X-Message-Number: 32231
Date: Thu, 17 Dec 2009 21:19:38 -0800 (PST)
From:
Subject: evidence based OTC treatment of Alzheimer's disease III
[Conflicting results, but ginkgo biloba is likely a dud.]
JAMA. 2008 Nov 19;300(19):2253-62.
Ginkgo biloba for prevention of dementia: a randomized controlled trial.
DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez
OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF,
Dunn L, Snitz BE, Nahin RL, Furberg CD; Ginkgo Evaluation of Memory (GEM) Study
Investigators. Collaborators (53) Nahin R, Sorkin B, Carlson MC, Fried LP,
Crowley P, Kawas C, Chaves P, Yasar S, Smith P, Chabot J, Robbins JA, Gundling
K, Theroux S, Kwong L, Pastore L, Kuller L, Moyer R, Albig C, Burke G, Rapp S,
Posey D, Lamb M, Horr R, Schmeller T, Herrmann J, Kronmal RA, Fitzpatrick AL,
Lin F, Solomon C, Arnold A, DeKosky ST, Saxton JA, Lopez OL, Ives DG, Dunn L,
Williamson JD, Furberg CD, Woolard N, Bender K, Margitic S, Tracy RP, Cornell E,
Meltzer C, Grimm R, Berman J, Bradford H, Calabrese C, Chappell R, Connor K,
Geller G, Iglewicz B, Panush RS, Shader R. University of Pittsburgh, Pittsburgh,
Pennsylvania, USA.
Erratum in: JAMA. 2008 Dec 17;300(23):2730.
CONTEXT: Ginkgo biloba is widely used for its potential effects on memory
and cognition. To date, adequately powered clinical trials testing the
effect of G. biloba on dementia incidence are lacking. OBJECTIVE: To
determine effectiveness of G. biloba vs placebo in reducing the incidence of
all-cause dementia and Alzheimer disease (AD) in elderly individuals with
normal cognition and those with mild cognitive impairment (MCI). DESIGN,
SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled
clinical trial conducted in 5 academic medical centers in the United States
between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand
sixty-nine community volunteers aged 75 years or older with normal cognition
(n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for
incident dementia. INTERVENTION: Twice-daily dose of 120-mg extract of G.
biloba (n = 1545) or placebo (n = 1524). MAIN OUTCOME MEASURES: Incident
dementia and AD determined by expert panel consensus. RESULTS: Five hundred
twenty-three individuals developed dementia (246 receiving placebo and 277
receiving G. biloba) with 92% of the dementia cases classified as possible
or probable AD, or AD with evidence of vascular disease of the brain. Rates
of dropout and loss to follow-up were low (6.3%), and the adverse effect
profiles were similar for both groups. The overall dementia rate was 3.3 per
100 person-years in participants assigned to G. biloba and 2.9 per 100
person-years in the placebo group. The hazard ratio (HR) for G. biloba
compared with placebo for all-cause dementia was 1.12 (95% confidence
interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P =
.11). G. biloba also had no effect on the rate of progression to dementia in
participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39). CONCLUSIONS:
In this study, G. biloba at 120 mg twice a day was not effective in reducing
either the overall incidence rate of dementia or AD incidence in elderly
individuals with normal cognition or those with MCI. Trial Registration
clinicaltrials.gov Identifier: NCT00010803.
PMID: 19017911
[Success here with ginkgo biloba, if you define success as no change.]
Eur J Neurol. 2006 Sep;13(9):981-5.
Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's
dementia in a randomized placebo-controlled double-blind study.
Mazza M, Capuano A, Bria P, Mazza S. Department of Psychiatry, Catholic
University of Sacred Heart, Rome, Italy.
The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective
effects in neurodegenerative diseases of multifactorial origin. There is
still debate about the efficacy of Ginkgo biloba special extract EGb 761
compared with second-generation cholinesterase inhibitors in the treatment
of mild to moderate Alzheimer's dementia. Our aim is to assess the efficacy
of the Ginkgo biloba special extract E.S. in patients with dementia of the
Alzheimer type in slowing down the disease's degenerative progression and
the patients' cognitive impairment compared with donepezil and placebo. The
trial was designed as a 24-week randomized, placebo-controlled, double-blind
study. Patients aged 50-80 years, suffering from mild to moderate dementia,
were allocated into one of the three treatments: Ginkgo biloba (160 mg
daily dose), donepezil (5 mg daily dose), or placebo group. The degree of
severity of dementia was assessed by the Syndrom Kurz test and the
Mini-Mental State Examination. Clinical Global Impression score was recorded
to assess the change in the patients' conditions and the therapeutic
efficacy of tested medications. Our results confirm the clinical efficacy of
Ginkgo biloba E.S. (Flavogin) in the dementia of the Alzheimer type,
comparable with donepezil clinical efficacy. There are few published trials
that have directly compared a cholinesterase inhibitor with Ginkgo for
dementia. This study directly compares a cholinesterase inhibitor with
Ginkgo biloba for dementia of the Alzheimer type and could be a valid
contribution in this debate. Our study suggests that there is no evidence of
relevant differences in the efficacy of EGb 761 and donepezil in the
treatment of mild to moderate Alzheimer's dementia, so the use of both
substances can be justified. In addition, this study contributes to
establish the efficacy and tolerability of the Ginkgo biloba special extract
E.S. in the dementia of the Alzheimer type with special respect to
moderately severe stages.
