Tacrine in Alzheimer's disease

Eagger, Sarah; Levy, Raymond; Sahakian, Barbara J.

doi:10.1016/0140-6736(91)92656-m

Cited by 328 publications

(122 citation statements)

References 24 publications

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“…However, unlike BC-PS, the anti-dementia effects of PC have been proven by a combination with cholinesterase inhibitors such as tetrahydroaminoacridine, and the efficacy dose of PC was about 30 times larger than that of BC-PS (6). Therefore, the anti-dementia mechanism of BC-PS would be different from that of PC which is considered to improve brain function by supplying choline for acetylcholine synthesis.…”

mentioning

confidence: 88%

Pharmacological Effects of Phosphatidylserine Enzymatically Synthesized from Soybean Lecithin on Brain Functions in Rodents.

Sakai

Yamatoya

Kudo

1996

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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SummarySoybean transphosphatidylated phosphatidylserine (SB -t PS) was prepared from soybean phosphatidylcholine by transphos phatidylation using phospholipase D, and the fatty acids composition and pharmacological properties were compared with those of bovine brain cortex-derived phosphatidylserine (BC-PS) which was reported to im prove cognitive disorders of senile dementia patients by oral administra tion (300mg/day). The molecular species of SB-tPS are rich in linoleic and palmitic acids whereas those of BC-PS are stearic and oleic acids. Despite the differences in fatty acid composition, SB-tPS displayed signifi cant activities on the increase in brain glucose concentrations in mice (79 mg/kg, i.v.) and the restoration of scopolamine-induced amnesia in rats (60mg/kg, i.p.) as did BC-PS. These results suggest the possibility that SB-tPS may prevent and/or improve senile dementia by oral administra tion.

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mentioning

confidence: 88%

Pharmacological Effects of Phosphatidylserine Enzymatically Synthesized from Soybean Lecithin on Brain Functions in Rodents.

Sakai

Yamatoya

Kudo

1996

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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“…Data from previous studies were used to determine the order of magnitude and standard deviation for the treatment effects as hypothesized [13]. Completion rates of 50 and 80% were assumed for the treatment and placebo group, respectively [10][11][12][13]. Data from patient follow-up visits were considered incomplete if a baseline MMSE score was outside the range of 10-26, the patient failed to take the treatment for more than 5 consecutive days or more than 20 doses in total in any 6-week treatment period, or took a prohibited concurrent medication.…”

Section: Discussionmentioning

confidence: 99%

“…Several drugs that enhance cholinergic activity have been investigated as potential therapeutic agents in the treatment of AD [7][8][9]. Tacrine hydrochloride (Cognex, Park-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Mich. USA) is the first agent approved by the United States FDA for the treatment of AD [10][11][12][13]. The major safety concern for patients receiving tacrine is the development of serum aminotransferase (ALT) elevations and the potential for the development of clinically significant hepatic toxicity [14].…”

Section: Introductionmentioning

confidence: 99%

A Double-Blind, Placebo-Controlled Study of Tacrine in Chinese Patients with Alzheimer’s Disease

Wong¹,

Liu²,

Fuh³

et al. 1999

Dement Geriatr Cogn Disord

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The purpose of the study was to evaluate the efficacy and safety of tacrine over 30 weeks in Chinese patients with probable Alzheimer’s disease (AD). A total of 100 patients with mild to moderate AD were recruited and randomly assigned to active or placebo treatment. The active group received 30 mg/day of tacrine for the first 6 weeks, 60 mg/day for the next 6 weeks, 90 mg/day for 6 more weeks and then 120 mg/day for the remaining 12 weeks. Safety evaluations included biweekly determinations of alanine aminotransferase (ALT). The primary outcome measures were Cognitive Abilities Screening Instrument (CASI), Clinical Global Impression of Change (CGIC) by investigator and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Secondary outcome measures were Mini-mental State Examination (MMSE), Alzheimer’s Deficit Scale (ADS) and CGIC by caregivers. Sixty-eight patients were included in an intent-to-treat analysis (48 active and 20 placebo); 56 patients had evaluable data at week 30 (36 active and 20 placebo). The results of the complete case analysis revealed a significant improvement in the CASI and MMSE scores of the active group in the 18th week (90 mg/day) and the 30th week (120 mg/day) (p < 0.01). In the intent-to-treat analysis, significant improvement of the active group was noted on CASI at week 30 (p = 0.05), but there was no significant difference in the measures of IQCODE, CGIC and ADS. The primary reasons for withdrawal of tacrine-treated patients (39 patients, 52%) were asymptomatic ALT elevation, anorexia and nausea/vomiting. These patients all recovered from the adverse events on discontinuation of treatment. Tacrine produced a statistically significant improvement in the CASI and MMSE in Chinese patients with mild to moderate AD using a lower dose than in western people.

