A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease

Davis, Kenneth L.; Thal, Leon J.; Gamzu, Elkan; Davis, Charles S.; Woolson, Robert F.; Gracon, Stephen I.; Drachman, David A.; Schneider, Lon S.; Whitehouse, Peter J.; Hoover, Toni M.; Morris, John C.; Kawas, Claudia H.; Knopman, David S.; Earl, N.; Kumar, Vinod; Doody, Rachelle S.

doi:10.1056/nejm199210293271801

Cited by 571 publications

(191 citation statements)

References 15 publications

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“…This indirect approach appears preferable over cholinomimetic strategies. In fact, cholinergic drugs used in most clinical trials have resulted in greater stimulation of inhibitory autoreceptors either by increasing the half-life of acetylcholine in the synaptic cleft [28] or by directly activating these receptors due to the poor selec-tivity of the agonists available [47]. Indirect stimulation of residual cholinergic neurons may be achieved with appropriate pharmacological intervention.…”

Section: Discussionmentioning

confidence: 99%

Interactions between histaminergic and cholinergic systems in learning and memory

Bacciottini

Passani

Mannaioni

et al. 2001

Behavioural Brain Research

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The aim of this review is to survey biochemical, electrophysiological and behavioral evidence of the interactions between the cholinergic and histaminergic systems and evaluate their possible involvement in cognitive processes. The cholinergic system has long been implicated in cognition, and there is a plethora of data showing that cholinergic deficits parallel cognitive impairments in animal models and those accompanying neurodegenerative diseases or normal aging in humans. Several other neurotransmitters, though, are clearly implicated in cognitive processes and interact with the cholinergic system. The neuromodulatory effect that histamine exerts on acetylcholine release is complex and multifarious. There is clear evidence indicating that histamine controls the release of central acetylcholine (ACh) locally in the cortex and amygdala, and activating cholinergic neurones in the nucleus basalis magnocellularis (NBM) and the medial septal area-diagonal band that project to the cortex and to the hippocampus, respectively. Extensive experimental evidence supports the involvement of histamine in learning and memory and the procognitive effects of H 3 receptor antagonists. However, any attempt to strictly correlate cholinergic/histaminergic interactions with behavioral outcomes without taking into account the contribution of other neurotransmitter systems is illegitimate. Our understanding of the role of histamine in learning and memory is still at its dawn, but progresses are being made to the point of suggesting potential treatment strategies that may produce beneficial effects on neurodegenerative disorders associated with impaired cholinergic function.

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Section: Discussionmentioning

confidence: 99%

Interactions between histaminergic and cholinergic systems in learning and memory

Bacciottini

Passani

Mannaioni

et al. 2001

Behavioural Brain Research

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“…Because to have significant benefit in the treatment of cognitive CYP1A2 activity has been shown to vary up to 60-fold deficits in patients with Alzheimer's disease. [1][2][3][4][5] It has among patients, we proposed that a convenient measure been estimated that approximately 3 to 4 million sured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the However, susceptibility to tacrine liver toxicity clearly standardized-dose CBT correlated well with the loga-varies greatly in the Alzheimer's population, and at rithm of the steady-state plasma tacrine level obtained least two patients receiving tacrine have developed in 10 patients (R 2 Å .69, P Å .003).…”

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confidence: 99%

The Caffeine Breath Test Does Not Identify Patients Susceptible to Tacrine Hepatotoxicity

et al. 1996

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position of the drug in vivo. (HEPATOLOGY 1996;23:1429-Therapy with tacrine, a promising new treatment for 1435.) Alzheimer's disease, must be discontinued in up to 15% of patients because of hepatocellular toxicity. Recent studies using human liver microsomes have suggested that a single liver enzyme, cytochrome P450 1A2 Tacrine (1,2,3,4-tetrahydro-9 acridinamine monohy-(CYP1A2), catalyzes the major route of metabolism and drochloride monohydrate; Cognex, Parke Davis Pharelimination of tacrine, and also catalyzes the pathway(s) maceuticals, Morris Plains, NJ), a potent acetylcholininvolved in the generation of reactive metabolites capa-esterase inhibitor, is the first therapeutic agent shown ble of covalent protein binding and cytotoxicity. Because to have significant benefit in the treatment of cognitive CYP1A2 activity has been shown to vary up to 60-fold deficits in patients with Alzheimer's disease. [1][2][3][4][5] It has among patients, we proposed that a convenient measure been estimated that approximately 3 to 4 million sured CYP3A4 and CYP2D6 activities also failed to predict the susceptible patients. However, the result of the However, susceptibility to tacrine liver toxicity clearly standardized-dose CBT correlated well with the loga-varies greatly in the Alzheimer's population, and at rithm of the steady-state plasma tacrine level obtained least two patients receiving tacrine have developed in 10 patients (R 2 Å .69, P Å .003). We conclude that the clinical jaundice indicative of severe hepatocellular in-CBT will not be clinically useful in determining the sub-jury. 8,9 A liver biopsy obtained in one of these patients set of patients most susceptible to tacrine hepatotoxic-revealed massive centrilobular necrosis. 8 In light of the ity. However, the correlation we observed between the potential risk for serious liver injury and the fact that CBT results and tacrine blood levels is the first evidence patients with serum transaminase elevations are gen-

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“…In this situation, it may be possible to identify a study population of potential responders not on any a priori basis but by using a clinical screening approach to select the participants in a subsequent randomized blinded trial. (Temple, 1994, p. 516) Temple's paper is one of the first published uses of the term enrichment to describe such approaches to trial design (see also Davis et al, 1992), and identifies the vasospastic angina drug nifedipine as the first to be approved by the FDA on the basis of EERW clinical trials. The paper was not widely cited or discussed in the literature at the time, but in recent years the topic has seen renewed attention (Arthritis Research UK, 2013).…”

Section: Background: the Road To Enrichmentmentioning

confidence: 99%

“Unsettling circularity”: Clinical trial enrichment and the evidentiary politics of chronic pain

Campbell

King

2017

BioSocieties

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The US Food and Drug Administration's approval of the controversial analgesic Zohydro has drawn attention to its endorsement of so-called 'enrichment strategies' for streamlining clinical trials. Among these is 'enriched enrollment randomized withdrawal' (EERW), a design intended to improve measures of drug efficacy by screening out patients who are non-responsive or suffer adverse effects. EERW has been promoted as a response to the problem of high trial failure rates for drugs that were previously thought to be effective for pain management. This article uses EERW as a window into the evidentiary politics of pain medicine in the twenty-first century, against the backdrop of concerns about prescription opioid abuse. We demonstrate that the reframing of negative trials as 'failed' trials poses a challenge to the evidence hierarchy of evidence-based medicine, and identify several rhetorical strategies used by proponents to normalize EERW by placing it in continuity with routine clinical trial practice and the promise of personalized medicine. Finally, we illustrate how EERW, in the current regulatory context, fails to contribute to the individualization of diagnosis or therapy, and reinforces the perceived gulf between trials for regulatory approval and clinical practice.

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A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease

Cited by 571 publications

References 15 publications

Interactions between histaminergic and cholinergic systems in learning and memory

Interactions between histaminergic and cholinergic systems in learning and memory

The Caffeine Breath Test Does Not Identify Patients Susceptible to Tacrine Hepatotoxicity

“Unsettling circularity”: Clinical trial enrichment and the evidentiary politics of chronic pain

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