Perspectivas no tratamento da doença de Alzheimer: uma revisão sobre substâncias farmacológicas promissoras

Cazarim, Maurílio de Souza; Moriguti, Julio Cesar; Ogunjimi, Abayomi Tolulope; Pereira, Leonardo Régis Leira

doi:10.1590/1516-3180.2015.01980112

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Sao Paulo Medical Journal

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REVIEW ARTICLE • Sao Paulo Med. J. 134 (04) • Jul-Aug 2016 • https://doi.org/10.1590/1516-3180.2015.01980112 copiar

Perspectivas no tratamento da doença de Alzheimer: uma revisão sobre substâncias farmacológicas promissoras

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

CONTEXTO E OBJETIVO:

A demência é uma síndrome caracterizada por declínio funcional e cognitivo, sendo a doença de Alzheimer (DA) uma das causas mais comuns e de alta prevalência em idosos. Sabe-se que não há medicamento capaz de interferir no curso da doença e as pesquisas para o tratamento da DA têm sido marcadas pelo surgimento e abandono de novas drogas. O objetivo deste estudo foi descrever as drogas capazes de influenciar o curso da DA que têm sido estudadas para o tratamento da doença.

TIPO DE ESTUDO E LOCAL:

Revisão narrativa de artigos originais publicados mundialmente.

MÉTODOS:

Foi realizada uma busca sistematizada nas bases de dados PubMed/MEDLINE, Cochrane Library/Cochrane e SciELO/Bireme. Cada um dos seguintes descritores "Mecanismos Moleculares de Ação Farmacológica" e "Quimioterapia" foram combinados com o descritor "Doença de Alzheimer", todos encontrados no MeSH e DeCS. Os descritores foram usados sozinhos ou em combinação, fixando como filtros as publicações de 2009 a 2015, em língua inglesa, espanhola e portuguesa.

RESULTADOS:

Foram encontrados 6.888 artigos, dos quais 37 foram incluídos nesta revisão; 70,3% dos artigos selecionados tiveram boa qualidade com baixo ou indefinido risco de viés. Foram elencadas 86 drogas promissoras ao tratamento da AD. Elas foram classificadas em 20 categorias farmacológicas.

CONCLUSÃO:

Não há fármacos capazes de interferir no curso da DA com efetividade e segurança no tratamento. Contudo, os imunomoduladores foram considerados promissores devido ao fato de apresentarem efetividade e qualidade nos artigos analisados.

PALAVRAS-CHAVE:
Doença de Alzheimer; Mecanismos moleculares de ação; farmacológica; Quimioterapia; Peptídeos beta-amiloides; Tauopatias