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“…By setting the · and ß statistical risks at 5 and 10% and accepting a 25% reduction in the percentage of patients with elevated ALAT levels as clinically significant, this number was 84 patients per group. Sample size was increased by 20% (to 102) to account for potential drop-outs which have been reported for adverse effects other than hepatotoxicity to be in the 9-17% range [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Statisticsmentioning

confidence: 99%

“…The risks involved with tacrine therapy were rapidly recognised: cholinergic and gastrointestinal disorders and risk of hepatic dysfunction reflected by elevated aminotransferase levels (ALAT, ASAT) in one half of treated patients [5,6]. The hepatotoxic effect is well characterised: clinical signs are reversible with drug withdrawal, the rise in aminotransaminase levels occurs within the first 8 weeks of treatment in 81% of patients, ALAT rises to three times the upper limit of normal (3 ULN) in 25% of treated patients, 10 ULN in 7% and 20 ULN in 2%.…”

Section: Introductionmentioning

confidence: 99%

Aminotransferase Levels and Silymarin in de novo Tacrine-Treated Patients with Alzheimer’s Disease

Allain

Schück

Lebreton³

et al. 1999

Dement Geriatr Cogn Disord

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Background: Silymarin is a well-known hepatoprotective agent. Tacrine, the first drug marketed for Alzheimer’s disease (AD), induces an elevation of serum liver transaminase prohibiting an effective dosage in many patients. This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability. Methods: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacrine + silymarin and tacrine + placebo. The study was double-blind for silymarin and open for tacrine and was conducted in 22 French neurology and geriatric centres. Silymarin (420 mg/day) was given first (1 week) and tacrine was added at 40 mg/day for 6 weeks, then increased to 80 mg/day (6 weeks). Serum ALAT was the main evaluation criterion (> upper limit of normal, ULN). Serum ASAT as well as adverse side effects and cognitive performance assessed by MMSE and the Syndrome Kurtz test (SKT) were secondary evaluation criteria. Null hypotheses were evaluated with Fisher’s exact test. Findings: 222 patients were recruited and received silymarin and tacrine (110 patients) or placebo and tacrine (112 patients). 28 patients dropped out; 217 were included in the intent-to-treat analysis. No statistical difference was observed between the two groups for serum ALAT (p = 0.39). Fewer patients had ALAT levels >5 ULN in the silymarin group (–33.3%). Side effects and notably gastrointestinal disorders were much less frequent in the silymarin group. Cognitive performance remained unchanged in both groups. Interpretation: Silymarin does not prevent tacrine-induced ALAT elevation but does reduce the rate of gastrointestinal and cholinergic side effects without any impact on cognitive status. As a consequence, silymarin (420 mg/day) could be co-administered with tacrine to improve tolerability in the initial phases of AD treatment.

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Tacrine in Alzheimer's disease

Cited by 328 publications

References 24 publications

Pharmacological Effects of Phosphatidylserine Enzymatically Synthesized from Soybean Lecithin on Brain Functions in Rodents.

Pharmacological Effects of Phosphatidylserine Enzymatically Synthesized from Soybean Lecithin on Brain Functions in Rodents.

A Double-Blind, Placebo-Controlled Study of Tacrine in Chinese Patients with Alzheimer’s Disease

Aminotransferase Levels and Silymarin in de novo Tacrine-Treated Patients with Alzheimer’s Disease

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