PMID: 16930364
[A combination of high-dose folate, vitamin B(6), and vitamin B(12) is a dud.]
JAMA. 2008 Oct 15;300(15):1774-83.
High-dose B vitamin supplementation and cognitive decline in Alzheimer disease:
a randomized controlled trial.
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF,
Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease
Cooperative Study.
Collaborators (126) Vicari S, Ala T, Luster K, Quinn J, Lear J, Clay T,
Schneider LS, Pawluczyk S, Dagerman K, Sian S, Fleisher A, Pay MM, Barbas N,
Lord J, Peskind E, Raskind MA, Mandelco L, Doody RS, Sims J, Roundtree S, Bell
K, Tejeda R, Dominguez-Rivera E, Harrell L, Marson D, Zamrini E, Grossman H,
Marzloff G, Nandipait S, Aggarwal N, Shah R, Bach J, Pfeiffer E, Luhn B, Hunter
J, Ferris SH, Monteiro I, Maya E, Clark C, Han M, Pham C, Watson M, DeKosky ST,
Simpson D, Ismail SM, Goldstein B, McCallum C, Mulnard RA, McAdams-Ortiz C,
Yanez B, Weiner M, Koch K, Moore C, Levey A, Cellar J, Kippels A, Ringman J,
Bardens J, Yau A, Graff-Radford NR, Parfitt F, Farlow MR, Hake A, Numberger P,
van Dyck C, MacAvoy M, Black N, Hoffman P, DeCarli C, Seavey W, Conover C, Ahern
G, Baldwin M, Malek-Ahmadi M, Bernick C, Munic D, Vranesh G, Marek-Mesulam M,
Johnson N, Epstein-Fields S, Mintzer JE, Davis FA, Kent J, Roffman M, Sadowdky
C, Villena T, Martinez WC, Johnson K, Reynolds B, Ward C, Salisbury S, Yesavage
JA, Ashford WJ, Pechonkina A, Kinoshita L, Sabbagh M, Connor D, Obradov S, Green
RC, Stern RA, Nair A, Brickley M, Caselli R, Lawrence J, Obisesan T, Obisesan
OA, Ahaghotu E, Ogrocki P, Sanders M, Ziol E, Ott BR, Grace J, Erbozkurt T,
Kieburtz K, Miller B, Kryscio R, Alexopoulos G, Croot K, Messick V, Pamoleras A,
Ryan-Jones R, Garcia-Camilo G, Schittini M, Brugger KG, Saunders PA, Kastelan
J.
Department of Neurosciences, University of California, San Diego, 9500 Gilman
Dr, M/C 0949, La Jolla, CA 92093, USA.
CONTEXT: Blood levels of homocysteine may be increased in Alzheimer disease
(AD) and hyperhomocysteinemia may contribute to disease pathophysiology by
vascular and direct neurotoxic mechanisms. Even in the absence of vitamin
deficiency, homocysteine levels can be reduced by administration of
high-dose supplements of folic acid and vitamins B(6) and B(12). Prior
studies of B vitamins to reduce homocysteine in AD have not had sufficient
size or duration to assess their effect on cognitive decline. OBJECTIVE: To
determine the efficacy and safety of B vitamin supplementation in the
treatment of AD. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized,
double-blind controlled clinical trial of high-dose folate, vitamin B(6),
and vitamin B(12) supplementation in 409 (of 601 screened) individuals with
mild to moderate AD (Mini-Mental State Examination scores between 14 and 26,
inclusive) and normal folic acid, vitamin B(12), and homocysteine levels.