Reference	Authors, year and country	Therapeutic classes	Results basis	Study design	Cochrane risk of bias classification*
18	^{Léon et al., 2013}18. León R, Garcia AG, Marco-Contelles J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer's disease. Med Res Rev. 2013;33(1):139-89. (England)	Cholinesterase inhibitors; statins: lipid-modifying agents; antioxidants; chelating agents	Clinical evidence	Narrative review	Unclear
19	^{Konrath et al., 2013}19. Konrath EL, Passos Cdos S, Klein LC Jr, Henriques AT. Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease. J Pharm Pharmacol. 2013;65(12):1701-25. (Brazil)	Cholinesterase inhibitors; alkaloids	Not specific	Narrative review	High
20	^{McGuinness et al., 2013}20. McGuinness B, O'Hare J, Craig D, et al. Cochrane review on 'Statins for the treatment of dementia'. Int J Geriatr Psychiatry. 2013;28(2):119-26. (Ireland)	Statins: lipid-modifying agents	Phase III clinical trial	Systematic review (randomized with meta-analysis)	Low
21	^{Rubio-Perez and Morrilas-Ruiz, 2012}21. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal. 2012;2012:756357. (Spain)	Anti-inflammatory agents; cytokines	Not specific	Narrative review	High
22	^{Appleby et al., 2013}22. Appleby BS, Nacopoulos D, Milano N, Zhong K, Cummings JL. A review: treatment of Alzheimer's disease discovered in repurposed agents. Dement Geriatr Cogn Disord. 2013;35(1-2):1-22. (USA)	Agents for treating diabetes mellitus; nicotinic receptor agonists; phosphodiesterase inhibitors	Clinical evidence	Narrative review	Unclear
25	^{Pettenati et al., 2003}25. Pettenati C, Annicchiarico R, Caltagirone C. Clinical pharmacology of anti-Alzheimer drugs. Fundam Clin Pharmacol. 2003;17(6):659-72. (Italy)	Cholinesterase inhibitors; immunomodulators; anti-inflammatory agents; NMDA receptor antagonists; antioxidants; phospholipase A2 inhibitors; nootropic drugs without elucidated mechanism of action for Alzheimer's disease; hormone therapy agents; chelating agents	Clinical evidence	Narrative review	Unclear
26	^{Sun et al., 2012}52. Sun GY, He Y, Chuang DY, et al. Integrating cytosolic phospholipase A2 with oxidative/nitrosative signaling pathways in neurons: a novel therapeutic strategy for AD. Mol Neurobiol. 2012;46(1):85-95. (China)	Cholinesterase inhibitors; muscarinic agonists; immunomodulators; anti-inflammatory agents; statins: lipid modifying agents; antioxidants; chelating agents; antihypertensive agents	Clinical evidence	Narrative review	Unclear
27	^{Yoo and Park, 2012}27. Yoo KY, Park SY. Terpenoids as potential anti-Alzheimer's disease therapeutics. Molecules. 2012;17(3):3524-38. (Korea)	Terpenoids; antioxidants	Not specific	Narrative review	High
28	^{Dodel, 2013}28. Dodel R. [Towards a vaccine against Alzheimer's?]. Drug Res (Stuttg). 2013;63 Suppl 1:S18-20. (Germany)	Immunomodulators	Clinical evidence	Narrative review	Unclear
29	^{Mikulka et al., 2014}29. Mikulca JA, Nguyen V, Gajdosik DA, et al. Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches. J Clin Pharm Ther. 2014;39(1):25-37. (USA)	Immunomodulators; secretase inhibitors; Inhibitors or modulators of beta and gamma-secretase	Phases I, II and III clinical trial	Systematic review (with clinical trial)	Low
30	^{Shukla et al., 2012}30. Shukla V, Skuntz S, Pant HC. Deregulated Cdk5 activity is involved in inducing Alzheimer's disease. Arch Med Res. 2012;43(8):655-62. (USA)	Immunomodulators; cyclin kinase-5 dependent modulators	Not specific	Narrative review	High
31	^{Doody et al., 2014}31. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):311-21. (Germany)	Immunomodulators	Phase III clinical trial	Randomized clinical trial (double blind)	Low
32	^{Salloway et al., 2014}32. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):322-33. (USA)	Immunomodulators	Phase III clinical trial	Randomized clinical trial (double blind)	Low
33	^{Enciu and Popescu, 2013}33. Enciu AM, Popescu BO. Is there a causal link between inflammation and dementia? Biomed Res Int. 2013;2013:316495. (Romania)	Anti-inflammatory agents	Clinical evidence	Narrative review	Unclear
34	^{Feng and Wang, 2012}34. Feng Y, Wang X. Antioxidant therapies for Alzheimer's disease. Oxid Med Cell Longev. 2012;2012:472932. (China)	Anti-inflammatory agents; antioxidants; phospholipase A2 inhibitors	Not specific	Systematic review	High risk of bias
35	^{Wolfe, 2012}35. Wolfe MS. γ-Secretase inhibitors and modulators for Alzheimer's disease. J Neurochem. 2012;120 Suppl 1:89-98. (USA)	Anti-inflammatory agents; Inhibitors or modulators of beta and gamma-secretase; chelating agents	Clinical evidence	Narrative review	Unclear
36	^{Ghosh et al., 2012}36. Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem. 2012;120 Suppl 1:71-83. (USA)	Inhibitors or modulators of beta and gamma-secretase	Phase II clinical trial	Narrative review	Low
37	^{Hopkins, 2011}37. Hopkins CR. ACS chemical neuroscience molecule spotlight on ELND006: another γ-secretase inhibitor fails in the clinic. ACS Chem Neurosci. 2011;2(6):279-80. (USA)	Inhibitors or modulators of beta and gamma-secretase	Phase III Clinical trial	Short report	Unclear
