Group Report 3: Early Clinical Testing of Cognition Enhancers: Prediction of Efficacy

Hall, Scott; Puech, Alain J.; Schaffler, K.; Wesnes, K. A.; Gamzu, Elkan

doi:10.1055/s-2007-1014534

Cited by 12 publications

(6 citation statements)

References 4 publications

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“…Several human models have been the subject of debate, particularly the scopolamine (hyoscine), benzodiazepine and hypoxia models of cognitive dysfunction. [37][38][39] The major problem in predicting clinical efficacy from human experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds.…”

Section: Experimental Modelsmentioning

confidence: 99%

Cognition Enhancers in Age-Related Cognitive Decline

Riedel

Jolles

1996

Drugs & Aging

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A review of recently published studies on the effect of cognition enhancers in non-demented human study participants is presented. The heterogeneity of the therapeutic target, age-associated cognitive decline, can be improved by separately treating groups in whom age-extrinsic factors may underlie cognitive pathology. Standardisation of cognitive assessments is necessary, since many different tests are applied to answer the same question. Modelling cognitive dysfunction, either by pharmacological or nonpharmacological means, in humans is highly recommended since it allows hypotheses to be tested in a clearly operationalised way. Predictive validity of the currently applied models for the clinical situation remains a problem, however. The scopolamine (hyoscine) model has, to a reasonable extent, predictive validity for the cholinergic agents. The results of 67 single-dose studies and 30 multiple-dose studies are summarised. All single-dose studies and 14 multiple-dose studies were carried out in young or elderly human volunteers. In 45 of 81 volunteer studies, models of cognitive dysfunction were employed. The scopolamine model was the most used (n = 21); the other studies induced cognitive dysfunction by means of benzodiazepines (8), hypoxia (7), alcohol (5) and sleep-deprivation (4). The remaining 16 multiple-dose studies were clinical trials of a duration varying between 2 weeks and 1 year (average duration was 14 weeks). In these trials, the effects of cognition enhancers were assessed in elderly people in whom impairment of memory, psychomotor performance or cognitive function was determined. These included age-associated memory impairment (AAMI) and age-associated cognitive decline (AACD). There were many studies in which the cognition enhancing properties of substances in humans were reliably demonstrated. The cognition enhancing properties of substances that are widely used, such as caffeine, nicotine and vitamins, may already be active against AACD. New developments such as serotonin (5-hydroxytryptamine3; 5-HT3) antagonists and N-methyl-D-aspartate (NMDA) antagonists have provided marginal and disappointing results in AAMI. There is no cognition enhancer that has reliably and repeatedly been demonstrated to be efficacious for the treatment of AACD. However, this situation may change as the selectivity, specificity and adverse effect profiles of substances that are being developed for the treatment of AD may be expected to be improved in the future.

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Section: Experimental Modelsmentioning

confidence: 99%

Cognition Enhancers in Age-Related Cognitive Decline

Riedel

Jolles

1996

Drugs & Aging

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“…The central nervous system (CNS) effects consist of drowsiness, reduced attention and memory impairment, and a range of other CNS effects including changes in several EEG frequency bands [4][5][6]. At present, scopolamine is the most extensively studied and documented model for cognitive deficits [7][8][9][10]. The scopolamine model is frequently used in preclinical studies of cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

Liem-Moolenaar

Boer²,

Timmers³

et al. 2011

Brit J Clinical Pharma

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Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK-PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems.

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“…[ 39 ] The scopolamine-induced memory deficit model has been widely used for identifying the potential of drug candidates to reverse the effects of cholinergic blockade. [ 40 ] Scopolamine causes memory impairment through inhibition of cholinergic system. [ 41 ] It was shown that muscarinic acetylcholine receptors, causing the consolidation of spatial memory.…”

Section: Discussionmentioning

confidence: 99%