Alzheimer's Drug Trial Put on Hold

Marx, Jean L.

doi:10.1126/science.3317822

Cited by 53 publications

(15 citation statements)

References 2 publications

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“…General tolerance of side effects was poor, with about one third experiencing significant nau sea or vomiting. In fact, the portion of this study con ducted in the United States (not included in the above results) was discontinued due to the severity of hepatic and gastrointestinal side effects [88]. Similarly, Fittcn et al [89], Eaggcr et al [90], Gauthier et al [91], and Wein stein et al [90], Gauthier et al [91], and Weinstein et al [92] have all reported minimal or no effect of THA com bined with lecithin.…”

Section: Tetraliydroami Noacridinementioning

confidence: 99%

The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

Holttum¹,

Gershon²

1992

Dement Geriatr Cogn Disord

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Efforts continue toward the goal of uncovering a dominant pathogenetic and therapeutic model for Alzheimer type dementia. This article critically reviews the evolution and current status of unitary transmitter concepts, the prototype of which is the cholinergic model proposed by Deutsch and others, from early animal studies to ongoing drug trials. We conclude that evidence is sufficient to dismiss such models as a means of directing treatment and further resources. A survey of novel approaches to Alzheimer type dementia, many of which transcend unitary thought, reveals a more promising direction for further research.

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Section: Tetraliydroami Noacridinementioning

confidence: 99%

The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

Holttum¹,

Gershon²

1992

Dement Geriatr Cogn Disord

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“…In light of this, it is worth mentioning that the 7-methoxy derivative of tacrine, 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA (2), Figure 1), [17] shows lower hepatotoxicity than tacrine. [18][19][20] Based on the MTDL approach, recent reports have described tacrine hybrids prepared by connecting tacrine or its derivatives to other pharmacologically relevant scaffolds with the aim of overcoming tacrine's hepatotoxicity. [21] Among these are the tacrine hybrids, such as the antioxidant tacrine-ferulic acid nitric oxide (NO) donor (hybrid 3, Figure 1), [22] or tacrine-caffeic acid (hybrid 4, Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

et al. 2014

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Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.

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“…Although a large number of known centrally active AChEI, such as tacrine and physostigmine, have been developed, the vast majority of such agents are not used clinically due to limitations related to short biological half‐life, poor blood‐brain barrier penetration, instability in plasma, unpredictable absorption, extensive adverse side effects, or narrow therapeutic range (Marx, 1987).…”

mentioning

confidence: 99%

Dehydroevodiamine·HCl Prevents Impairment of Learning and Memory and Neuronal Loss in Rat Models of Cognitive Disturbance

Park

Lee

et al. 2000

Journal of Neurochemistry

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Abstract:We previously reported that dehydroevodiamine⅐HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia. Key Words: Dehydroevodiamine⅐HCl-Learning and memory-Brain ischemia-Entorhinal cortex-Alzheimer's disease.

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Alzheimer's Drug Trial Put on Hold

Cited by 53 publications

References 2 publications

The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

The Cholinergic Model of Dementia, Alzheimer Type: Progression from the Unitary Transmitter Concept

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

Dehydroevodiamine·HCl Prevents Impairment of Learning and Memory and Neuronal Loss in Rat Models of Cognitive Disturbance

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