38	^{Piccinni et al., 2013}38. Piccinni A, Origlia N, Veltri A, et al. Neurodegeneration, β-amyloid and mood disorders: state of the art and future perspectives. Int J Geriatr Psychiatry. 2013;28(7):661-71. (Italy)	Inhibitors or modulators of beta and gamma-secretase	Not specific	Narrative review	High
39	^{Eschecerria et al., 2012}39. Echeverria V, Zeitlin R. Cotinine: a potential new therapeutic agent against Alzheimer's disease. CNS Neurosci Ther. 2012;18(7):517-23. (USA)	Nicotinic receptor agonists	Clinical evidence	Narrative review	Unclear
40	^{Freiherr et al., 2013}40. Freiherr J, Hallschmid M, Frey WH 2nd , et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27(7):505-14. (Germany)	Agents for treating diabetes mellitus	Clinical evidence	Narrative review	Unclear
41	^{Morris and Burns, 2012}41. Morris JK, Burns JM. Insulin: an emerging treatment for Alzheimer's disease dementia? Curr Neurol Neurosci Rep. 2012;12(5):520-7. (USA)	Agents for treating diabetes mellitus	Clinical evidence	Narrative review	Unclear
42	^{Xu et al., 2015}42. Xu S, Liu G, Bao X, et al. Rosiglitazone prevents amyloid-β oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number. J Alzheimers Dis. 2014;39(2):239-51. (China)	Agents for treating diabetes mellitus	In vitro, in laboratory	Experimental study	High
43	^{Papadopoulos et al., 2013}43. Papadopoulos P, Rosa-Neto P, Rochford J, Hamel E. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology. PloS One. 2013;8(7):e68612. (Canada)	Agents for treating diabetes mellitus	In vivo, in laboratory	Experimental study	High
44	^{Fukasawa et al., 2012}44. Fukasawa H, Nakagomi M, Yamagata N, et al. Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biol Pharm Bull. 2012;35(8):1206-12. (Japan)	Retinoids	In vivo, in laboratory	Experimental study	High
45	^{Wong et al., 2013}45. Wong WB, Lin VW, Boudreau D, Devine EB. Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf. 2013;22(4):345-58. (USA)	Statins: lipid-modifying agents	Not specific	Systematic review (randomized with meta-analysis)	Unclear
46	^{Calcul et al., 2012}46. Calcul L, Zhang B, Jinwal UK, Dickey CA, Baker BJ. Natural products as a rich source of tau-targeting drugs for Alzheimer's disease. Future Med Chem. 2012;4(13):1751-61. (USA)	Polyphenols	Clinical evidence	Narrative review	Unclear
47	^{García-Osta et al., 2012}47. García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R. Phosphodiesterases as therapeutic targets for Alzheimer's disease. ACS Chem Neurosci. 2012;3(11):832-44. (Spain)	Phosphodiesterase inhibitors	Clinical evidence	Narrative review	Unclear
48	^{Evans et al., 2014}48. Evans DA, Morris MC, Rajan KB. Vitamin E, memantine, and Alzheimer disease. JAMA. 2014;311(1):29-30. (USA)	Antioxidants; NMDA receptor antagonists	Phase III clinical trial	Randomized controlled clinical trial	Low
49	^{Revett et al., 2013}49. Revett TJ, Baker GB, Jhamandas J, Kar S. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. J Psychiatry Neurosci. 2013;38(1):6-23. (Canada)	Antioxidants; NMDA receptor antagonists	Not specific	Narrative review	High
50	^{Kellermann et al., 2011}50. Kellermann AJ, Kloft C. Is there a risk of bleeding associated with standardized Ginkgo biloba extract therapy? A systematic review and meta-analysis. Pharmacotherapy. 2011;31(5):490-502. (Germany)	Antioxidants	Phase III clinical trial	Systematic review (randomized with meta-analysis)	Low
51	^{Freund Levi et al., 2014}51. Freund Levi Y, Vedin I, Cederholm T, et al. Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study. J Intern Med. 2014;275(4):428-36. (USA)	Antioxidants	Phase II clinical trial	Randomized controlled clinical trial	Low
52	^{Sun et al., 2012}52. Sun GY, He Y, Chuang DY, et al. Integrating cytosolic phospholipase A2 with oxidative/nitrosative signaling pathways in neurons: a novel therapeutic strategy for AD. Mol Neurobiol. 2012;46(1):85-95. (USA)	Phospholipase A2 inhibitors	Not specific	Narrative review	High
53	^{Koliaki et al., 2012}53. Koliaki CC, Messini C, Tsolaki M. Clinical efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors, in patients with cognitive impairment: a comparative open study. CNS Neurosci Ther. 2012;18(4):302-12. (Greece)	Nootropic drugs without elucidated mechanism of action for Alzheimer's disease	Phase III clinical trial	Randomized controlled clinical trial	Low
54	^{Maki and Henderson, 2012}54. Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on. Climacteric. 2012;15(3):256-62. (USA)	Hormone therapy agents	Randomized clinical trial	Narrative review	Low
55	^{Anekonda and Quinn, 2011}55. Anekonda TS, Quinn JF. Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine. Biochim Biophys Acta. 2011;1812(12):1584-90. (Canada)	Antihypertensive agents	Clinical trials	Narrative review	Low
56	^{Valenzuela et al., 2012}56. Valenzuela M, Esler M, Ritchie K, Brodaty H. Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention. Transl Psychiatry. 2012;2:e107. (Australia)	Antihypertensive agents	Randomized controlled clinical trial	Narrative review	Low

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[1] Address for correspondence: Maurílio de Souza Cazarim Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica (CPAFF), sala 23, bloco S, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Av. Café, s/n^o Ribeirão Preto (SP) - Brasil CEP 14040-903 Tel. (+55 16) 3315-4236 E-mail: maurilio.jf@gmail.com