Safety of Tacrine: Clinical Trials, Treatment IND, and Postmarketing Experience

Gracon, Stephen I.; Knapp, Margaret J.; Berghoff, William G.; Pierce, Mark; DeJong, Richard G.; Lobbestael, Sandra J.; Symons, James P.; Dombey, Stuart L.; Luscombe, Faye A.; Kraemer, Dale F.

doi:10.1097/00002093-199806000-00007

Cited by 95 publications

(51 citation statements)

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“…Currently, four AChE inhibitors (tacrine, donepezil, rivastigmine and galantamine) have been approved to treat AD in the United States (Lahiri et al, 2002). Unfortunately, these drugs are not so ideal in clinical use because of their potentially adverse side effects such as hepatotoxicity and peripheral cholinergic events which most frequently happen in tacrine therapy (Gracon et al, 1998). For this reason, it is necessary to continue to seek some materials for the treatment of AD and AAMI with little or no damage to the body.…”

Section: Introductionmentioning

confidence: 99%

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

Rong

Xie

et al. 2009

Phytotherapy Research

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The major purpose of this study was to determine the effect of procyanidins extracted from the lotus seedpod (LSPC) on the learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) in mice. The capacities of memory and learning were evaluated by the Morris water maze and the step-down avoidance test. LSPC (50, 100, 150 mg/kg BW, p.o.) significantly reversed scopolamine-induced learning and memory impairments in the Morris water maze test, as evaluated by shortened escape latency and swimming distance. In the step-down avoidance test, LSPC (50, 100, 150 mg/kg BW, p.o.) treatment significantly reduced the number of errors and shortened latency compared with that of scopolamine. In addition, LSPC was also found to inhibit acetyl cholinesterase (AChE) activity. These results of this study suggest that LSPC may play a useful role in the treatment of cognitive impairment caused by AD and aging.

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Section: Introductionmentioning

confidence: 99%

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

Rong

Xie

et al. 2009

Phytotherapy Research

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“…The first two widely used ChE inhibitors were physostigmine and tacrine. In clinical trials with these compounds, undesirable cholinergic side effects were reported [3][4][5][6][7]. The use of tacrine was also associated with dose-limiting hepatotoxicity [3,8].…”

Section: Introductionmentioning

confidence: 99%

An Observational Clinical Study of the Efficacy and Tolerability of Donepezil in the Treatment of Alzheimer’s Disease

Häger¹,

Calabrese²,

Frölich

et al. 2003

Dement Geriatr Cogn Disord

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An open-label, observational Post-Marketing Surveillance (PMS) study was undertaken in Germany to examine the efficacy and tolerability of donepezil in routine clinical practice. Alzheimer’s disease (AD) patients were treated with donepezil (5 or 10 mg once daily) and observed for a period of approximately 3 months. Study assessments included the Mini-Mental State Examination (MMSE), the Nurses’ Observation Scale for Geriatric Patients (NOSGER), and adverse events (AEs). A total of 2,092 patients (mean age 73.0 years; mean ± SD MMSE score 17.8 ± 5.8) were included in the efficacy assessments. MMSE and NOSGER scores showed statistically significant improvements in the total patient population and in the subpopulations with severe AD or AD with concomitant Parkinsonian symptoms (ADPS cohort). AEs were reported in a total of 12% of patients and were mostly due to peripheral cholinergic effects. In this observational PMS study, donepezil was shown to be an effective and well-tolerated therapy in the overall patient population, in patients with severe AD, and in the ADPS cohort.

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“…[4,5] The exploitation of this therapeutic approach has led to the development of approved drugs, among which tacrine (Cognex), the first US food and drug administration (FDA)-approved drug for the treatment of Alzheimer's symptoms, has been withdrawn from the market on account of severe adverse effects. [6] Assuming that other proposed molecules still exhibit residual hepatic toxicity [7] and that the treatment must be taken life-long, there is an urgent need for more potent inhibitors allowing a decrease of the efficient doses. In this context, very active compounds, called huprines (Figure 1), have been developed at the end of the last decade by combining two previously known inhibitors: the marketed drug tacrine and the natural product (À)-huperzine A.…”

Section: Introductionmentioning

confidence: 99%

New Huprine Derivatives Functionalized at Position 9 as Highly Potent Acetylcholinesterase Inhibitors

Ronco

Foucault²,

Gillon³

et al. 2011

ChemMedChem

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A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues (1, 2, 6-9, 13-15, and 23) are active in the low nanomolar range (IC(50) <5 nM), very close to the parent compound huprine X. Compounds 2, 6, and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700-1160-fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl-binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines (2, 6, and 7) showed that most of the difference in K(D) is accounted by a decrease in k(on) , which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC(50) =1.1 nM) and showed a rather weak toxicity (LD(50) =40 mg kg(-1) ) and an ability to cross the blood-brain barrier with doses above 15 mg kg(-1).

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Safety of Tacrine: Clinical Trials, Treatment IND, and Postmarketing Experience

Cited by 95 publications

References 0 publications

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

An Observational Clinical Study of the Efficacy and Tolerability of Donepezil in the Treatment of Alzheimer’s Disease

New Huprine Derivatives Functionalized at Position 9 as Highly Potent Acetylcholinesterase Inhibitors

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