Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer's disease

Journal of Alzheimer's Disease

Volumn 44, Issue 2, 2015, Pages 705-720

  Wischik, Claude M ^a   Staff, Roger T ^b   Wischik, Damon J ^c   Bentham, Peter ^d   Murray, Alison D ^a   Storey, John M D ^a   Kook, Karin A ^e   Harrington, Charles R ^a  

^a UNIVERSITY OF ABERDEEN   (United Kingdom)

^b ABERDEEN ROYAL INFIRMARY   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^e Salamandra LLC   (United States)

Author keywords

Alzheimer's disease; controlled clinical trial; intervention studies; methylthioninium; safety; tau protein

Indexed keywords

HEMOGLOBIN; METHEMOGLOBIN; METHYLENE BLUE; PLACEBO; TAU PROTEIN; MAPT PROTEIN, HUMAN; NEUROPROTECTIVE AGENT;

AGED; ALZHEIMER DISEASE; ALZHEIMER DISEASE ASSESSMENT SCALE; ALZHEIMER DISEASE ASSESSMENT SCALE COGNITIVE SUBSCALE; ARTICLE; BRAIN BLOOD FLOW; BRAIN REGION; CLINICAL DEMENTIA RATING; CONSTIPATION; CONTROLLED STUDY; DEPRESSION; DIARRHEA; DISEASE COURSE; DISEASE SEVERITY; DIZZINESS; DOSE CALCULATION; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG CAPSULE; DRUG EFFICACY; DRUG ERUPTION; DRUG SAFETY; DRUG SOLUBILITY; DYSPEPSIA; DYSURIA; ERYTHROCYTE COUNT; FALLING; FEMALE; FRONTAL LOBE; HEMOGLOBIN BLOOD LEVEL; HUMAN; IN VITRO STUDY; LOWER RESPIRATORY TRACT INFECTION; MAJOR CLINICAL STUDY; MALE; MICTURITION DISORDER; MINI MENTAL STATE EXAMINATION; MOLECULAR IMAGING; MULTICENTER STUDY; NAUSEA; OUTCOME ASSESSMENT; PERIPHERAL EDEMA; PHASE 2 CLINICAL TRIAL; POLLAKISURIA; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RASH; RATING SCALE; SIDE EFFECT; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; TREATMENT RESPONSE; URINARY TRACT INFECTION; URINE INCONTINENCE; UROGENITAL TRACT DISEASE; VOMITING; ANTAGONISTS AND INHIBITORS; BRAIN; BRAIN CIRCULATION; DRUG EFFECTS; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; PSYCHOLOGICAL RATING SCALE; SCINTISCANNING; TREATMENT OUTCOME;

AGED; ALZHEIMER DISEASE; BRAIN; CEREBROVASCULAR CIRCULATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ERYTHROCYTE COUNT; FEMALE; HUMANS; MALE; METHYLENE BLUE; NEUROPROTECTIVE AGENTS; PSYCHIATRIC STATUS RATING SCALES; TAU PROTEINS; TOMOGRAPHY, EMISSION-COMPUTED, SINGLE-PHOTON; TREATMENT OUTCOME;

EID: 84921531217     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-142874     Document Type: Article

References (39)

1. Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psych Psych-gerich Med 64, 146-148.
2. Wischik CM, Crowther RA, Stewart M, Roth M (1985) Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol 100, 1905-1912.
3. Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85, 4884-4888.
4. Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R,Walker JE, Milstein C, Roth M, Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer's disease. Proc Natl Acad Sci U S A 85, 4506-4510.
5. Arriagada PW, Growdon JH, Hedley-White ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631-639.
6. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60, 1495-1500.
7. Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, Boeve BF, Parisi JE, Petersen RC, Dickson DW, Jack CR (2008) β-Amyloid burden is not associated with rates of brain atrophy. Ann Neurol 63, 204-212.
8. Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, Zhang M-R, Trojanowski John Q, Lee Virginia MY, Ono M, Masamoto K, Takano H, Sahara N, Iwata N, Okamura N, Furumoto S, Kudo Y, Chang Q, Saido Takaomi C, Takashima A, Lewis J, Jang M-K, Aoki I, Ito H, Higuchi M (2013) Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094-1108.
9. Wischik CM, Harrington CR, Storey JMD (2014) Tauaggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 88, 529-539.
10. Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204-1222.
11. Wischik CM, Wischik DJ, Storey JMD, Harrington CR (2010) Rationale for tau aggregation inhibitor therapy in Alzheimer's disease and other tauopathies In Emerging Drugs and Targets for Alzheimer's Disease. Volume 1: Beta-amyloid, tau protein and glucose metabolism, Martinez A, ed. Royal Society of Chemistry, Cambridge, pp. 210-232.
12. Mansouri A, Lurie AA (1993) Concise review: Methemoglobinemia. Am J Hematol 42, 7-12.
13. Boyce WH, McKinney WM, Long TT, Drach GW (1967) Oral administration of methylene blue to patients with renal calculi. J Urol 97, 783-789.
14. Naylor GJ, Martin B, Hopwood SE,Watson Y (1986) A twoyear double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry 21, 915-920.
15. Wein AJ, Benson GS, Raezer DM, Mulholland SG (1976) Oral methylene blue and the dissolution of renal calculi. J Urol 116, 140-141.
16. Wischik CM, Edwards PC, Lai RYK, Roth M, Harrington CR (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A 93, 11213-11218.
17. Baddeley TC, McCaffrey J, Storey JMD, Cheung JKS, Melis V, Horsley D, Harrington CR, Wischik CM, (2015) Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Ther 352, 110-118.
18. Harrington CR, Louwagie J, Rossau R,Vanmechelen E, Perry RH, Perry EK, Xuereb JH, Roth M,Wischik CM(1994) Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease. Am J Pathol 145, 1472-1484.
19. DiSanto AR, Wagner JG (1972) Pharmacokinetics of highly ionized drugs. II. Methylene blue -absorption, metabolism, and excretion in man and dog after oral administration. J Pharmacol Sci 61, 1086-1090.
20. Peter C, Hongwan D, Küpfer A, Lauterburg BH (2000) Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 56, 247-250.
21. Royal Pharmaceutical Society of Great Britain (2002) Methylene blue. In Martindale: The Complete Drug Reference, Sweetman SC, ed. Pharmaceutical Press, London and Chicago, pp. 1012-1014.
22. García-Sierra F, Wischik CM, Harrington CR, Luna-Muñoz J, Mena R (2001) Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's disease. J Chem Neuroanat 22, 65-77.
23. Westfall PH (1997) Multiple testing of general contrasts using logical constraints and correlations. J Am Stat Assoc 92, 299-306.
24. Syed GM, Eagger S, Toone BK, Levy R, Barrett JJ (1992) Quantification of regional cerebral blood flow (rCBF) using 99Tcm-HMPAO and SPECT: Choice of the reference region. Nucl Me Commun 13, 811-816.
25. NishimuraT, Hashikawa K, Fukuyama H,KubotaT, Kitamura S, Matsuda H, Hanyu H, Nabatame H, Oku N, Tanabe H, Kuwabara Y, Jinnouchi S, Kubo A (2007) Decreased cerebral blood flow and prognosis of Alzheimer's disease: A multicenter HMPAO-SPECT study. Ann Nucl Med 21, 15-23.
26. May JM, Qu Z-c, Cobb CE (2004) Reduction and uptake of methylene blue by human erythrocytes. Am J Physiol Cell Physiol 286, C1390-C1398.
27. Murthy ASN, Reddy KS (1984) Cyclic-voltammetric studies of some phenothiazine dyes. J Chem Soc Faraday Trans 1 Phys Chem Condensed Phases 80, 2745-2750.
28. Green RC, Schneider LS, Hendrix SB, Zavitz KH, Swabb E (2008) O3-04-01: Safety and efficacy of tarenflurbil in subjects with mild Alzheimer's disease: Results from an 18-month multi-center phase 3 trial. Alzheimers Dement 4, T165.
29. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 370, 322-333.
30. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl JMed 370, 311-321.
31. Gold M (2007) Study design factors and patient demographics and their effect on the decline of placebo-treated subjects in randomized clinical trials in Alzheimer's disease. J Clin Psychiatry 68, 430-438.
32. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH,Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, for the Alzheimer Disease Cooperative, Study (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: A randomized controlled trial. J Am Med Assoc 300, 1774-1783.
33. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA (2008) Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: A randomised phase II trial. Lancet Neurol 7, 483-493.
34. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ, for the Alzheimer's Disease Cooperative, Study (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: A randomized controlled trial. JAMA 289, 2819-2826.
35. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M,Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ, The Members of the Alzheimer's Disease Cooperative, Study (1997)Acontrolled trial of selegiline, alpha-tocopherol, or both as nt for Alzheimer's disease. N Engl J Med 336, 1216-1222.
36. Bradley KM, O'Sullivan VT, Soper NDW, Nagy Z, King EM-F, Smith AD, Shepstone BJ (2002) Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease. Brain 125, 1772-1781.
37. Matsuda H (2007) Role of neuroimaging in Alzheimer's disease, with emphasis on brain perfusion SPECT. J Nucl Med 48, 1289-1300.
38. Herholz K, Schopphoff H, Schmidt M, Mielke R, Eschner W, Scheidhauer K, Schicha H, HeissW-D, Ebmeier K (2002) Direct comparison of spatially normalized PET and SPECT scans in Alzheimer's disease. J Nucl Med 43, 21-26.
39. Mukaetova-Ladinska EB, Garcia-Sierra F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA, Paykel ES, McGee M, Jakes R, Honer WG, Harrington CR, Wischik CM (2000) Staging of cytoskeletal and β-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease. Am J Pathol 157, 623-636.