefi cits in animal models of Alzheimer’s disease.8Current treatments for Alzheimer’s disease are moderatelyeff ective, but not for every patient. Additionof treatment options is good news for patients andclinicians—it promotes choice and off ers the possibilityof bespoke treatment packages which maximise thechances of a response. Doody and colleagues’ trialshows that dimebon is better than placebo (which is nomean feat considering the positive placebo responsesin dementia). Further work will establish its effi cacy (orotherwise) in addition to, or compared with, establishedtreatments, and indeed a second phase III trial hasrecently been announced.9*Alistair Burns, Robin JacobyPsychiatry Research Group, University of Manchester,Manchester M13 9PL, UK (AB); and Department of Psychiatry,University of Oxford, Oxford, UK (RJ) receives research grants and consultancy fees from Pfi zer, Eisai, Shire Janssen,and Novartis. RJ is chairman of the Global Initiative on Psychiatry, which worksto reform psychiatric services and practice in former Soviet countries. 1 Ferri C, Prince M, Brayne C, et al. Global prevalence of dementia.Lancet 2006; 366: 2112–17.2 LSE, King’s College London, Alzheimer’s Society. Dementia UK. 2007. http://www.alzheimers.org.uk/downloads/Dementia_UK_Full_Report.pdf(accessed July 4, 2008).3 Gilman S, Koller M, Black RS, et al, for the AN1792(QS-21)-201 Study Team.Clinical eff ects of Abeta immunization (AN1792) in patients with AD in aninterrupted trial. Neurology 2005; 64: 1553–62.4 Aisen PS. The development of anti-amyloid therapy for Alzheimer’s disease:from secretase modulators to polymerisation inhibitors. CNS Drugs 2005;19: 989–96.5 Peters R, Beckett N, Forette F, et al, for the HYVET Investigators. Incidentdementia and blood pressure lowering in the Hypertension in the VeryElderly Trial cognitive function assessment (HYVET-COG): a double-blind,placebo controlled trial. Lancet Neurol 2008; published online July 8.DOI:10.1016/S1474-4422(08)70143-1.6 Forette F, Seux M-L, Staessen J, et al, on behalf of the Syst-EurInvestigators. Prevention of dementia in randomised double-blindplacebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.Lancet 1998; 352: 1347–51.7 Doody RS, Gavrilova SI, Sano M, et al, on behalf of the dimeboninvestigators. Eff ect of dimebon on cognition, activities of daily living,behaviour, and global function in patients with mild-to-moderateAlzheimer’s disease: a randomised, double-blind, placebo-controlled study.Lancet 2008; 372: 207–15.8 Choi Y, Kim HS, Shin KY, et al. Minocycline attenuates neuronal cell deathand improves cognitive impairment in Alzheimer’s disease models.Neuropsychopharmacol 2007; 32: 2393–404.9 Medivation. Connection: an Alzheimer’s disease investigational trial. 2008.http://connectionstudy.com (accessed July 4, 2008).

 

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