The study was conducted between February 20, 2003, and December 15, 2006, at
clinical research sites of the Alzheimer Disease Cooperative Study located
throughout the United States. INTERVENTION: Participants were randomly
assigned to 2 groups of unequal size to increase enrollment (60% treated
with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1
mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of
treatment was 18 months. MAIN OUTCOME MEASURE: Change in the cognitive
subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). RESULTS: A
total of 340 participants (202 in active treatment group and 138 in placebo
group) completed the trial while taking study medication. Although the
vitamin supplement regimen was effective in reducing homocysteine levels
(mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in
placebo group; P < .001), it had no beneficial effect on the primary
cognitive measure, rate of change in ADAS-cog score during 18 months (0.372
points per month for placebo group vs 0.401 points per month for active
treatment group, P = .52; 95% confidence interval of rate difference, -0.06
to 0.12; based on the intention-to-treat generalized estimating equations
model), or on any secondary measures. A higher quantity of adverse events
involving depression was observed in the group treated with vitamin
supplements. CONCLUSION: This regimen of high-dose B vitamin supplements
does not slow cognitive decline in individuals with mild to moderate AD.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056225.
PMID: 18854539
[Curcumin is a dud. Curcumin continues to be actively researched, and the poor
results of this clinical trial were buried in a letter to the editor.]
J Clin Psychopharmacol. 2008 Feb;28(1):110-3.
Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of
curcumin in patients with Alzheimer disease.
Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C,
Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS,
Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V.
PMID: 18204357
[Rosmarinic acid is highly effective while curcumin is a dud in an animal model
of Alzheimer's disease. We'll be taking a further look at rosmarinic acid
later.]
Am J Pathol. 2009 Nov 5. [Epub ahead of print]
Phenolic Compounds Prevent Alzheimer's Pathology through Different Effects on
the Amyloid-{beta} Aggregation Pathway.
Hamaguchi T, Ono K, Murase A, Yamada M. From the Department of Neurology and
Neurobiology of Aging, Kanazawa University Graduate School of Medical Science,
Kanazawa, Japan.
Inhibition of amyloid-beta (Abeta) aggregation is an attractive therapeutic
strategy for Alzheimer's disease (AD). Certain phenolic compounds have been
reported to have anti-Abeta aggregation effects in vitro. This study
systematically investigated the effects of phenolic compounds on AD model
transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin,
ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic
acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in
both the NDGA- and RA-treated groups, Abeta deposition was significantly
decreased in the brain (P < 0.05). In the RA-treated group, the level of
Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01),
whereas that of oligomers, as probed with the A11 antibody (A11-positive
oligomers), was decreased (P < 0.001). However, in the NDGA-treated group,
the abundance of A11-positive oligomers was increased (P < 0.05) without any
change in the levels of TBS-soluble or TBS-insoluble Abeta. In the
curcumin- and myricetin-treated groups, changes in the Abeta profile were
similar to those in the RA-treated group, but Abeta plaque deposition was
not significantly decreased. In the ferulic acid-treated group, there was no
significant difference in the Abeta profile. These results showed that oral
administration of phenolic compounds prevented the development of AD
pathology by affecting different Abeta aggregation pathways in vivo.
Clinical trials with these compounds are necessary to confirm the anti-AD
effects and safety in humans.
PMID: 19893028
[Aspirin is a dud.]
Lancet Neurol. 2008 Jan;7(1):41-9.
Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial.
AD2000 Collaborative Group, Bentham P, Gray R, Sellwood E, Hills R, Crome P,
Raftery J.
Comment in: Lancet Neurol. 2008 Jan;7(1):20-1.
BACKGROUND: Cardiovascular risk factors and a history of vascular disease
can increase the risk of Alzheimer's disease (AD). AD is less common in
aspirin users than non-users, and there are plausible biological mechanisms
whereby aspirin might slow the progression of either vascular or
Alzheimer-type pathology. We assessed the benefits of aspirin in patients
with AD. METHODS: 310 community-resident patients who had AD and who had no
potential indication or definite contraindication for aspirin were randomly
assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated
tablet per day, to continue indefinitely) or to avoid aspirin (n=154).
Primary outcome measures were cognition (assessed with the mini-mental state
examination [MMSE]) and functional ability (assessed with the Bristol
activities of daily living scale [BADLS]). Secondary outcomes were time to
formal domiciliary or institutional care, progress of disability,
behavioural symptoms, caregiver wellbeing, and care time. Patients were
assessed at 12-week intervals in the first year and once each year
thereafter. Analysis of the primary outcome measures was by intention to
treat. This study is registered as an International Standard Randomised
Controlled Trial, number ISRCTN96337233. FINDINGS: Patients had a median age
of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had
concomitant vascular dementia. Over the 3 years after randomisation, in
patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI
-0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to
0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no
obvious differences between the groups in any other outcome measurements. 13
(8%) patients on aspirin and two (1%) patients in the control group had
bleeds that led to admission to hospital (relative risk=4.4, 95% CI
1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal
cerebral bleeds. INTERPRETATION: Although aspirin is commonly used in
dementia, in patients with typical AD 2 years of treatment with low-dose
aspirin has no worthwhile benefit and increases the risk of serious bleeds.
PMID: 18068522
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