알츠하이머 치매 치료제: 현위치와 향후 전망 = Alzheimer’s Disease: Clinical Trials and Future Perspectives

다국어 초록 (Multilingual Abstract)

Alzheimer’s disease is increasingly common in elderly population with a large socioeconomic burden. Current available drugs for Alzheimer’s disease are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist. Much effort is directed towards not just symptomatic treatments but disease-modifying treatments. Several drugs with differing targets and mechanisms of action are under development for the treatment of Alzheimer’s disease. Phase III trials of dimebon,Ginkgo biloba, non-steroidal anti-inflammatory drugs, phenserine, statins, semagacestat, tarenflurbil, tramiprosate, valproate,xaliproden have been completed without demonstrating adequate efficacy. Encouraging results would be expected from ongoing phase III trials of bapineuzumab and solanezumab. The clinical trials for the disease-modifying treatment of Alzheimer’s disease have resulted in both promise and disappointment.

국문 초록 (Abstract)

알츠하이머병의 치료에 대한 연구들은 현재까지 증상경감의 차원에서는 어느 정도 성공을 거두었다고 볼 수 있으나, 반대로 질병의 경과를 변화시키는 근본적인 치료에는 실패를 겪고 있다. 비록 2002년 NMDA 수용체 길항제인 memantine이 알츠하이머병 치료제로 승인을 받은 이후 현재까지 10년이 지나도록 어떠한 신약도 발견하지 못했지만, 시간이 갈수록 신약개발을 위한 연구의 범위뿐 아니라 깊이도 깊어지고 있다. 약물이 타겟으로 하는 부위가 다양화되어 단순히 Aβ나 tau와 같은 단백질에서 벗어나서 미토콘드리아까지 넓어졌으며, 작용기전 또한 한 가지에서 벗어나 여러가지 복합적인 작용기전을 가진 약물들을 연구 중에 있다. 현 상태에서는 bapineuzumab, solanezumab과 같은 단일클론항체를 이용한 수동면역치료가 가장 기대를 모으고 있다.

참고문헌 (Reference)

• 1 Friedhoff LT, "Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide" 4 : 127-130, 2001
• 2 Aisen PS, "Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study)" 7 : 102-111, 2011
• 3 Wimo A, "The worldwide societal costs of dementia: estimates for 2009" 6 : 98-103, 2010
• 4 Hardy J, "The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal" 110 : 1129-1134, 2009
• 5 Tariot PN, "The ADCS valproate neuroprotection trial: primary efficacy and safety results" 5 (5): 84-85, 2009
• 6 Jick H, "Statins and the risk of dementia" 356 : 1627-1631, 2000
• 7 Li G, "Statin therapy and risk of dementia in the elderly: a community- based prospective cohort study" 63 : 1624-1628, 2004
• 8 Fassbender K, "Simvastatin strongly reduces levels of Alzheimer’s disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo" 98 : 5856-5861, 2001
• 9 Gold M, "Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebocontrolled phase III study" 30 : 131-146, 2010
• 10 Stewart WF, "Risk of Alzheimer’s disease and duration of NSAID use" 48 : 626-632, 1997
• 11 Pimplikar SW, "Reassessing the amyloid cascade hypothesis of Alzheimer’s disease" 41 : 1261-1268, 2009
• 12 Feldman HH, "Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe" 74 : 956-964, 2010
• 13 Shepherd J, "Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial" 360 : 1623-1630, 2002
• 14 Doody RS, "Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology" 56 : 1154-1166, 2001
• 15 Wenk GL, "Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine" 17 : 411-424, 2006
• 16 Klein J, "Phenserine" 16 : 1087-1097, 2007
• 17 Medivation, "Pfizer and Medivation announce results from two phase3 studies in dimebon (latrepirdine*) Alzheimer’s disease clinical developmentprogram"
• 18 in t’ Veld BA, "Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease" 345 : 1515-1521, 2001
• 19 Pei JJ, "Neurofibrillary degeneration in Alzheimer’s disease: from molecular mechanisms to identification of drug targets" 21 : 555-561, 2008
• 20 ADAPT Research Group, "Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial" 68 : 1800-1808, 2007
• 21 Sano M, "Multi-center, randomized, double-blind, placebo controlled trial of simvastatin to slow the progression of Alzheimer’s disease" 4 (4): 200-, 2008
• 22 Winblad B, "Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials" 24 : 20-27, 2007
• 23 Tariot PN, "Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial" 291 : 317-324, 2004
• 24 Reisberg B, "Memantine Study Group. Memantine in moderate-to-severe Alzheimer’s disease" 348 : 1333-1341, 2003
• 25 Nordberg A, "Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease" 20 (20): 12-18, 2006
• 26 Heart Protection Study Collaborative Group, "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 highrisk individuals: a randomised placebo-controlled trial" 360 : 7-22, 2002
• 27 DeKosky ST, "Ginkgo biloba for prevention of dementia: a randomized controlled trial" 300 : 2253-2262, 2008
• 28 Cordy JM, "Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition upregulates beta-site processing of the amyloid precursor protein" 100 : 11735-11740, 2003
• 29 Aisen PS, "Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial" 289 : 2819-2826, 2003
• 30 Mecocci P, "Effects of memantine on cognition in patients with moderate to severe Alzheimer’s disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies" 24 : 532-538, 2009
• 31 Green RC, "Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial" 302 : 2557-2564, 2009
• 32 Doody RS, "Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study" 372 : 207-215, 2008
• 33 Winblad B, "Donepezil in severe Alzheimer’s disease" 24 : 185-192, 2009
• 34 Cappai R, "Delineating the mechanism of Alzheimer’s disease A beta peptide neurotoxicity" 33 : 526-532, 2008
• 35 Wolozin B, "Decreased prevalence of Alzheimer disease associated with 3-hydroxy- 3-methyglutaryl coenzyme A reductase inhibitors" 57 : 1439-1443, 2000
• 36 Grundman M, "Clinical trials of bapineuzemab, a beta-amyloid- targeted immunotherapy in patients with mild to moderate Alzheimer’s disease" 4 (4): 166-, 2008
• 37 Rogers J, "Clinical trial of indomethacin in Alzheimer’s disease" 43 : 1609-1611, 1993
• 38 Birks J, "Cholinesterase inhibitors for Alzheimer’s disease" CD005593-, 2006
• 39 Wahrle S, "Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains" 9 : 11-23, 2002
• 40 Wolozin B, "Cholesterol and the biology of Alzheimer’s disease" 41 : 7-10, 2004
• 41 Tariot PN, "Can lithium or valproate untie tangles in Alzheimer’s disease?" 70 : 919-921, 2009
• 42 Reddy PH, "Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease" 14 : 45-53, 2008
• 43 Mudher A, "Alzheimer’s disease-do tauists and baptists finally shake hands?" 25 : 22-26, 2002
• 44 Salloway S, "A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease" 73 : 2061-2070, 2009
• 45 Scharf S, "A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease" 53 : 197-201, 1999