Cognition enhancers impairment

To reveal the cognition-enhancing potential of the S-HTj antagonists, studies in age-related memory impairment have been carried out with psy-chiatrically healthy subjects impaired with scopolamine and patients with dementia. In a randomized double-blind, double-dummy, four-way crossover study in a small number of subjects, each psychiatrically healthy male subject received placebo, scopolamine [0.4 mg im], scopolamine plus alosetron [10 J,g iv], or alosetron [250 Jg] [Preston 1994 Preston et al. 1991). Assessments of verbal and spatial memory, sedation, and sustained attention were performed before and after treatment. The main results from the study were that scopolamine induced robust deficits on all primary variables measured, the reduction in verbal and spatial memories being attenuated by 10- Jg and 250- Jg doses of alosetron, respectively. No effects on the sedation or on changes in attention were noted. 

Passive avoidance procedures are essentially procedures for detecting impairing effects of test substances. It is more difficult to demonstrate cognition enhancement because of ceiling effects. In terms of safety pharmacology, this is not a major drawback as impairment represents the major cognitive risk. 

Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF. Mutation of the a -adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 2002 22 8771-8777. 

RJR-2403 has been described as equal to or better than nicotine as a cognitive enhancer in behavioral assays (274). This compound ameliorated scopolamine-induced impairments in passive avoidance as well as working and reference memory impairments in a radial arm maze task caused by NBM lesions in rats... 

Other Chemotypes. Several other 5-HT, antagonists have demonstrated cognition-enhancing effects in animal models. However, data from human studies have yet to be reported. (i2)-Zacopride (170 in Fig. 14.18 Synthelabo) is undergoing clinical development as a potential treatment for cancer chemotherapy-induced emesis. In atropine-treated rats, (jR)-zacopride significantly attenuated memory impairments in a spatial navi-... 

Confirmation that drug effects were mediated via CBi receptor activation was obtained through co-administration of the selective receptor antagonist rimonabant, which reversed deficits induced by A THC (Lichtman and Martin 1997 Mishima et al. 2001). Rimonabant alone had no effect when delays between entries 1-4 and 5-8 were short (Lichtman 2000 Lichtman and Martin 1997 Mishima et al. 2001), but there was a memory enhancement for delays of several hours (Lichtman 2000). This result suggests that blockade of CBi receptors may aid the development of short-term memory, and receptor antagonists may become important as cognitive enhancers not only for future animal research but also with respect to treatment of cognitive impairment in humans. 

No clear evidence from controlled human trials that Gingko biloba preparations have significant memory-enhancing or cognition-enhancing effect in non-impaired individuals. 

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

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